Modified oligonucleotides containing both A-form conformation geometry and B-from conformation geometry nucleotides are disclosed. The B-form geometry allows the oligonucleotide to serve as substrates for RNase H when bound to a target nucleic acid strand. The A-form geometry imparts properties to the oligonucleotide that modulate binding affinity and nuclease resistance. By utilizing C2xe2x80x2 endo sugars or O4xe2x80x2 endo sugars, the B-form characteristics are imparted to a portion of the oligonucleotide. The A-form characteristics are imparted via use of either 2xe2x80x2-O-modified nucleotides that have 3xe2x80x2 endo geometries or use of end caps having particular nuclease stability or by use of both of these in conjunction with each other.

The present invention relates to oligonucleotides that have both A-form and B-form conformational geometry and methods of using such oligonucleotides. The oligonucleotides of the invention are useful in therapeutic and investigative purposes. More specifically, the present invention is directed to oligonucleotides having particular modifications that will increase affinity and nuclease resistance while concurrently serving as substrates for RNase H when bound to a target RNA strand.
It is well known that most of the bodily states in mammals, including most disease states, are affected by proteins. Classical therapeutic modes have generally focused on interactions with such proteins in an effort to moderate their disease-causing or disease-potentiating functions. However, recently, attempts have been made to moderate the actual production of such proteins by interactions with molecules that direct their synthesis, such as intracellular RNA. By interfering with the production of proteins, maximum therapeutic effect and minimal side effects may be realized. It is the general object of such therapeutic approaches to interfere with or otherwise modulate gene expression leading to undesired protein formation.
One method for inhibiting specific gene expression is the use of oligonucleotides. Oligonucleotides are now accepted as therapeutic agents. A first such oligonucleotide has been approved for human therapeutic use by the FDA and is available in commercial marketplace.
Oligonucleotides are known to hybridize to single-stranded DNA or RNA molecules. Hybridization is the sequence-specific base pair hydrogen bonding of nucleobases of the oligonucleotide to the nucleobases of the target DNA or RNA molecule. Such nucleobase pairs are said to be complementary to one another. The concept of inhibiting gene expression through the use of sequence-specific binding of oligonucleotides to target RNA sequences, also known as antisense inhibition, has been demonstrated in a variety of systems, including living cells (for example see: Wagner et al., Science (1993) 260: 1510-1513; Milligan et al., J. Med. Chem., (1993) 36:1923-37; Uhlmann et al., Chem. Reviews, (1990) 90:543-584; Stein et al., Cancer Res., (1988) 48:2659-2668).
The events that provide the disruption of the nucleic acid function by antisense oligonucleotides (Cohen in Oligonucleotides: Antisense Inhibitors of Gene Expression, (1989) CRC Press, Inc., Boca Raton, Fla.) are thought to be of two types. The first, hybridization arrest, denotes the terminating event in which the oligonucleotide inhibitor binds to the target nucleic acid and thus prevents, by simple steric hindrance, the binding of essential proteins, most often ribosomes, to the nucleic acid. Methyl phosphonate oligonucleotides: Miller, P. S. and Ts""O, P. O. P. (1987) Anti-Cancer Drug Design, 2:117-128, and xcex1-anomer oligonucleotides are the two most extensively studied antisense agents which are thought to disrupt nucleic acid function by hybridization arrest.
The second type of terminating event for antisense oligonucleotides involves the enzymatic cleavage of the targeted RNA by intracellular RNase H. A 2xe2x80x2-deoxyribofuranosyl oligonucleotide or oligonucleotide analog hybridizes with the targeted RNA and this duplex activates the RNase H enzyme to cleave the RNA strand, thus destroying the normal function of the RNA. Phosphorothioate oligonucleotides are probably the most prominent example of an antisense agent that operates by this type of antisense terminating event.
Oligonucleotides may also bind to duplex nucleic acids to form triplex complexes in a sequence specific manner via Hoogsteen base pairing (Beal et al., Science, (1991) 251:1360-1363; Young et al., Proc. Natl. Acad. Sci. (1991) 88:10023-10026). Both antisense and triple helix therapeutic strategies are directed towards nucleic acid sequences that are involved in or responsible for establishing or maintaining disease conditions. Such target nucleic acid sequences may be found in the genomes of pathogenic organisms including bacteria, yeasts, fungi, protozoa, parasites, viruses, or may be endogenous in nature. By hybridizing to and modifying the expression of a gene important for the establishment, maintenance or elimination of a disease condition, the corresponding condition may be cured, prevented or ameliorated.
In determining the extent of hybridization of an oligonucleotide to a complementary nucleic acid, the relative ability of an oligonucleotide to bind to the complementary nucleic acid may be compared by determining the melting temperature of a particular hybridization complex. The melting temperature (Tm), a characteristic physical property of double helices, denotes the temperature (in degrees centigrade) at which 50% helical (hybridized) versus coil (unhybridized) forms are present. Tm is measured by using the UV spectrum to determine the formation and breakdown (melting) of the hybridization complex. Base stacking, which occurs during hybridization, is accompanied by a reduction in UV absorption (hypochromicity). Consequently, a reduction in UV absorption indicates a higher Tm. The higher the Tm, the greater the strength of the bonds between the strands.
Oligonucleotides may also be of therapeutic value when they bind to non-nucleic acid biomolecules such as intracellular or extracellular polypeptides, proteins, or enzymes. Such oligonucleotides are often referred to as xe2x80x98aptamersxe2x80x99 and they typically bind to and interfere with the function of protein targets (Griffin, et al., Blood, (1993), 81:3271-3276; Bock, et al., Nature, (1992) 355: 564-566).
Oligonucleotides and their analogs have been developed and used for diagnostic purposes, therapeutic applications and as research reagents. For use as therapeutics, oligonucleotides must be transported across cell membranes or be taken up by cells, and appropriately hybridize to target DNA or RNA. These critical functions depend on the initial stability of the oligonucleotides toward nuclease degradation. A serious deficiency of unmodified oligonucleotides which affects their hybridization potential with target DNA or RNA for therapeutic purposes is the enzymatic degradation of administered oligonucleotides by a variety of intracellular and extracellular ubiquitous nucleolytic enzymes referred to as nucleases. For oligonucleotides to be useful as therapeutics or diagnostics, the oligonucleotides should demonstrate enhanced binding affinity to complementary target nucleic acids, and preferably be reasonably stable to nucleases and resist degradation. For a non-cellular use such as a research reagent, oligonucleotides need not necessarily possess nuclease stability.
A number of chemical modifications have been introduced into oligonucleotides to increase their binding affinity to target DNA or RNA and resist nuclease degradation.
Modifications have been made to the ribose phosphate backbone to increase the resistance to nucleases. These modifications include use of linkages such as methyl phosphonates, phosphorothioates and phosphorodithioates, and the use of modified sugar moieties such as 2xe2x80x2-O-alkyl ribose. Other oligonucleotide modifications include those made to modulate uptake and cellular distribution. A number of modifications that dramatically alter the nature of the internucleotide linkage have also been reported in the literature. These include non-phosphorus linkages, peptide nucleic acids (PNA""s) and 2xe2x80x2-5xe2x80x2 linkages. Another modification to oligonucleotides, usually for diagnostic and research applications, is labeling with non-isotopic labels, e.g., fluorescein, biotin, digoxigenin, alkaline phosphatase, or other reporter molecules.
A variety of modified phosphorus-containing linkages have been studied as replacements for the natural, readily cleaved phosphodiester linkage in oligonucleotides. In general, most of them (such as the phosphorothioate, phosphoramidates, phosphonates and phosphorodithioates) result in oligonucleotides with reduced binding to complementary targets and decreased hybrid stability. At least one dozen phosphorothioate oligonucleotides and derivatives are presently being used as antisense agents in human clinical trials for the treatment of various disease states. The antisense drug Vitravine(trademark), for use to treat cytomegalovirus (CMV) retinitis in humans, has been approved by regulatory agencies and is comedically marketed.
The structure and stability of chemically modified nucleic acids is of great importance to the design of antisense oligonucleotides. Over the last ten years, a variety of synthetic modifications have been proposed to increase nuclease resistance, or to enhance the affinity of the antisense strand for its target mRNA (Crooke et al., Med. Res. Rev., 1996, 16,319-344; De Mesmaeker et al., Acc. Chem. Res., 1995, 28, 366-374).
RNA exists in what has been termed xe2x80x9cA Formxe2x80x9d geometry, while DNA exists in xe2x80x9cB Formxe2x80x9d geometry. In general, RNA:RNA duplexes are more stable, or have higher melting temperatures (Tm) than DNA:DNA duplexes (Sanger et al., Principles of Nucleic Acid Structure, 1984, Springer-Verlag; New York, N.Y.; Lesnik et al., Biochemistry, 1995, 34, 10807-10815; Conte et al., Nucleic Acids Res., 1997,25,2627-2634). The increased stability of RNA has been attributed to several structural features, most notably the improved base stacking interactions that result from an A-form geometry (Searle et al., Nucleic Acids Res., 1993, 21, 2051-2056). The presence of a hydroxyl group in the 2xe2x80x2-pentofuranosyl (i.e., 2xe2x80x2-sugar) position in RNA is believed to bias the sugar toward a C3xe2x80x2 endo pucker (also known as a Northern pucker), which causes the duplex to favor the A-form geometry. On the other hand, 2xe2x80x2-deoxy nucleic acids (those having 2xe2x80x2-deoxy-erythro-pentofuranosyl nucleotides) prefer a C2xe2x80x2 endo sugar pucker (also known as Southern pucker), which is thought to impart a less stable B-form geometry (Sanger, W. (1984) Principles of Nucleic Acid Structure, Springer-Verlag, New York, N.Y.). In addition, the 2xe2x80x2 hydroxyl groups of RNA can form a network of water mediated hydrogen bonds that help stabilize the RNA duplex (Egli et al., Biochemistry, 1996, 35, 8489-8494).
DNA:RNA hybrid duplexes are usually less stable than pure RNA:RNA duplexes, and depending on their sequence may be either more or less stable than DNA:DNA duplexes (Searle et al., Nucleic Acids Res., 1993, 21, 2051-2056). The structure of a hybrid duplex is intermediate between A- and B-form geometries, which may result in poor stacking interactions (Lane et al., Eur. J. Biochem., 1993, 215, 297-306; Fedoroff et al., J. Mol. Biol., 1993, 233, 509-523; Gonzalez et al., Biochemistry, 1995, 34, 4969-4982; Horton et al., J. Mol. Biol., 1996, 264, 521-533). The stability of a DNA:RNA hybrid is central to antisense therapies as the mechanism requires the binding of a modified DNA strand to a mRNA strand. To effectively inhibit the mRNA, the antisense DNA should have a very high binding affinity with the mRNA. Otherwise the desired interaction between the DNA and target mRNA strand will occur infrequently, thereby decreasing the efficacy of the antisense oligonucleotide.
One synthetic 2xe2x80x2-modification that imparts increased nuclease resistance and a very high binding affinity to nucleotides is the 2xe2x80x2-methoxyethoxy (MOE, 2xe2x80x2-OCH2CH2OCH3) side chain (Baker et al., J. Biol. Chem., 1997, 272, 11944-12000; Freier et al., Nucleic Acids Res., 1997, 25, 4429-4443). One of the immediate advantages of the MOE substitution is the improvement in binding affinity, which is greater than many similar 2xe2x80x2 modifications such as O-methyl, O-propyl, and O-aminopropyl (Freier and Altmann, Nucleic Acids Research, (1997) 25:4429-4443). 2xe2x80x2-O-Methoxyethyl-substituted compounds also have been shown to be antisense inhibitors of gene expression with promising features for in vivo use (Martin, P., Helv. Chim. Acta, 1995, 78, 486-504; Altmann et al., Chimia, 1996, 50, 168-176; Altmann et al., Biochem. Soc. Trans., 1996, 24, 630-637; and Altmann et al., Nucleosides Nucleotides, 1997, 16, 917-926). Such compounds typically display improved RNA affinity and higher nuclease resistance relative to DNA. Chimeric oligonucleotides with 2xe2x80x2-O-methoxyethyl-ribonucleoside wings and a central DNA-phosphorothioate window also have been shown to effectively reduce the growth of tumors in animal models at low doses. MOE substituted oligonucleotides have shown outstanding promise as antisense agents in several disease states. One such MOE substituted oligonucleotide is presently being investigated in clinical trials for the treatment of CMV retinitis.
Recently Damha et. al., published two paper describing certain oligonucleotides that utilized arabino-pentofuranosyl nucleotides as building blocks (Damha et. al., J.A.C.S., 1998, 120, 12976-12977 and Damha et. al., Bioconjugate Chem., 1999, 10, 299-305). The arabino-pentofuranosyl oligonucleotides, i.e., arabinonucleic acids, described by Damha et. al., utilized either arabinose or 2xe2x80x2-deoxy-2xe2x80x2-fluoro arabinose as the sugar unit of their respective nucleotides. In one of the two arabinonucleic acids described, all of the nucleotides of the nucleic acid were arabinose and in the other, all of the nucleotides were 2xe2x80x2-deoxy-2xe2x80x2-fluoro arabinose. In both of these nucleic acids, the nucleotides were joined via phosphodiester linkages. These authors were able to show that the 2xe2x80x2-fluoro arabino-containing oligonucleotides when bound to RNA activated cleavage of the RNA by E. coli and HIV-RT RNase H. The authors further noted that while the two arabinonucleic acids they described were more stable to serum and cellular nucleases than DNA they were less stable than normal phosphorothioate deoxyoligonucleotides.
Although the known modifications to oligonucleotides have contributed to the development of oligonuclotides for various uses, including use in diagnostics, therapeutics and as research reagents, there still exists a need in the art for further oligonucleotides having enhanced hybrid binding affinity and/or increased nuclease resistance and that can take advantage of the RNase H termination mechanism.
In one aspect, the present invention is directed to oligonucleotides having multiple properties. One of these properties is the ability to form a double stranded structure with an RNA and elicit RNase H cleavage of the RNA. Further properties of the oligonucleotides include having improved binding affinity and nuclease resistance. The oligonucleotides of the invention comprise oligonucleotide formed from a plurality of nucleotides. A first portion of the nucleotides are joined together in a contiguous sequence with each nucleotide of this portion selected as a nucleotide that has B-form conformational geometry when joined in a contiguous sequence with other nucleotides. Included in this first portion of nucleotides are ribonucleotides or arabino nucleotides. The oligonucleotides include a further portion of nucleotides that are joined together in at least one contiguous sequence. Each of these further nucleotides are selected as ribonucleotides that have A-form conformational geometry when joined in a contiguous sequence.
In preferred embodiments of the invention, each of the nucleotides of the first portion of nucleotides, independently, are selected to be 2xe2x80x2-SCH3 ribonucleotides, 2xe2x80x2-NH2 ribonucleotides, 2xe2x80x2-NH(C1-C2 alkyl) ribonucleotides, 2xe2x80x2-N(C1-C2 alkyl)2 ribonucleotides, 2xe2x80x2-CF3 ribonucleotides, 2xe2x80x2=CH2 ribonucleotides, 2xe2x80x2=CHF ribonucleotides, 2xe2x80x2=CF2 ribonucleotides, 2xe2x80x2-CH3 ribonucleotides, 2xe2x80x2-C2H5 ribonucleotides, 2xe2x80x2-CHxe2x95x90CH2 ribonucleotides or 2xe2x80x2-Cxe2x89xa1CH ribonucleotides. These are joined together in a contiguous sequence by phosphate, phosphorothioate, phosphorodithioate or boranophosphate linkages.
In a further preferred embodiment of the invention, each of the nucleotides of said further portion of nucleotides, independently, are selected to be 2xe2x80x2-fluoro nucleotides or nucleotides having a 2xe2x80x2-substituent having the formula I or II:
wherein
E is C1-C10 alkyl, N(Q1)(Q2) or Nxe2x95x90C(Q1)(Q2);
each Q1 and Q2 is, independently, H, C1-C10 alkyl, dialkylaminoalkyl, a nitrogen protecting group, a tethered or untethered conjugate group, a linker to a solid support, or Q1 and Q2, together, are joined in a nitrogen protecting group or a ring structure that can include at least one additional heteroatom selected from N and O;
R3 is OX, SX, or N(X)2;
each X is, independently, H, C1-C8 alkyl, C1-C8 haloalkyl, C(xe2x95x90NH)N(H)Z, C(xe2x95x90O)N(H)Z or OC(xe2x95x90O)N(H)Z;
Z is H or C1-C8 alkyl;
L1, L2 and L3 comprise a ring system having from about 4 to about 7 carbon atoms or having from about 3 to about 6 carbon atoms and 1 or 2 hetero atoms wherein said hetero atoms are selected from oxygen, nitrogen and sulfur and wherein said ring system is aliphatic, unsaturated aliphatic, aromatic, or saturated or unsaturated heterocyclic;
Y is alkyl or haloalkyl having 1 to about 10 carbon atoms, alkenyl having 2 to about 10 carbon atoms, alkynyl having 2 to about 10 carbon atoms, aryl having 6 to about 14 carbon atoms, N(Q1)(Q2), O(Q1), halo, S(Q1), or CN;
each q1 is, independently, from 2 to 10;
each q2 is, independently, 0 or 1;
m is 0, 1 or 2;
p is from 1 to 10; and
q3 is from 1 to 10 with the proviso that when p is 0, q3 is greater than 1.
A more preferred group for use as the further portion of nucleotides are 2xe2x80x2-F ribonucleotides, 2xe2x80x2-Oxe2x80x94(C1-C6 alkyl) ribonucleotides, or 2xe2x80x2-Oxe2x80x94(C1-C6 substituted alkyl) ribonucleotides wherein the substitution is C1-C6 ether, C1-C6 thioether, amino, amino(C1-C6 alkyl) or amino(C1-C6 alkyl)2. These nucleotides are joined together in sequence by 3xe2x80x2-5xe2x80x2 phosphodiester, 2xe2x80x2-5xe2x80x2 phosphodiester, phosphorothioate, Sp phosphorothioate, Rp phosphorothioate, phosphorodithioate, 3xe2x80x2-deoxy-3xe2x80x2-amino phosphoroamidate, 3xe2x80x2-methylenephosphonate, methylene(methylimino), dimethylhydazino, amide 3 (i.e., (3xe2x80x2)xe2x80x94CH2xe2x80x94NHxe2x80x94C(O)xe2x80x94(5xe2x80x2)), amide 4 (i.e., (3xe2x80x2)xe2x80x94CH2xe2x80x94C(O)xe2x80x94NHxe2x80x94(5xe2x80x2)) or boranophosphate linkages.
In one preferred embodiment of the invention, at least two of the nucleotides of the further portion of nucleotides are joined together in a contiguous sequence that is position 3xe2x80x2 to the contiguous sequence of the first portion of nucleotides. In an additional preferred embodiment of the invention, at least two of the further portion of nucleotides are joined together in a continuous sequence that is position 5xe2x80x2 to the continuous sequence of the first portion of nucleotides.
In a further preferred embodiment of the invention, at least two of the nucleotides of the further portion of nucleotides are joined together in a continuous sequence that is position 3xe2x80x2 to the continuous sequence of the first portion of nucleotides and at least two of the further portion of nucleotides are joined together in a continuous sequence that is position 5xe2x80x2 to the continuous sequence of the first portion of nucleotides.
A first preferred group of nucleotides for use as the first portion of nucleotides include 2xe2x80x2-SCH3 ribonucleotides, 2xe2x80x2-NH2 ribonucleotides, 2xe2x80x2-NH(C C2 alkyl) ribonucleotides, 2xe2x80x2-N(C1-C2 alkyl)2 ribonucleotides, 2xe2x80x2=CH2 ribonucleotides, 2xe2x80x2-CH3 ribonucleotides, 2xe2x80x2-C2H5 ribonucleotides, 2xe2x80x2-CHxe2x95x90CH2 ribonucleotides and 2xe2x80x2-Cxe2x89xa1CH ribonucleotides. A more preferred group include 2xe2x80x2-SCH3 ribonucleotides, 2xe2x80x2-NH2 ribonucleotides, 2xe2x80x2-NH(C1-C2 alkyl) ribonucleotides, 2xe2x80x2-N(C1-C2 alkyl)2 ribonucleotides and 2xe2x80x2-CH3 ribonucleotides. A further preferred group include 2xe2x80x2-SCH3 ribonucleotides, 2xe2x80x2-NH2 ribonucleotides and 2xe2x80x2-CH3 ribonucleotides. Particularly preferred are is 2xe2x80x2-SCH3 ribonucleotides.
A further group of nucleotides that are preferred of use as the nucleotides of the first portion of the oligonucleotides of the inventions are 2xe2x80x2-CN arabino nucleotides, 2xe2x80x2-F arabino nucleotides, 2xe2x80x2-Cl arabino nucleotides, 2xe2x80x2-Br arabino nucleotides, 2xe2x80x2-N3 arabino nucleotides, 2xe2x80x2-OH arabino nucleotides, 2xe2x80x2-Oxe2x80x94CH3 arabino nucleotides and 2xe2x80x2-dehydro-2xe2x80x2-CH3 arabino nucleotides. A more preferred group include 2xe2x80x2-F arabino nucleotides, 2xe2x80x2-OH arabino nucleotides and 2xe2x80x2-Oxe2x80x94CH3 arabino nucleotides. A further preferred group include 2xe2x80x2-F arabino nucleotides and 2xe2x80x2-OH arabino nucleotides. Particularly preferred are 2xe2x80x2-F arabino nucleotides.
Particularly preferred oligonucleotides of the invention include selecting the nucleotides of the first portion of nucleotides to be 2xe2x80x2-SCH3 ribonucleotides, 2xe2x80x2-NH2 ribonucleotides, 2xe2x80x2-NH(C1-C2 alkyl) ribonucleotides, 2xe2x80x2-N(C1-C2 alkyl)2 ribonucleotides, 2xe2x80x2-CH3 ribonucleotides, 2xe2x80x2-CHxe2x95x90CH2 ribonucleotides or 2xe2x80x2-Cxe2x89xa1CH ribonucleotides and selecting the nucleotides of the further portion of nucleotides to be 2xe2x80x2-F ribonucleotides, 2xe2x80x2-Oxe2x80x94(C1-C6 alkyl) ribonucleotides or 2xe2x80x2-Oxe2x80x94(C1-C6 substituted alkyl) ribonucleotides wherein the substitution is C1-C6 ether, C1-C6 thioether, amino, amino(C1-C6 alkyl) or amino(C1-C6 alkyl)2.
Further preferred oligonucleotides of the invention include selecting the nucleotides of said first portion of nucleotides to be 2xe2x80x2-CN arabino nucleotides, 2xe2x80x2-F arabino nucleotides, 2xe2x80x2-Cl arabino nucleotides, 2xe2x80x2-Br arabino nucleotides, 2xe2x80x2-N3 arabino nucleotides, 2xe2x80x2-OH arabino nucleotides, 2xe2x80x2-Oxe2x80x94CH3 arabino nucleotides or 2xe2x80x2-dehydro-2xe2x80x2-CH3 arabino nucleotides and selecting the nucleotides of the further portion of nucleotides to be 2xe2x80x2-F ribonucleotides, 2xe2x80x2-Oxe2x80x94(C1-C6 alkyl) ribonucleotides or 2xe2x80x2-Oxe2x80x94(C1-C6 substituted alkyl) ribonucleotides wherein the substitution is C1-C6 ether, C1-C6 thioether, amino, amino(C1-C6 alkyl) or amino(C1-C6 alkyl)2.
Particularly preferred are oligonucleotide of the invention where each nucleotide of the first portion of nucleotides is a 2xe2x80x2-F arabino nucleotides or a 2xe2x80x2-OH arabino nucleotides and each nucleotide of the further portion of nucleotides is a 2xe2x80x2-Oxe2x80x94(C1-C6 substituted alkyl) ribonucleotide wherein the substitution is C1-C6 ether, C1-C6 thioether, amino, amino(C1-C6 alkyl) or amino(C1-C6 alkyl)2.
In further preferred oligonucleotides of the invention the further portion of the plurality of nucleotides comprise at least two nucleotides joined together in a contiguous sequence that is position at the 3xe2x80x2 terminus end of the oligonucleotide. In an additional preferred oligonucleotide of the invention the further portion of said plurality of nucleotides comprise at least two nucleotides joined together in a contiguous sequence that is position at the 5xe2x80x2 terminus end of the oligonucleotide. In even further preferred oligonucleotides of the invention the further portion of the plurality of nucleotides comprise at least two nucleotides joined together in a contiguous sequence that is position at the 3xe2x80x2 terminus end of the oligonucleotide and at least two nucleotides joined together in a contiguous sequence that is position at the 5xe2x80x2 terminus end of the oligonucleotide. Preferred linkages for joining these nucleotides together in an oligonucleotide of the invention include 2xe2x80x2-5xe2x80x2 phosphodiester linkages, 3xe2x80x2-methylenephosphonate linkages, Sp phosphorothioate linkages, methylene(methylimino)linkages, dimethyhydrazino linkages, 3xe2x80x2-deoxy-3xe2x80x2-amino phosphoroamidate linkages, amide 3 linkages or amide 4 linkages. Particularly preferred joining linkages are 2xe2x80x2-5xe2x80x2 phosphodiester linkages, 3xe2x80x2-methylenephosphonate linkages, Sp phosphorothioate linkages or methylene(methylimino) linkages.
In further preferred oligonucleotides of the invention, nucleotides for use in the further portion of nucleotides comprises 2xe2x80x2-alkylamino substituted nucleotides located at the 3xe2x80x2 terminus, the 5xe2x80x2 terminus or both the 3xe2x80x2 and 5xe2x80x2 terminus of the oligonucleotide. Particularly preferred are 2xe2x80x2-O-alkylamines such as 2xe2x80x2-O-ethylamine and 2xe2x80x2-O-propylamine.
Further oligonucleotides of the invention comprise oligonucleotides made up of a plurality of linked nucleotides at least two of which comprise nucleotides that are not 2xe2x80x2-deoxy-erythro-pentofuranosyl nucleotides and that have a C2xe2x80x2 endo type pucker or an O4xe2x80x2 endo type pucker and that are joined together in a contiguous sequence and other nucleotides comprising nucleotides that have a C3xe2x80x2 endo type pucker. Preferred are oligonucleotides having the C3xe2x80x2 endo type pucker nucleotides joined together in a contiguous sequence that is positioned 3xe2x80x2 to the contiguous sequence of the nucleotides having the C2xe2x80x2 endo type pucker or O4xe2x80x2 endo type pucker. Further preferred oligonucleotides are oligonucleotides wherein the nucleotides having the C3xe2x80x2 endo type pucker are joined together in a contiguous sequence that is positioned 5xe2x80x2 to the contiguous sequence of having the C2xe2x80x2 endo type pucker or O4xe2x80x2 endo type pucker. Additional preferred oligonucleotide are oligonucleotides where a portion of the nucleotides having the C3xe2x80x2 endo type pucker are joined together in a contiguous sequence that is positioned 3xe2x80x2 to the contiguous sequence of nucleotides having the C2xe2x80x2 endo type pucker or O4xe2x80x2 endo type pucker and a further portion of nucleotides having the C3xe2x80x2 endo type pucker are joined together in a contiguous sequence that is positioned 5xe2x80x2 to the contiguous sequence of nucleotides having the C2xe2x80x2 endo type pucker or O4xe2x80x2 endo type pucker.

Oligonucleotides having A-DNA form and B-DNA form conformational geometry


A crude helium product is produced from a natural gas stream containing helium by rectification of the feed gas in a dephlegmator heat exchanger. The process is fully auto-refrigerated, and is capable of achieving a helium recovery of 99% without the use of a recycle compressor or a heat pump compressor. A nitrogen product stream can be produced by addition of a second rectification circuit in the dephlegmator heat exchanger.

Helium occurs in very low concentrations in certain natural gas fields. Natural gas streams from which helium can be economically recovered typically contain approximately 0.1% to 0.5% helium. This helium must be upgraded to produce a crude helium stream containing typically at least 30% helium.
Producing a crude helium product stream is usually done in two or more successive upgrading steps. The first upgrading step generally produces a crude helium stream containing about 1 to 10% helium, and successive upgrading steps are required to boost the helium content of this stream to 30% or greater.
Due to the high value of the helium, high recovery is usually required. Achieving the high recovery as the helium content is increased from 1 to 10% up to 30% or greater has in the past required the addition of compression machinery. A process which could achieve high helium recovery without the need for additional compression machinery would therefore represent an improvement over the current practice.
In addition to producing crude helium, a helium upgrading process is typically required to also produce a high purity nitrogen stream to be used for cold box purge. The ability of the process to produce this additional product stream with a minimum of added equipment would be a further advantage.
The current practice for producing a crude helium product stream (i.e; >30% helium) includes the multi-stage flash process and the distillation process. Each of these processes requires additional compression to achieve high helium recovery.
In the flash cycle, which is disclosed in U.S. Pat. No. 3,260,058, feed gas is partially liquefied and phase separated. The vapor thus produced contains about 90% or more of the helium contained in the feed stream. Helium which remains dissolved in the liquid is recovered by subsequent flash steps in which helium-rich vapors are flashed off. These vapors are combined, rewarmed, compressed back to feed pressure and mixed with the feed gas so the helium can be recovered.
In the distillation process, which is disclosed in "A New Approach to Helium Recovery", Kellogram Issue No. 3, M. H. Kellogg Co., 1963, feed gas is partially condensed and fed to a distillation column which produces a helium-rich vapor product stream containing at least 99% of the helium in the feed gas. A heat pump compressor is used to supply reboil to the bottom of the column by condensing high pressure heat pump fluid and reflux to the top of the column by boiling low pressure heat pump fluid.
In each of these cases, additional compression is required to achieve high helium recovery.

Dephlegmator process for the recovery of helium


A method is provided for preserving changes to a configuration of a running virtual machine. The method includes reading an initial configuration, starting the virtual machine under application of the initial configuration, modifying the configuration of the virtual machine during runtime, storing the modified configuration of the virtual machine during shutdown, and reading the modified configuration at re-start of the virtual machine and re-starting the virtual machine under application of the modified configuration.

The present invention relates to a method for preserving changes to a configuration of a running virtual machine. The present invention further relates to a computer-readable medium such as a storage device, a floppy disk, CD, DVD, Blu-Ray disk, or a random access memory (RAM), containing a set of instruction that causes a computer to perform the above method. The present invention further relates to a computer program product comprising a computer usable medium including computer usable program code, wherein the computer usable program code is adopted to execute the above method.
Virtualization is becoming more and more important in IT systems, as it allows the use of central servers for performing different tasks as required by a user. This includes, that different operating systems can run on a single hardware environment, which offers high flexibility for the user. A virtual machine manager, also called hypervisor, is running on the hardware environment and provides an environment for execution of virtual machines, which are also called guests, for executing the each one operating system. The guests are virtual instances of operating systems, which are encapsulated inside the virtual machine manager and can be executed like running directly on the hardware environment. The hypervisor itself can be running directly on a hardware of a computer, which means without an underlying operating system, or as an application within a standard operating system like a Linux, Windows or others. Also virtual machine managers running on an intermediate instruction layer are known in the art.
Running a virtual machine on a hypervisor comprises the hypervisor providing a virtual environment comprising virtualized and virtual devices, as usually available as real hardware devices in the hardware environment. Accordingly, real hardware devices of the hardware environment have to be mapped to virtualized devices, so that they can be used by the virtual machine. In contrast, the pure virtual devices are not linked to any real hardware device. Depending on the requirements of a virtual machine or available resources, different configurations comprising virtual and virtualized devices can be provided for running a virtual machine. Also modifications on the hardware environment, e.g. by adding or removing devices, have to be adapted for the virtual environment. Furthermore, availability of virtual devices can be limited for performance reasons.
Accordingly, configuration of a virtual environment for a virtual machine is an important task for efficiently running the virtual machine and efficiently using the resources of the hypervisor. It is known in the art to provide and change a configuration of a virtual machine persistently only when the virtual machine is not running. This makes configuration changes very time-consuming because the configuration can only be tested after starting the virtual machine. It is further known, e.g. from the U.S. Publication No. 2010/0138829A1 entitled "Systems and Methods for Optimizing Configuration of a Virtual Machine Running at Least One Process," Hanquez et al., published Jun. 3, 2010, which is hereby incorporated by reference herein in its entirety, to change a configuration of a virtual machine at runtime. Nevertheless, these changes are lost when the virtual machine is stopped. When restarting the virtual machine, the configuration changes have to be applied again, so that time is lost.

This patent is subject to a terminal disclaimer.

Preserving changes to a configuration of a running virtual machine

INTERNATIONAL BUSINESS MACHINES CORPORATION


Provided are a compact and low-cost motor driver circuit capable of achieving an appropriate brake time and restraining heat generated by a regenerative resistance within a specific temperature range without employing a regenerative resistance having a greater capacity, a heat sink, or a FAN generating a larger volume of air, and a vacuum pump having the motor driver circuit. Regenerative current is controlled so that a speed characteristic gradually approaches inclination “a” from inclination “b” depending on the motor speed in the initial stage of regeneration. In addition, a limit is set not to pass further current when the regenerative current reaches a maximum brake current value Iset—brake—max. As stated above, when the motor is braked, control is performed so that the initial brake current value at the maximum rated speed is set low and the brake current is increased as the rotational speed decelerates.

With the recent years' development of electronics, there is a rapidly increasing demand for semiconductors for forming memories, integrated circuits, etc.
Such semiconductors are manufactured, for example, by doping a semiconductor substrate of a very high purity with impurities to impart electrical properties thereto, or by stacking together semiconductor substrates with minute circuit patterns formed thereon.
The operation of manufacturing such semiconductors must be conducted in a high vacuum chamber in order to avoid the influences of dust, etc. in the air. This chamber is generally evacuated by a vacuum pump. In particular, a turbo-molecular pump, which is a kind of vacuum pump, is widely used since it entails little residual gas and is easy of maintenance.
A semiconductor manufacturing process includes a number of steps in which various process gases are caused to act on a semiconductor substrate, and the turbo-molecular pump is used not only to evacuate the chamber but also to discharge these process gases from the chamber.
Further, in an apparatus like an electron microscope, a turbo-molecular pump is used to create a high vacuum state in the chamber of the apparatus in order to prevent refraction, etc. of an electron beam due to the presence of dust or the like.
Such a turbo-molecular pump is composed of a turbo-molecular pump main body for sucking and discharging gas from the chamber of a semiconductor manufacturing apparatus, an electron microscope, or the like, and a control device for controlling the turbo-molecular pump main body.
FIG. 8 is a longitudinal sectional view of a turbo-molecular pump main body.
In FIG. 8, a turbo-molecular pump main body 100 includes an outer cylinder 127, on top of which there is formed an intake hole 101. Provided inside the outer cylinder 127 is a rotor 103 having in its periphery a plurality of rotary blades 102a, 102b, 102c, . . . serving as turbine blades for sucking and discharging gas and formed radially in a number of stages.
At the center of the rotor 103, there is mounted a rotor shaft 113, which is supported in a levitating state and controlled in position, for example, by a so-called 5-axis control magnetic bearing.
Upper radial electromagnets 104 consist of four electromagnets arranged in pairs in X- and Y-axis directions, perpendicular to each other, and opposed to each other with the rotor shaft 113 therebetween. It is to be assumed that the X- and Y-axes are in a plane perpendicular to the axis of the rotor shaft 113 when the rotor shaft 113 is at a control target position of the magnetic bearing. Further, there is provided an upper radial sensor 107 consisting of four coils which are opposed to each other with the rotor 103 therebetween and arranged in close proximity to and in correspondence with the four upper radial electromagnets 104. The upper radial sensor 107 detects radial position of the rotor 103, transmitting a detection signal to a control device.
The rotor shaft 113 is formed of a high-magnetic-permeability material (e.g., iron) and is adapted to be attracted by the magnetic force of the upper radial electromagnets 104.
Further, lower radial electromagnets 105 and a lower radial sensor 108 are arranged in the same way as the upper radial electromagnets 104 and the upper radial sensor 107. The lower radial sensor 108 detects the radial position of the lower portion of the rotor shaft 113 and transmits a detection signal to the control device. The radial positions of the upper and lower portions of the rotor shaft 113 are adjusted by the magnetic bearing feedback control means in the control device.
Further, axial electromagnets 106A and 106B are arranged respectively on the upper and lower sides of a metal disc 111 provided in the lower portion of the rotor shaft 113. The metal disc 111 is formed of a high-magnetic-permeability material, such as iron. To detect axial position of the rotor 103, there is provided an axial sensor 109, which transmits an axial position signal to the control device.
The axial electromagnet 106A magnetically attracts the metal disc 111 upwardly, and the axial electromagnet 106B magnetically attracts the metal disc 111 downwardly.
In this way, in the control device, the magnetic force the axial electromagnets 106A and 106B exert on the metal disc 111 is appropriately controlled by the magnetic bearing feedback control means, magnetically levitating the rotor shaft 113 in the axial direction and retaining it in the space in a non-contact state.
A motor 121 is equipped with a plurality of magnetic poles consisting of permanent magnets arranged circumferentially on the rotor side so as to surround the rotor shaft 113. A torque for rotating the rotor shaft 113 is imparted to these permanent magnets from the electromagnets on the stator side of the motor 121, thereby rotating the rotor 103.
Further, an RPM sensor and a motor temperature sensor (not shown) are mounted to the motor 121, and the rotation of the rotor shaft 113 is controlled in the control device in response to detection signals from the RPM sensor and the motor temperature sensor.
A plurality of stationary blades 123a, 123b, 123c, . . . are arranged so as to be spaced apart from the rotary blades 102a, 102b, 102c, . . . by small gaps. In order to downwardly transfer the molecules of exhaust gas through collision, the rotary blades 102a, 102b, 102c, . . . are inclined by a predetermined angle with respect to a plane perpendicular to the axis of the rotor shaft 113.
Similarly, the stationary blades 123 are also inclined by a predetermined angle with respect to a plane perpendicular to the axis of the rotor shaft 113, and extend toward the inner side of the outer cylinder 127 to be arranged alternately with the rotary blades 102.
The stationary blades 123 are supported at one end by being inserted into gaps between a plurality of stationary blade spacers 125a, 125b, 125c, . . . stacked together in stages.
The stationary blade spacers 125 are ring-shaped members, which are formed of a metal, such as aluminum, iron, stainless steel, or copper, or an alloy containing such metal as a component.
In the outer periphery of the stationary blade spacers 125, the outer cylinder 127 is secured in position with a small gap therebetween. At the bottom of the outer cylinder 127, there is arranged a base portion 129, and a threaded spacer 131 is arranged between the lowermost one of the stationary blade spacers 125 and the base portion 129.
In the portion of the base portion 129 below the threaded spacer 131, there is formed a discharge outlet 133. Connected to the discharge outlet 133 is a dry-sealed vacuum pump passage (not shown), and the discharge outlet 133 is connected to a dry-sealed vacuum pump (not shown) through this dry-sealed vacuum pump passage.
The threaded spacer 131 is a cylindrical member formed of a metal, such as aluminum, copper, stainless steel, or iron, or an alloy containing such metal as a component, and has a plurality of spiral thread grooves 131a in its inner peripheral surface.
The spiral direction of the thread grooves 131a is determined such that when the molecules of the exhaust gas move in the rotating direction of the rotor 103, these molecules are transferred toward the discharge outlet 133.
Connected to the lowermost one of the rotary blades 102a, 102b, 102c, . . . of the rotor 103 is a cylindrical portion 102d, which extends vertically downwards. The outer peripheral surface of this cylindrical portion 102d sticks out toward the inner peripheral surface of the threaded spacer 131, and is in close proximity to the inner peripheral surface of the threaded spacer 131 with a predetermined gap therebetween.
The base portion 129 is a disc-like member constituting the base of the turbo-molecular pump main body 100, and is generally formed of a metal, such as iron, aluminum, or stainless steel. The base portion 129 physically retains the turbo-molecular pump main body 100, and also functions as a heat conduction passage. Thus, the base portion 129 is preferably formed of a metal that is rigid and of, high heat conductivity, such as iron, aluminum, or copper.
Further, connected to the base portion 129 is a connector 160, to which a cable is connected to electrically connect the turbo-molecular pump main body 100 and the control device.
In the above-described construction, when the rotary blades 102 are driven and rotated by the motor 121 together with the rotor shaft 113, an exhaust gas from a chamber (not shown) is sucked in through the intake hole 101, due to the action of the rotary blades 102 and the stationary blades 123.
The exhaust gas sucked in through the intake hole 101 passes between the rotary blades 102 and the stationary blades 123, and is transferred to the base portion 129. The exhaust gas transferred to the base portion 129 is sent to the discharge outlet 133 while being guided by the thread grooves 131a of the threaded spacer 131.
FIG. 9 is a block diagram of a motor driver circuit for driving the motor 121. A motor driver circuit 200 includes a three-phase bridge circuit 210 formed of six FET elements V18, V19, V20, V21, V22, and V23 in order to pass three phase current through a U-phase winding, a V-phase winding, and a W-phase winding of the stator of the motor 121 in accordance with the flow chart of FIG. 10. For example, in section 1, V18 and V21 are turned ON to pass current in the direction from the U phase to the V phase. Further, in section 2, V18 and V23 are turned ON to pass current in the direction from the U phase to the W phase. Also in the sections following section 3, the FET elements are sequentially switched in accordance with the flow chart to generate a rotating magnetic field.
One end of the three-phase bridge circuit 210 is connected to one end of a capacitor 203 through a short-circuit protection element 201. The other end of the three-phase bridge circuit 210 is connected to the other end of the capacitor 203 through a motor current detecting circuit 205. One end of the capacitor 203 is further connected to one end of a regenerative resistance 207 and a positive pole 209 of a power source. The other end of the capacitor 203 is connected to the other end of the regenerative resistance 207 through a regeneration resistance drive FET 211 and is connected to a negative pole 213 of the power source. Both ends of the regenerative resistance 207 are connected to a diode 215 in parallel with this regenerative resistance 207.
When accelerating the pump, a driver control CPU (not shown) performs PWM control on each FET of the three-phase bridge circuit 210 so that the value of current which is detected by the motor current detecting circuit 205 and is supplied to the motor 121 becomes a predetermined constant current value, while letting the current reversely flow through each phase in accordance with the timing of FIG. 10 by using a rotational speed sensor (not shown) so that the motor rotates at a predetermined rotation number. Further, when the motor is braked, the driver control CPU performs PWM control on each FET of the three-phase bridge circuit 210 so that the current has a predetermined current value, and makes the regenerative resistance 207 consume electric power regenerated from the motor 121 as heat energy with the current flowing through each phase in the direction reverse to that when accelerating the motor, thereby the regeneration resistance drive FET 211 being turned ON/OFF.
In order to consume more energy, the regenerative resistance 207 is a high-capacity (large-scaled) type, or is cooled by an air-cooling FAN mounted on a heat sink.
In order to let the regenerative resistance consume energy within a safe range, in a disclosed conventional technique, regeneration energy is calculated and whether or not to perform regenerative braking can be automatically selected with respect to each of a plurality of motors to prevent the regeneration energy from exceeding a predetermined value (Patent document 1). [Patent Document 1] Japanese Patent Laid-Open. Pub. No. 2006-194094

Motor driver circuit and vacuum pump having the motor driver circuit


A conductive network, which can be flexible or rigid, can have self-aligning conductors which connect with corresponding conductors of other networks. The conductive network can be fabricated into densely packed contact clusters for use as electrical interconnectors or circuits. The contact clusters, which can be configured to substantially any shape, are the essential components of high density connector assemblies. The methods and apparatus for making the conductive network and cluster contacts are also described.

The growth which the computer and electronics industries have experienced in the last three decades has dramatically increased the demand for conductive networks (for example, printed circuit boards (PCB's)). Manufacturers have responded to this demand by increasing the reliability of their products and by packing more electronics into smaller packages. This requires the use of more densely packed electrical modules and circuits, each requiring multiple interconnections to one another. This requirement to increase printed circuit (PC) board density to accommodate yet another generation of new high power integrated circuit (IC) chips, combined with the requirement to incorporate surface mount technology, continues to drive PC board density to new levels of sophistication. However, there is a practical limit to the density that can be achieved using conventional circuit board connectors.
To perform their defined functions, PC boards must be interconnected electrically to other modules and PC boards within a product. This is often accomplished by means of a flexible printed circuit or jumper cable. These jumpers offer users a unique combination of features, namely, they are reliable, they have unique terminating capabilities, they accommodate surface mount requirements and they are extremely lightweight and flexible. Most importantly, such jumper circuits are capable of very high density. Because of these attributes, users have been willing to pay the relatively high cost of such jumper circuits (due to a high rejection rate) and to suffer the inconvenience and expense of hard soldering these jumpers to the PC boards and modules with which they interconnect.
There is a great need for high quality, low cost, densely packed interconnect cables and equally densely packed connector clusters for coupling the cables to the surface mounted terminals of PC boards and modules. In a typical present day application, a floppy disk drive may require a flexible connection to a recording head whose conductors are only on the order of 0.008 inches on center. This means that the jumper's conductors must have a similar spacing. Also, the new liquid crystal displays have conductors which are even more closely packed (for example, 0.004 inches on center) and which must be interconnected to other PC boards and modules. Still further, there is growing use of ceramic PC boards to accommodate multiple IC chip arrays which also require high density connectors and customer interconnect cables for purposes of terminating those components.
As a direct result of the growth in the circuit board industry, there has been a parallel increase in the volume of environmentally-hazardous chemicals generated by the conventional etching and deposition processes. For example, it is not uncommon for one circuit board fabrication facility to generate 1,000 gallons per day of photoresist stripper and 1,200 gallons per week of developer solution. These toxic wastes must be transported off-site for proper disposal at hazardous waste management sites. Thus, there is an urgent need for a non-chemical method for the manufacture of conductive networks.
It is an object of this invention to provide a relatively inexpensive, high-quality, densely packed, conductive network for use in fabricating rigid or flexible circuit boards, that can be built without the use or generation of environmentally hazardous chemicals.
Another object of the invention is to provide a flexible conductive network having conductive paths which are profiled to self-align with corresponding conductors of other conductive networks. A further object of the invention is to provide contact clusters which can be configured to substantially any shape.
Still another object of the invention is to provide a connector assembly with densely packed contact clusters having the self-aligning capabilities.
A further object of the invention is to provide a connector assembly having contact clusters attached which significantly increase the number of signals that each contact position can interconnect and which are specially profiled to align and to interlock with the conductive paths of networks to which they are connected.
Yet another object of the invention is to provide methods of making conductive networks and contact clusters having one or more of the above advantages.

Method of making high density self-aligning conductive networks and contact clusters


Truck bed tool box. The truck bed tool box includes a tool box holder attachable to a bed of a truck and plural removable tool boxes that fit securely into the tool box holder. The tool box holder includes security mechanism to keep the plural removable tool boxes safe from theft and prevent them from moving around the truck bed.

There are many types of tool boxes. These tool boxes are often placed in pick-up or other trucks with open beds. Such tool boxes are exposed to the weather and are subject to theft and loss. Such tool boxes are also not secured and often slide around the bed of the truck, causing damage to the toolbox and the interior of the bed of the truck. In addition, carpenters, mechanics and other professionals often have many different types toolboxes with many different types of tools that are commonly used for various jobs.
There have been attempts to solve some of the problems associated with truck bed tool boxes. For example, U.S. Pat. No. 6,006,971, entitled "Truckbed toolbox system," that issued to Coleman, et al., teaches "Provided herein is a toolbox system especially well suited for use on pickup trucks. The system provides quick and easy access to a wide variety of tools which may be contained in the toolboxes. The assemblies are modular and are readily loaded and unloaded from the bed portion of a pickup truck. An increased degree of safety and convenience is realized from use of the devices herein set forth."
U.S. Pat. No. 6,007,129, "Long handled tool holder," that issued to Kearney, teaches "an apparatus for holding and restraining long handled tools is described. The tool box is comprised of a top wall, two side walls and a bottom wall within which separate compartments are formed by slidable shelves. The shelves may further compartmentalize the enclosed areas by having partitioning walls to subdivide longitudinal sections. The shelves are supported by brackets and the entire tool box rests within the bed of a truck. The tool holder is retained within the bed of the truck by attaching bolts which extend outward from the truck side wall and through the side wall of the tool box. The tool box may also rest upon the wheel well of the truck in the truck bed to provide further support."
U.S. Pat. No. 6,328,365, entitled "Integrated bed drawer assembly for vehicles," that issued to Adsit teaches "An integrated bed drawer assembly is provided for a vehicle having a bed with a floor and sides extending upwardly and along the sides. The integrated bed drawer assembly includes a plurality of rails adapted to be spaced longitudinally and extend laterally between the sides above the floor of the bed. The integrated bed drawer assembly also includes a drawer operatively cooperating with the rails for sliding movement therealong.
U.S. Pat. No. 6,923,354 entitled "Tailgate toolbox," that issued to Axelson teaches "A toolbox assembly for mounting in the box of a pickup truck includes a rectangular casing with an open front end; a drawer slidable in said casing; a lock on said drawer for locking the drawer in the casing; a pair of L-shaped brackets for mounting on the floor of the box immediately rearwardly of the wheel wells, the brackets slidably receiving the casing; and a lock mechanism for releasably locking the casing in said brackets.
However, none of these solutions solves all of the problems associated with truck bed tool boxes. Thus, it is desirable to provide truck bed tool boxes.


Engine anti-idling and restart may be implemented in a machine having a power source, a movable work tool, a pump driven by the power source, an actuator receiving fluid from the pump and moving the work tool, a high-pressure fluid reservoir, and an assist motor operatively connected to the power source. Engine restart may include detecting operator input to start the power source, and fluidly connecting the fluid reservoir to the assist motor to assist in starting the power source in response to detecting the operator input. Prior to shutting down the power source during anti-idling, fluid from the pump may be input to the assist motor, pressurized and communicated to the high-pressure fluid reservoir in response to determining that idle condition exists and a reservoir charge pressure is less than a reservoir minimum restart pressure needed to restart the power source.

Hydraulic machines such as excavators, dozers, loaders, backhoes, motor graders, and other types of heavy equipment use one or more hydraulic actuators to accomplish a variety of tasks. These actuators are fluidly connected to an engine-driven pump of the machine that provides pressurized fluid to chambers within the actuators. As the pressurized fluid moves into or through the chambers, the pressure of the fluid acts on hydraulic surfaces of the chambers to affect movement of the actuators and a connected work tool.
Swing-type excavation machines, for example hydraulic excavators and front shovels, require significant hydraulic pressure and flow to transfer material from a dig location to a dump location. These machines direct the high-pressure fluid from an engine-driven pump through a swing motor to accelerate a loaded work tool at the start of each swing, and then restrict the flow of fluid exiting the motor at the end of each swing to slow and stop the work tool.
One problem associated with this type of hydraulic arrangement involves efficiency. In particular, the pressurized oil provided by the pump may slowly accelerate the work tool to its steady state swing speed, making the hydraulic system less responsive to the operator swing commands than is desirable to efficiently complete the required tasks. Moreover, the fluid exiting the swing motor at the end of each swing is under a relatively high pressure due to deceleration of the loaded work tool. Unless recovered, energy associated with the high-pressure fluid may be wasted. In addition, restriction of this high-pressure fluid exiting the swing motor at the end of each swing can result in heating of the fluid, which must be accommodated with an increased cooling capacity of the machine.
One attempt to recover swing kinetic energy in a swing-type machine is disclosed in U.S. Pat. No. 8,850,806 to Zhang et al. issued on Oct. 7, 2014 (the '806 patent). The '806 patent discloses a hydraulic control system for a machine that may have a work tool movable through segments of an excavation cycle, a motor configured to swing the work tool during the excavation cycle, at least one accumulator configured to selectively receive fluid discharged from the motor and to discharge fluid to the motor during the excavation cycle, and a controller. The controller may be configured to receive input regarding a current excavation cycle of the work tool, and make a determination based on the input that the current excavation cycle is associated with one of a set of known modes of operation. The controller may be further configured to cause the at least one accumulator to receive fluid by actuating an electro-hydraulic charging valve, and to discharge fluid by actuating an electro-hydraulic discharge valve, during different segments of the excavation cycle based on the determination. The arrangement with two electro-hydraulic valves provides flexibility in design as the performance of the valves is tuned to the particular machine in which the hydraulic control system is implemented. The discharge valve discharges recovered energy in the accumulator directly back to the swing motor during swing acceleration. However, swing acceleration performance can vary based on the pressure within the accumulator at a given time. Moreover, the discharge valve cannot be opened during charging portions of the excavation cycle, so excess kinetic energy may be wasted or lost once the accumulator is fully charged. Therefore, opportunities exist for providing energy recovery systems in swing-type machines that provide more consistent performance in swing acceleration, are more portable between different sizes and types of machines, and are more efficient at capturing kinetic energy.
Another efficiency issue associated with these types of hydraulic arrangements arises during times when the hydraulic machine is idle and yet still operational. For example, during a truck loading cycle, when an excavator finishes loading a first truck, the excavator must wait for the first truck to depart and a second truck to arrive before additional loading tasks can be completed. During this time, the engine of the machine may still be turned on (often at high speeds) and needlessly consuming fuel. In these situations, it may be beneficial to selectively turn the engine off to consume fuel. However, restarting the engine can be harsh on the machine's electrical circuit and cause delays in the work cycle of the machine. Specifically, the electrical circuit could be called on to restart the engine hundreds of times during a particular work shift. In some applications, this overuse of the electrical circuit could cause premature wear and/or failure. In addition, it may take some time for the engine to be turned on and ramp up to required speeds. This time delay could result in loss of productivity and/or become a nuisance for the operator.
An engine-assist device and industrial machine is disclosed in Int'l. Publ. No. 2014/115645 A1 to Shigeo et al. published on Jul. 31, 2014 (the '645 publication). The '645 publication discloses a low-cost engine-assist device that can perform stable energy regeneration from an accumulator, and an industrial machine equipped with the engine-assist device. Variable-capacity main pumps and a variable-capacity assist pump having a motor function and a pump function are directly coupled to an engine. Return pressure fluid that has flowed out of fluid pressure actuators is temporarily stored by a sub-accumulator and supplied to an inlet of the assist pump, and the assist pump provides increased pressure to the main accumulators. A controller calculates and controls an assist pump swash plate angle by means of engine load torque, or of assist starting torque or charge starting torque set by an engine speed setting means, and the controller conducts the stored pressure fluid discharged from the main accumulators to the inlet of the assist pump or conducts the increased-pressure fluid discharged from the outlet of the assist pump to the main accumulators.
Current engine anti-idling systems such as that disclosed in the '645 publication have their own charge/discharge system. The separate system shares the accumulator with the swing circuit to store the energy required to restart the engine, and uses the assist motor with the boom circuit to restart the engine. The accumulator is charged if necessary before shutting down the engine by using main pump flow. Such systems may not be highly efficient because the main pump works at high pressure and low flow rate, and hardware redundancy occurs where separate accumulate charge and discharge valves are provided for the anti-idling system. Therefore, opportunities exist for improving the efficiency and integration of anti-idling systems with the swing and boom circuits.

Integration of swing energy recovery and engine anti-idling systems


In a piezoelectric element, a cubic or tetragonal orientation control layer (15) is provided on a first electrode layer (14), and formed on the orientation control layer (15) is a piezoelectric layer (16) having a rhombohedral or tetragonal crystalline structure and made of lead zirconate titanate to which a Pb-containing complex perovskite compound expressed by the chemical formula Pb(AaBb)O3 has been added in an amount that is from 1 mol % to 50 mol %. The piezoelectric layer (16) is formed so that the crystal grains thereof become columnar grains which extend in the thickness direction of the piezoelectric layer (16) and in which the ratio of the average cross-sectional diameter to the length is from 1/50 to 1/14.

1. Field of the Invention
The present invention relates to a piezoelectric element having an electromechanical conversion function, an ink jet head using the piezoelectric element, an angular velocity sensor, a method for manufacturing the same, and an ink jet recording apparatus including the ink jet head as printing means.
2. Description of Conventional Art
Generally, a piezoelectric material is a material capable of converting a mechanical energy to an electrical energy and vice versa. A typical example of a piezoelectric material is lead zirconate titanate having a perovskite crystalline structure (Pb(Zr,Ti)O3) (hereinafter referred to as "PZT"). In PZT, the greatest piezoelectric displacement is obtained in the <001> direction (the c axis direction) in the case of a tetragonal system, and in the <111> direction in the case of a rhombohedral system. However, many of the piezoelectric materials are polycrystals made up of a collection of crystal grains, and the crystallographic axes of the crystal grains are oriented randomly. Therefore, the spontaneous polarizations Ps are also arranged randomly.
Along with the recent downsizing of electronic appliances, there is a strong demand for reducing the size of piezoelectric elements using a piezoelectric material. In order to meet the demand, more piezoelectric elements are already used in the form of thin films whose volumes can be significantly reduced from those of sinters, which have conventionally been used in various applications, and active researches and developments have been made for reducing the thickness of thin-film piezoelectric elements. For example, in the case of tetragonal PZT, the spontaneous polarization Ps is oriented in the c axis direction. Therefore, in order to realize superior piezoelectric characteristics even with a reduced thickness, the c axes of crystal grains forming a PZT thin film need to be aligned vertical to the substrate plane. In order to realize such an alignment, a sputtering method has been used in the prior art. Specifically, on a single crystal substrate made of magnesium oxide (MgO) having an NaCl-type crystalline structure, which has been cut out so that the surface thereof is along the crystal orientation of the (100) plane, a (100)-oriented Pt electrode thin film is formed as a lower electrode on the substrate, and a PZT thin film whose c axis is oriented vertical to the surface of the Pt electrode is formed on the Pt electrode at a temperature of 600 to 700° C. (see, for example, Journal of Applied Physics vol. 65 No. 4 (published on 15 Feb. 1989 from the American Physical Society) pp. 1666-1670, and Japanese Unexamined Patent Publication No. 10-209517). In such a case, if a piezoelectric layer having a thickness of 0.1 μm and made of PbTiO3 or (Pb,La)TiO3, free of Zr, is formed as a base layer for the PZT thin film on the (100)-oriented Pt electrode before the formation of the PZT thin film, and then the PZT thin film having a thickness of 2.5 μm is formed on the piezoelectric layer by a sputtering method, it is less likely that a layer of a low crystallinity made of a Zr oxide is formed early in the formation of the PZT thin film, thereby allowing the PZT thin film to have a higher crystallinity. Specifically, in the obtained PZT thin film, the degree of (001) orientation ("α(001)") is about 100%.
Herein, α(001) is defined as follows:α(001)=I(001)/ΣI(hkl).
ΣI(hkl) is the sum of diffraction peak intensities from various crystal planes of PZT having a perovskite crystalline structure for a Cu—Kα 2θ range of 10° to 70° in an X-ray diffraction method. Note that the (002) plane and the (200) plane are not included in ΣI(hkl) as they are equivalent to the (001) plane and (100) plane.
However, this method uses an MgO single crystal substrate as a base substrate, thereby increasing the cost of the piezoelectric element, and thus the cost of an ink jet head using the piezoelectric element. Moreover, another drawback is that the variety of the substrate material is limited to the MgO single crystal.
In view of this, various methods have been developed for forming a (001)- or (100)-oriented film of a perovskite piezoelectric material such as PZT on an inexpensive substrate such as a silicon substrate. For example, Japanese Patent Publication No. 3021930 discloses that a PZT film that is preferentially oriented along the (100) plane can be produced by applying a precursor solution of PZT or lanthanum-containing PZT on a (111)-oriented Pt electrode, performing a thermal decomposition process at 450 to 550° C. before the precursor solution is crystallized and then heating and crystallizing the precursor solution at 550 to 800° C. (a sol-gel method).
Moreover, Japanese Unexamined Patent Publication No. 2001-88294 discloses that by forming a very thin titanium layer on an iridium lower electrode, it is possible to control the crystal orientation of a PZT film to be formed thereon. This manufacturing method includes: forming a base layer whose main component is zirconium oxide on a substrate made of silicon, or the like; forming a lower electrode containing iridium on the base layer; depositing a very thin titanium layer on the lower electrode; forming an amorphous piezoelectric precursor thin film containing metal element and oxygen element, which forms a ferroelectric having piezoelectric characteristics, on the titanium layer; and heating and crystallizing the amorphous thin film at a high temperature (a sol-gel method), thereby turning the amorphous thin film into a perovskite piezoelectric thin film. With this manufacturing method, the crystal orientation of the piezoelectric thin film such as PZT can be controlled by the thickness of the titanium layer, and a (100)-oriented film is obtained when the thickness of the titanium layer is set to be 2 to 10 nm, while a (111)-oriented film is obtained when the thickness of the titanium layer is set to be 10 to 20 nm
Also, Japanese Unexamined Patent Publication No. 11-191646 discloses that where a piezoelectric thin film is formed by using a sol-gel method, a (100)-oriented PZT film can be obtained by forming a titanium layer having a thickness of 4 to 6 nm on a (111)-oriented Pt electrode and using titanium oxide, which is formed through oxidization of titanium in the titanium layer, as a nucleus.
Furthermore, attempts have also been made to form on a silicon substrate a piezoelectric thin film having higher piezoelectric characteristics than a PZT thin film by adding an additive to PZT. For example, Japanese Unexamined Patent Publication No. 10-81016 discloses a piezoelectric element that uses a PZT thin film to which lead magnesium niobate has been added, while disclosing that the lead-magnesium-niobate-added PZT thin film can be formed on a Pt electrode by a sol-gel method so as to be preferentially oriented along the (100) plane in a rhombohedral system. Also, the piezoelectric characteristics of a PZT thin film (0.9PZT−0.1PMN thin film) to which Pb(Mg1/3Nb2/3)O3 has been added are evaluated in pp. 886-889 in Japanese Journal of Applied Physics vol. 38 No. 2A published in February in 1999 by the Japan Society of Applied Physics. This PZT thin film is tetragonal and oriented along two directions, that is, the (100) plane and the (111) plane. It has been reported that the PZT thin film exhibits a very high piezoelectric constant d31 of 190 pm/V at an electric field strength of 170 kV/cm.
However, while the methods described above are desirable methods that do not use an expensive MgO single-crystal substrate, it is difficult to obtain a well-oriented film having a desirable crystallinity in the film formation process, as in the case of forming a piezoelectric thin film on an MgO single-crystal substrate, because the piezoelectric thin film is formed by a sol-gel method. In view of this, an amorphous piezoelectric thin film is first formed, and then the layered structure including the substrate and the piezoelectric thin film is subjected to a heat treatment, so that the crystallographic axes are preferentially oriented in a desirable direction.
Moreover, when piezoelectric elements are mass-produced with a sol-gel method, the amorphous piezoelectric precursor thin film is likely to be cracked due to changes in the volume during the degreasing step of removing organic substances. Furthermore, in the step of heating and crystallizing the amorphous piezoelectric precursor thin film at a high temperature, the film is likely to be cracked or peeled off from the lower electrode due to crystal changes.
As a solution to these problems with a sol-gel method, Japanese Unexamined Patent Publication Nos. 10-81016 and 2000-252544 disclose that it is effective to add titanium or titanium oxide in the lower electrode. Particularly, Japanese Unexamined Patent Publication No. 10-81016 shows that a (100)-oriented PZT film can be obtained even with a sputtering method. Note however that a perovskite PZT film is not obtained directly on the lower electrode. First, a PZT film having an amorphous or pyrochlore crystalline structure is formed at a low temperature of 200° C. or less, which is then crystallized through a heat treatment at a high temperature of 500 to 700° C. in an oxygen atmosphere. Therefore, as with a sol-gel method, the film is likely to be cracked or peeled off from the lower electrode due to crystal changes in the step of heating and crystallizing the film at a high temperature. Moreover, the degree of (001) orientation or the degree of (100) orientation of the PZT film formed by a sol-gel method or a sputtering method as described above is 85% or less with either method.
Furthermore, with a sol-gel method, the maximum thickness of the PZT film to be formed in a single iteration of the step (including the application of the precursor solution and the following heat treatment) is about 100 nm at maximum. Therefore, in order to obtain a thickness of 1 μm or more, which is required for a piezoelectric element, it is necessary to repeat this step ten times or more, whereby the production yield may be reduced.
On the other hand, according to Japanese Unexamined Patent Publication No. 2001-88294, supra, states that attempts were made to control the orientation of PZT on an Ir base electrode with a very thin titanium layer formed thereon by using a method other than a sol-gel method (including an MOD method) (in which an amorphous thin film is once formed and then the thin film is turned into a crystalline thin film through an aftertreatment such as a heat treatment), i.e., by using a method in which a crystalline thin film is directly formed without the crystallization step using a heat treatment, e.g., a sputtering method, a laser ablation method or a CVD method, and that a well-oriented film was not obtained with any method other than a sol-gel method. The reason is stated to be as follows. The crystallization of the PZT film proceeds gradually from the lower electrode side to the upper electrode side with a sol-gel method, whereas with a CVD method or a sputtering method, the crystallization of the PZT film proceeds randomly, resulting in irregular crystallization, and thus making the orientation control difficult.
Moreover, when a titanium oxide film whose thickness is 12 nm or less is formed on a (111)-oriented Pt electrode layer, and a lead titanate film or a PZT film having a perovskite crystalline structure is formed directly by a sputtering method, either film exhibits a (111) orientation property, and a (100)- or (001)-oriented film is not obtained (see Journal of Applied Physics vol. 83 No. 7 (published on 1 Apr. 1998 from the American Physical Society) pp. 3835-3841).
Furthermore, even if a (100)- or (001)-oriented film is obtained, there is a problem in that such a film cracks when driven continuously as a piezoelectric element. And even the (111)-oriented film cracks as in the case of the (100)- or (001)-oriented film. Such cracks were often observed in a piezoelectric thin film having a crystalline structure in which the crystal grains of the piezoelectric thin film grew in the direction vertical to the thickness direction of the piezoelectric thin film (i.e., the direction along the film surface), and were hardly seen in a piezoelectric thin film having a crystalline structure in which the crystal grains of the piezoelectric thin film were columnar grains that grew appropriately in the thickness direction of the piezoelectric thin film. This is presumably because a stress produced when the piezoelectric thin film is driven is relaxed at the grain boundaries, while the adhesion strength of the thin film is high.

Piezoelectric element, ink jet head, angular velocity sensor, and ink jet recording apparatus

Matsushita Electric Industrial Co., Ltd.


An LED projector includes a plurality of light sources; and an image generator which includes an arrangement of pixels, each pixel including at least one light source; wherein the LEDs are stacked epi-LEDs which include layers arranged above one another for different colors, or each pixel includes an emission surface and at least two LEDs are arranged adjacent one another in the emission surface.

Projection systems are usually produced using discharge lamps which have elevated power consumption and a short service life. LED projectors with a significantly longer service life and more efficient mode of operation are also known. Drawbacks of LED projectors are, however, their lower light output due to the light sources they use and losses in the optical system. In conventional projection systems, light emerging from the light source is mixed, homogenized and broken down by a color wheel into the colors red, green and blue. The light of the individual colors is projected onto the image-generating element. Typical image generators are an arrangement of LCDs (liquid crystal displays), LCoS (Liquid Crystal on Silicon) or DLP (Digital Light Processing) with an arrangement of small tiltable mirrors. In polarization-based systems with LCDs or LCoS, only one polarization direction is usable. In systems with DLP, the images are sequentially superimposed such that each light source of a particular color is only switched on with interruptions. In this case too, the light output from the light source is thus not fully utilized.
DE 10 2008 013 030 and DE 10 2008 014 094, for example, describe the basic principles of color mixing and contacting of layer stacks of substrateless diodes. DE 10 2008 008 599, DE 10 2008 006 757 and DE 10 2007 062 042 describe contacting methods for substrateless diodes on or between dielectric interlayers.
DE 199 25 318 C1 describes a color image projector with time-controlled LED light sources. WO 03/056876 A2 describes an illumination system with planar multilayer arrangements of LED light sources. US 2008/0211413 A1 describes a display device produced from LEDs. DE 100 63 200 A1 describes a method and a device with LCD reflective modulators. EP 1 609 835 A1 describes a potting compound for LEDs.
It could therefore be helpful to provide a projection system with a long service life and elevated efficiency despite having a low structural height.


A system and method of booting an embedded system having a processor, nonvolatile memory and a remote media interface connected to the processor. Boot code is executed within the nonvolatile memory. The processor determines if a storage device is connected to the remote media interface and, if a storage device is connected to the remote media interface, program code loaded from the storage device to the processor is executed.

1. Field of the Invention
The present invention is related to embedded computer systems, and more particularly to a system and method for booting embedded systems using removable storage.
2. Background Information
Embedded systems range from low-end systems such as networked sensors and smart cards to high-end systems such as routers, storage servers and web servers. Embedded devices typically boot from a flash, ROM or EPROM over a serial or parallel bus interface. Typically the type of boot is configured from within the chip as part of its setup. Among other things, this boot system will usually perform initial diagnostic tests, discover and initialize the hardware system and load the application program.
Today, on an embedded system, software is typically loaded on flash memory. The flash memory is tightly coupled to the system bus. This is done because the processor only knows to get its boot information from interfaces defined within the chip. In order to get the boot code into the flash, the chip must by programmed ahead of time using a programmer or new code must be loaded using a debugger interface. The flash may also be downloaded by other code currently running, but this then requires a reboot.
To date, embedded systems have had limited access to external memory. One reason for limiting access to external memory was to reduce cost. Another reason was to limit the opportunities to compromise the embedded device. Such limits have their cost. For instance, it can be difficult to swap in a new software system on an embedded device. And it can be difficult to recover a embedded system that has been disabled by an error, or by compromised code.
What is needed is a system and method for addressing these issues and others that will become apparent in reading the following disclosure.

System and method for booting embedded systems using removable storage


An absorbent pad for use with an ostomy appliance or similar apparatus connected to a stoma extending through the skin of a patient, is formed of a flexible laminate with a liquid-permeable inner layer facing toward the patient's skin, an intermediate layer of absorbent material, and a liquid-impermeable outer layer. The layers are sealed together, and the laminate has a central opening for fitting around the connection between the ostomy appliance flange and body portion. An adhesive layer is provided on the peripheral border of the pad for sealing to the patient's skin. The adhesive layer is applied so that it encircles the absorbent surface area of the pad. The adhesive layer cooperates with the impermeable outer layer of the laminate to surround the fluid-absorbing intermediate layers of the pad and prevent fluid and odor absorbed therein from being released. The absorbent pad is further characterized in that it can be applied and disposed of separate and apart from the ostomy appliance.

In urostomy, colostomy, ileostomy, tracheotomy, and other similar operations, part or all of a patient's bladder, intestine, or other internal organ is removed, and is replaced with a conduit for channeling body fluids or waste out of the patient's body via a stoma or tube. In the case of a colostomy, ileostomy or urostomy, body waste is collected by an external apparatus, usually attached to the patient's skin around the stoma or tube. For example, a conventional ostomy appliance is a relatively flat plastic bag having an aperture to receive the stoma, the bag usually being formed with a flange for fitting around the stoma and for being sealed to the skin of the abdomen with an adhesive layer.
The adhesive layer of the appliance flange will sometimes leak due to an imperfect seal. Such a break in the seal can be caused by abdominal folds, wrinkles in the flange when it is first applied, strenuous physical activity, humidity, or other stresses placed on the adhesive, including those arising from the inflexibility of the flange in the central region where the flange is connected to the bag. The leak can result in stains on the patient's clothing and embarrassing odors. It is often inconvenient or impossible for the patient to change the appliance before a leak becomes noticeable.
Various types of absorbent pads have been designed for absorbing such leakage, including a pad designed to fit around the aperture of the collecting appliance. For example, in U.S. Pat. No. 4,406,659, a removable U-shaped absorbent pad is mounted with an adhesive strip, or held in a pouch on the inner, or skin-facing, surface of the urostomy bag over the lower half of the receptacle flange receiving the stoma. In U.S. Pat. No. 4,085,752, an absorbent pad is formed by doubling over the absorbent layers and providing a slit and annular opening for fitting immediately around the stoma against the patient's skin and underneath the receptacle flange of a colostomy appliance.
The absorbent pad of U.S. Pat. No. 4,085,752 is first placed on the skin around the stoma, and the appliance flange is next positioned on top of the pad. A belt must then be used to hold the bag and pad in place. This type of absorbent ostomy pad can only be used with the small proportion of appliances that do not use adhesive on the flange as the means of attachment. The pad, it should be noted, can only be applied or removed at the same time as the appliance itself. Further, in U.S. Pat. No. 4,085,752, the pad acts like a sponge releasing retained fluid and odor when pressure is applied thereto. There is no provision made for trapping liquid absorbed by the pad and preventing it from leaking out when the pad becomes saturated and pressure is applied thereto. This circumstance would occur any time the wearer bent forward from the waist. In addition, there is the disadvantage that the skin in contact with a wet pad would remain wet and, over a sustained period, could become irritated and excoriated.
Accordingly, it is a principle object of the present invention to provide a separately disposable, self-adhering absorbent pad, for use with an ostomy appliance or other external collecting apparatus fitting around a stoma or tube extending from a patient, adapted so that fluid which is not passed into the appliance will be absorbed and retained by the pad without leakage of fluid or odor therefrom for prolonged periods of time.
Another object of the invention is to provide such a construction wherein the fluid which cannot be accommodated by the pad is not released onto the patient's skin or clothing.
Still another object is to provide an absorbent pad which can be conveniently applied around the aperture of a collecting appliance, can be adjustingly fitted thereon despite variations in the dimensions thereof, and will remain securely in position.
A further object of the invention is to provide an absorbent pad adapted to cover the entire flange of the ostomy appliance for providing 360 degrees of protection against appliance failure.
Yet a further object is to provide an absorbent pad which is a totally separate device from the appliance, which can be removed completely independently of the appliance, and which is not subject to the stresses applied to the appliance flange by the rigid appliance aperture to which the flange is directly attached.
Still another object of the invention is to provide an absorbent pad adapted to be worn on the outside of the appliance flange and which is suitable for use with substantially all ostomy appliances including those attached with adhesive or by means of a belt.
Still a further object of the present invention is to provide an auxilliary means contained within such a pad for trapping large amounts of liquid by converting the same into a gel.
Another object of the present invention is to provide a flexible absorbent pad of substantially reduced bulk, as compared to the presently disclosed pads, which will contain odor in addition to leakage and which will trap liquid out of contact with the patient's skin.
These and other objects and advantages of the invention will be appreciated from the following disclosure.


This invention provides a system and a method for monitoring a patient's Formation number (Fn) and comparing the measured Fn to the baseline data of healthy persons population or to the patient's past history data to assess the degree of ventricular and/or valvular dysfunction, wherein the valvular dysfunction may comprise dilated cardiomyopathy, hypertrophic cardiomyopathy, ischemic cardiomyopathy, restrictive cardiomyopathy, or the like.

The valvular and ventricular dysfunctions affect the quality life of tens of thousands patients. More than 28,000 deaths in 2001 are caused by cardiomyopathy. However, there is little convenient noninvasive assessment approach for quantifying the severity of the valvular dysfunction for the early to moderate stage patients as an aid for later therapeutic management.
The circulatory system consists of a heart and blood vessels. In its path through the heart, the blood encounters four valves. The valve on the right side that separates the right atrium from the right ventricle has three cusps and is called the tricuspid valve. It closes when the ventricle contracts during a phase known as systole and it opens when the ventricle relaxes, a phase known as diastole.
The pulmonary valve separates the right ventricle from the pulmonary artery. It opens during systole, to allow the blood to be pumped toward the lungs, and it closes during diastole to keep the blood from leaking back into the heart from the pulmonary artery. The pulmonary valve has three cusps, each one resembling a crescent and it is also known as a semi-lunar valve.
The mitral valve, so named because of its resemblance to a bishop's mitre, is in the left ventricle and it separates the left atrium from the ventricle. It opens during diastole to allow the blood stored in the atrium to pour into the ventricle, and it closes during systole to prevent blood from leaking back into the atrium. The mitral valve and the tricuspid valve differ significantly in anatomy. The annulus of the mitral valve is somewhat D-shaped whereas the annulus of the tricuspid valve is more nearly circular.
The fourth valve is the aortic valve. It separates the left ventricle from the aorta. It has three semi-lunar cusps and it closely resembles the pulmonary valve. The aortic valve opens during systole allowing a stream of blood to enter the aorta and it closes during diastole to prevent any of the blood from leaking back into the left ventricle.
In a venous circulatory system, a venous valve is to prevent the venous blood from leaking back into the upstream side so that the venous blood can return to the heart and the lungs for blood oxygenating purposes.
The effects of valvular dysfunction vary. Mitral regurgitation has more severe physiological consequences to the patient than does tricuspid valve regurgitation. In patients with valvular insufficiency it is an increasingly common surgical practice to retail the natural valve, and to attempt to correct the defects. Many of the defects are associated with dilation of the valve annulus. This dilatation not only prevents competence of the valve but also results in distortion of the normal shape of the valve orifice or valve leaflets. A suitable approach for treating an annulus, including repair of a valve, valve replacement, implantation of an annuloplasty ring or annulus tissue shrinkage depends on the detection and determination of the severity of the valvular dysfunction.
Cardiomyopathy is a type of heart diseases in which the heart is abnormally enlarged, thickened and/or stiffened. As a result, the heart muscle's ability to pump blood is usually weakened. The condition typically begins in the walls of the heart's lower chambers, and more severe cases may affect the walls of the upper chambers, as well. This damage to the heart walls inhibits the ability of the heart to function effectively, which commonly results in congestive heart failure. Dilated cardiomyopathy (DCM) is a condition in which the heart's ability to pump blood is decreased because the heart's main pumping chamber, the left ventricle, is enlarged and stiff; this causes a decreased ejection fraction (the amount of blood pumped out with each heart beat). In general, it prevents the heart from relaxing and filling with blood as it should. Over time, it can affect the other heart chambers as well.
Hueb and associates studied the behavior of the mitral valve ring and the left ventricle in dilated cardiomyopathy (J Thorac Cardiovasc Surg 2002; 124:1216-24). They reported in ischemic or idiopathic dilated cardiomyopathy, dilation of mitral ring is proportional and does not exclusively affect the posterior portion. The degree of left ventricular dilation does not determine the degree of dilation of the mitral ring because they are independent processes. It is, therefore, one object of the present invention to provide a method for measuring a patient's Formation number (Fn) and comparing the measured Fn to the baseline data of healthy persons to assess the degree of valvular normality or valvular dysfunction
Therefore, it is one aspect of the present invention to provide a system and method for assessing the patient's valvular dysfunction due to cardiomyopathy or fibrillation by analyzing the data from noninvasive ultrasound scanning or magnetic resonance imaging.

Noninvasive methods for assessing valvular and ventricular dysfunction


A merchandising display assembly mounted to and extending from an upwardly extending support surface, the support surface having an elongate and single slotted backplate with a plurality of spaced apart and linearly extending slots. A horizontally extending member is mounted to and extends from the support surface. The horizontally extending member in one specific embodiment includes first and second elongated portions and axially adjusting means for establishing a length between the elongated portions and in a further embodiment is formed by a single fixed and extending portion. An elongated display member is secured to an outer end of the a horizontal member in freely swinging and suspended fashion and extends in parallel fashion relative to the vertical support surface at a spaced distance. The display member exhibits a substantially flattened display area for securing thereon a plurality of hanger portions which are in turn capable of supporting large volumes of small sized merchandise without obscuring additional merchandise located on the vertical support surface.

1. Field of the Invention
The present invention relates generally to merchandising display assemblies and, more particularly, to a merchandising display assembly mounted to and extending from an upwardly extending support surface and which includes an elongated and substantially flattened or planar display surface area attached in a freely swinging manner to a single upper horizontally extending members and being spaced a distance from the vertical support, the display surface area being capable of supporting volumes of smaller sized merchandise.
2. Description of the Prior Art
Shelving structures and related display units for displaying merchandise are a common sight in any type of store or commercial establishment. The desire of any merchant is and always has been to maximize the available shelf or display capacity within the limited confines of the store. Vertically extending pegboard surfaces are particularly effective for displaying small, high volume merchandise on hooks and other horizontally extending fasteners.
U.S. Pat. No. 3,677,415, issued to Radek, teaches a cantilever merchandise support including an article supporting hanger bar or bracket which is adapted to be attached to a perforated board or panel by a plurality of legs extending from a mounting plate. The hanger bar or bracket portion is in each instance an integrally formed single piece which is mounted to extend outwardly from the vertical surface and upon which the merchandise is supported. The disadvantage of cantilevered merchandise supports such as those taught by Radek is that their merchandise carrying capacity is limited to the bar or bracket portion. The axial length which such supports extend is likewise limited such that they are unable to utilize to any great extent the air space extending from the pegboard or other surface for displaying merchandise.
U.S. Pat. No. 5,014,954, issued to Merl, discloses an adjustable display arm assembly securable to a vertical support structure which includes a pair of nesting segments selectively adjustable at longitudinal positions to establish an overall length of the display arm. The Merl device is somewhat of an improvement over Radek in that the display arm can be extended outward a greater horizontal distance, however its merchandise carrying ability is still limited to the display arm itself and it does not include any additional bracketry for carrying large volumes of merchandise.
Applicant's preceding application Ser. No. 08/888,558, filed Jul. 7, 1997, discloses a reinforced strip display assembly which is capable of supporting high volumes of smaller impulse merchandise and which includes an elongate and planar shaped reinforced body which is suspended in a freely swinging manner from a horizontally extending upper bracket. The reinforced body includes a plurality of apertures formed in front and rear planar faces and which are capable of receiving individual merchandise support members. The bracket further includes one or more hook portions which engage the upper end of the elongate body to array the body in its freely suspended manner a spaced distance from the shelving construction.
Applicant's preceding application Ser. No. 09/225,671, filed Jan. 5, 1999, discloses a merchandising display structure mounted to a vertical support surface and including at least one horizontally extending and adjustable member which is secured at one end to the vertical support surface and which at the opposite end supports an elongate and substantially flattened display member. The display member includes receiving means at spaced intervals therealong for receiving a volume of merchandise. According to alternate preferred embodiments, the display member can further include first and second parallel spaced grid patterns of interlocking wire elements which establish first and second faces. The display member may also include an elongated and substantially flattened sheet of material, such as a durable polymer construction and having disposed therein a large plurality of apertures at spaced intervals.

Mechandising display assembly incorporating a swinging planar display member