The present invention relates in part to hWART nucleic acid molecules. The invention also relates in part to nucleic acid molecules encoding portions of hWART full-length proteins, nucleic acid vectors containing hWART nucleic acid molecules, recombinant cells containing such nucleic acid vectors, polypeptides purified from such recombinant cells, antibodies to such polypeptides, and methods of identifying compounds that modulate the function of an hWART polypeptide. Also disclosed are methods for diagnosing abnormal cell proliferative conditions in an organism using hWART-related molecules or compounds.

The present invention relates in part to protein kinases. In particular, the invention concerns the identification of protein kinase proteins which are human orthologues of the drosophila WART gene (hWART).
The following description is provided to aid in understanding the invention, but is not admitted to describe or constitute prior art to the invention.
Cellular signal transduction is a fundamental mechanism whereby extracellular stimuli are relayed to the interior of cells and thereby regulate diverse cellular processes. One of the key biochemical mechanisms of signal transduction involves the reversible phosphorylation of proteins. Phosphorylation of polypeptides regulates the activity of mature proteins by altering their structure and function. Phosphate most often resides on the hydroxyl moiety of serine, threonine, or tyrosine amino acids in proteins.
Enzymes that mediate phosphorylation of cellular effectors generally fall into two classes. The first class consists of protein kinases which transfer a phosphate moiety from nucleotide triposphates to protein substrates. The second class consists of protein phosphatases which hydrolyze phosphate moieties from phosphoryl protein substrates. The converse functions of protein kinases and protein phosphatases balance and regulate the flow of signals in signal transduction processes.
Protein kinases are generally divided into two classes: receptor and non-receptor type proteins. Protein kinases may also be divided into three classes based upon the amino acids they act upon: (1) Some catalyze the addition or hydrolysis of phosphate on serine or threonine only; (2) some catalyze the addition or hydrolysis of phosphate on tyrosine only; and (3) some catalyze the addition or hydrolysis of phosphate on serine, threonine, and tyrosine.
Altered protein kinase activity has been associated with multiple abnormal cellular functions, including increased cell proliferation. Increased cell proliferation can result from at least two cellular events: (i) mutation, chromosome translocation, or gene amplification of proto-oncogenes (Bishop, Cell 64:235-248, 1991), or (ii) inactivation, loss by mutation, chromosomal loss, mitotic recombination, or gene conversion of tumor suppressor genes (Lasko et al., Ann Rev Genet 25:281-314).
A large number of potential tumor suppressor genes have been isolated from Drosophila melanogaster, a species of fruit fly. Watson et al., J. Cell Sci. 18:19-33 , 1994. Potential tumor suppressor genes are identified in this organism by first deleting, obstructing, or mutating a gene, and then detecting over-proliferative cell growth of specific tissues in dissected larvae and pupae. Xu et al., Development 121:1053-1063, 1995. This organism provides an ideal system for identifying potential tumor suppressor genes as it reproduces rapidly and its genome is readily manipulated by persons skilled in the art.
An example of a putative tumor suppressor gene, identified in Drosophila is the wts gene. Loss or inactivation of both copies of the wts gene results in the growth of tumors on the legs and wings of the flies. Bryant et al., Development 1993 Supplement: 239-249, 1993. The large size of these tumors suggests that the cells undergo more divisions than normal. Id. In addition, the rounded shape of the tumors suggests that the division of the mutant cells is not preferentially oriented. Id. These observations taken together with the increased thickness of the cuticles around the mutant cells suggest that the wts gene regulates cell adhesion, cell contact inhibition, and/or cell boundary recognition in Drosophila.
Several of the genes characterized as potential tumor suppressors in Drosophila are cloned. In particular, the wts gene contains a region that bears sequence similarity to the catalytic regions of mammalian non-receptor serine/threonine protein kinases. Watson, BioEssays 17:673-676, 1995. However, the human orthologues of the drosophila wts gene have not been reported.
The invention relates in part to novel human orthologues of the Drosophila wts gene (hWARTs). The Drosophila wts gene encodes a non-receptor serine/threonine kinase. The properties of the human orthologues are described herein. The present invention concerns polypeptides of hWART, nucleic acids encoding such polypeptides, cells, tissues and animals containing such nucleic acids, antibodies to the polypeptides, assays utilizing the polypeptides, and methods relating to all of the foregoing.
The term xe2x80x9corthologuexe2x80x9d as used herein, refers to a gene that is more c related, in terms of nucleic acid sequence, to another gene than a gene which is a homologue. In the context of this invention, xe2x80x9chomologousxe2x80x9d indicates that the nucleotide sequences of two genes and/or the sequences of the gene products (e.g., amino acid sequences) have significant similarity, and that the gene products perform a similar cellular function. Thus, two homologous genes may have sequences which have 50, 60, 70, 80, 90, or greater percent nucleotide sequence identity. By xe2x80x9cclosely relatedxe2x80x9d in the context of this invention, it is meant nucleic acid sequences that have greater than 90% identity.
The hWARTS genes encode proteins that are potential drug targets for controlling aberrant cell proliferation. Unlike their Drosophila ortholog, the hWARTS genes may not function as tumor suppressor genes. While their mRNA is absent from most normal cells they are abundantly expressed in many types of tumor cells. However, based on the high degree of sequence identity in the catalytic and non-catalytic regions between the hWART proteins and the Drosophila wts, it is likely that the hWART genes are involved in regulating cell adhesion, cell contact inhibition, and/or cell boundary recognition, and in regulation of signal transduction pathways related to cell proliferation.
Thus, in a first aspect, the invention features an isolated, enriched, or purified nucleic acid molecule encoding an hWART polypeptide.
By xe2x80x9cisolatedxe2x80x9d in reference to nucleic acid it is meant a polymer of 14, 17, 21 or more nucleotides conjugated to each other, including DNA or RNA that is isolated from a natural source or that is synthesized. The isolated nucleic acid of the present invention is unique in the sense that it is not found in a pure or separated state in nature. Use of the term xe2x80x9cisolatedxe2x80x9d indicates that a naturally occurring sequence has been removed from its normal cellular (i.e., chromosomal) environment. Thus, the sequence may be in a cell-free solution or placed in a different cellular environment. The term does not imply that the sequence is the only nucleotide sequence present, but that it is essentially free (about 90-95% pure at least) of non-nucleotide material naturally associated with it and thus is meant to be distinguished from isolated chromosomes.
By the use of the term xe2x80x9cenrichedxe2x80x9d in reference to nucleic acid it is meant that the specific DNA or RNA sequence constitutes a significantly higher fraction (2-5 fold) of the total DNA or RNA present in the cells or solution of interest than in normal or diseased cells or in the cells from which the sequence was taken. This could be caused by a person by preferential reduction in the amount of other DNA or RNA present, or by a preferential increase in the amount of the specific DNA or RNA sequence, or by a combination of the two. However, it should be noted that xe2x80x9cenrichedxe2x80x9d does not imply that there are no other DNA or RNA sequences present, just that the relative amount of the sequence of interest has been significantly increased.
The term xe2x80x9csignificantxe2x80x9d here is used to indicate that the level of increase is useful to the person making such an increase, and generally means an increase relative to other nucleic acids of about at least 2 fold, more preferably at least 5 to 10 fold or even more. The term also does not imply that there is no DNA or RNA from other sources. The other source DNA may, for example, comprise DNA from a yeast or bacterial genome, or a cloning vector such as pUC19. This term distinguishes the sequence from naturally occurring enrichment events, such as viral infection, or tumor type growths, in which the level of one mRNA may be naturally increased relative to other species of mRNA. That is, the term is meant to cover only those situations in which a person has intervened to elevate the proportion of the desired nucleic acid.
It is also advantageous for some purposes that a nucleotide sequence be in purified form. The term xe2x80x9cpurifiedxe2x80x9d in reference to nucleic acid does not require absolute purity (such as a homogeneous preparation); instead, it represents an indication that the sequence is relatively purer than in the natural environment (compared to the natural level this level should be at least 2-5 fold greater, e.g., in terms of mg/ml). Individual clones isolated from a cDNA library may be purified to electrophoretic homogeneity. The claimed DNA molecules obtained from these clones can be obtained directly from total DNA or from total RNA. The cDNA clones are not naturally occurring, but rather are preferably obtained via manipulation of a partially purified naturally occurring substance (messenger RNA). The construction of a cDNA library from mRNA involves the creation of a synthetic substance (cDNA) and pure individual cDNA clones can be isolated from the synthetic library by clonal selection of the cells carrying the cDNA library. Thus, the process which includes the construction of a cDNA library from mRNA and isolation of distinct cDNA clones yields an approximately 106-fold purification of the native message. Thus, purification of at least one order of magnitude, preferably two or three orders, and more preferably four or five orders of magnitude is expressly contemplated. The term is also chosen to distinguish clones already in existence which may encode hWARTs but which have not been isolated from other clones in a library of clones. Thus, the term covers clones encoding hWART which are isolated from other non-hWART clones.
The term xe2x80x9cnucleic acid moleculexe2x80x9d describes a polymer of deoxyribonucleotides (DNA) or ribonucleotides (RNA). The nucleic acid molecule may be isolated from a natural source by cDNA cloning or subtractive hybridization or synthesized manually. The nucleic acid molecule may be synthesized manually by the triester synthetic method or by using an automated DNA synthesizer.
The term xe2x80x9ccDNA cloningxe2x80x9d refers to hybridizing a small nucleic acid molecule, a probe, to genomic cDNA. The probe hybridizes (binds) to complementary sequences of cDNA.
The term xe2x80x9ccomplementaryxe2x80x9d describes two nucleotides that can form multiple favorable interactions with one another. For example, adenine is complementary to thymine as they can form two hydrogen bonds. Similarly, guanine and cytosine are complementary since they can form three hydrogen bonds. Thus if a nucleic acid sequence contains the following sequence of bases, thymine, adenine, guanine and cytosine, a xe2x80x9ccomplementxe2x80x9d of this nucleic acid molecule would be a molecule containing adenine in the place of thymine, thymine in the place of adenine cytosine in the place of guanine, and guanine in the place of cytosine. Because the complement can contain a nucleic acid sequence that forms optimal interactions with the parent nucleic acid molecule, such a complement can bind with high affinity to its parent molecule.
The term xe2x80x9chybridizexe2x80x9d refers to a method of interacting a nucleic acid sequence with a DNA or RNA molecule in solution or on a solid support, such as nitrocellulose, nylon or some combination of these materials. If a nucleic acid sequence binds to the DNA or RNA molecule with high affinity, it is said to xe2x80x9chybridizexe2x80x9d to the DNA or RNA molecule. The strength of the interaction between the probing sequence and its target can be assessed by varying the stringency of the hybridization conditions. Under highly stringent hybridization conditions only highly complementary nucleic acid sequences hybridize. Preferably, such conditions prevent hybridization of nucleic acids having one or two mismatches out of 20 contiguous nucleotides.
Various low or high stringency hybridization conditions may be used depending upon the specificity and selectivity desired. Stringency is controlled by varying salt or denaturant concentrations. Examples of hybridization conditions are shown in the examples described herein. High stringent conditions may mean conditions that are at least as stringent as the following: hybridization in 50% formamide, 5xc3x97SSC, 50 mM NaH3PO4, pH 6.8, 0.5% SDS, 0.1 mg/mL sonicated salmon sperm DNA, and 5xc3x97Denhart solution at 42 C. overnight; washing with 2xc3x97SSC, 0.1% SDS at 45 C.; and washing with 0.2xc3x97SSC, 0.1% SDS at 45 C. Those skilled in the art will recognize how such conditions can be varied to vary specificity and selectivity.
cDNAs are molecules that may be reverse-transcribed from fragments of message RNA from a genomic source. These fragments form a cDNA library of nucleic acid molecules. cDNA libraries are constructed from natural sources such as mammalian blood, semen, or tissue.
The term xe2x80x9csubtractive hybridizationxe2x80x9d refers to a method similar to cDNA cloning except that cDNA prepared from mRNA in unstimulated cells is added to mRNA in stimulated or different types of cells. cDNA/mRNA can then be precipitated to enrich the mRNA specific to the stimulation signal or different cell type.
The term xe2x80x9chWART nucleic acid moleculexe2x80x9d as used herein refers to a nucleic acid molecule that encodes an hWART polypeptide. hWART nucleic acid molecules can be identified by hybridization procedures and cloning procedures as described herein.
An hWART polypeptide can be encoded by a full-length nucleic acid sequence or any portion of the full-length nucleic acid sequence. In preferred embodiments, the isolated nucleic acid comprises, consists essentially of, or consists of a nucleic acid sequence set forth in SEQ ID NO:1, or SEQ ID NO:2, a nucleic acid sequence that hybridizes to the nucleic acid sequence set forth in SEQ ID NO:1, or SEQ ID NO:2, or a functional derivative (as defined below) of either of the foregoing. The nucleic acid may be isolated from a natural source by cDNA cloning or subtractive hybridization; the natural source may be mammalian (human) blood, semen, or tissue and the nucleic acid may be synthesized by the triester or other method or by using an automated DNA synthesizer.
The term xe2x80x9cmammalianxe2x80x9d refers to such organisms as mice, rats, rabbits, goats, more preferably monkeys and apes, and most preferably humans.
In other preferred embodiments, the nucleic acid molecule of the invention comprises a nucleotide sequence that (a) encodes a polypeptide having the full length amino acid sequence set forth in SEQ ID NO:3 or SEQ ID NO:4; (b) is the complement of the nucleotide sequence of (a); (c) hybridizes under highly stringent conditions to the nucleotide molecule of (a) and encodes a naturally occurring hWART polypeptide; (d) encodes an hWART polypeptide having the full length amino acid sequence of the sequence set forth in SEQ ID NO:3 or SEQ ID NO:4, except that it lacks one or more of the following segments of amino acid residues: 12-45, 55-151, 236-377, 404-520, 555-559, 601-702, 691-998, 1011-1086 of SEQ ID NO:3, or 1-33, 43-139, 342-466, 467-480, 514-518, 974-1048 of SEQ ID NO:4; (e) is the complement of the nucleotide sequence of (d); (f) encodes a polypeptide having the amino acid sequence set forth in SEQ ID NO:3 or SEQ ID NO:4 from amino acid residues 12-45, 55-151, 236-377, 404-520, 555-559, 601-702, 691-998, 1011-1086 of SEQ ID NO:3, or 1-33, 43-139, 342-466, 467-480, 514-518, 974-1048 of SEQ ID NO:4; (g) is the complement of the nucleotide sequence of (f); (h) encodes a polypeptide having the full length amino acid sequence set forth in SEQ ID NO:3 or SEQ ID NO:4, except that it lacks one or more of the domains selected from the group consisting of an N-terminal domain, a catalytic domain, and a C-terminal domain; or (i) is the complement of the nucleotide sequence of (h). The nucleic acid molecule of the invention is isolated, enriched, or purified from, preferably, a mammal, or most preferably from a human.
In yet other preferred embodiments, the nucleic acid is an isolated conserved or unique region, for example those useful for the design of hybridization probes to facilitate identification and cloning of additional polypeptides, or for the design of PCR probes to facilitate cloning of additional polypeptides.
By xe2x80x9cconserved nucleic acid regionsxe2x80x9d, it is meant regions present on two or more nucleic acids encoding an hWART polypeptide, to which a particular nucleic acid sequence can hybridize under lower stringency conditions. Examples of lower stringency conditions suitable for screening for nucleic acids encoding hWARTs polypeptides are provided in Abe, et al. J. Biol. Chem. 19:13361, 1992 (hereby incorporated by reference herein in its entirety, including any drawings). Preferably, conserved regions differ by no more than 5 out of 20 contiguous nucleotides.
By xe2x80x9cunique nucleic acid regionxe2x80x9d it is meant a sequence present in a full length nucleic acid coding for an hWART polypeptide that is not present in a sequence coding for any other known naturally occurring polypeptide. Such regions preferably comprise 14, 17, 21 or more contiguous nucleotides present in the full length nucleic acid encoding an hWART polypeptide. In particular, a unique nucleic acid region is preferably of human origin.
In yet another aspect, the invention relates to a nucleic acid vector comprising a nucleic acid molecule encoding an hWART polypeptide and a promoter element effective to initiate transcription in a host cell.
The term xe2x80x9cnucleic acid vectorxe2x80x9d relates to a single or double stranded circular nucleic acid molecule that can be transfected or transformed into cells and replicate independently or within the host cell genome. A circular double stranded nucleic acid molecule can be cut and thereby linearized upon treatment with restriction enzymes. An assortment of vectors, restriction enzymes, and the knowledge of the nucleotide sequences that the restriction enzymes operate upon are readily available to those skilled in the art. A nucleic acid molecule of the invention can be inserted into a vector by cutting the vector with restriction enzymes and ligating the two pieces together.
Many techniques are available to those skilled in the art to facilitate transformation or transfection of the expression construct into a prokaryotic or eukaryotic organism. The terms xe2x80x9ctransformationxe2x80x9d and xe2x80x9ctransfectionxe2x80x9d refer to methods of inserting an expression construct into a cellular organism. These methods involve a variety of techniques, such as treating the cells with high concentrations of salt, an electric field, or detergent, to render the host cell outer membrane or wall permeable to nucleic acid molecules of interest.
The term xe2x80x9cpromoter elementxe2x80x9d describes a nucleotide sequence that is incorporated into a vector that, once inside an appropriate cell, can facilitate transcription factor and/or polymerase binding and subsequent transcription of portions of the vector DNA into mRNA. The promoter element precedes the 5xe2x80x2 end of the hWART nucleic acid molecule such that the latter is transcribed into mRNA. Host cell machinery then translates mRNA into a polypeptide.
Those skilled in the art would recognize that a nucleic acid vector can contain many other nucleic acid elements besides the promoter element and the hWART nucleic acid molecule. These other nucleic acid elements include, but are not limited to, origins of replication, ribosomal binding sites, nucleic acid sequences encoding drug resistance enzymes or amino acid metabolic enzymes, and nucleic acid sequences encoding secretion signals, periplasm or peroxisome localization signals, or signals useful for polypeptide purification.
The invention also features a nucleic acid probe for the detection of a nucleic acid encoding an hWART polypeptide in a sample.
The term xe2x80x9cnucleic acid probexe2x80x9d refers to a nucleic molecule that is complementary to and can bind a nucleic acid sequence encoding the amino acid sequence substantially similar to that set forth in SEQ ID NO:3, or SEQ ID NO:4.
In preferred embodiments, the nucleic acid probe hybridizes to nucleic acid molecules encoding at least 46 contiguous amino acids of the sequences set forth in SEQ ID NO:3, SEQ ID NO:4, or a functional derivative thereof. Various low or high stringency hybridization conditions may be used depending upon the specificity and selectivity desired. Under highly stringent hybridization conditions only highly complementary nucleic acid sequences hybridize. Preferably, such conditions prevent hybridization of nucleic acids having 1 or 2 mismatches out of 20 contiguous nucleotides.
Methods for using the probes include detecting the presence or amount of hWART RNA in a sample by contacting the sample with a nucleic acid probe under conditions such that hybridization occurs and detecting the presence or amount of the probe bound to hWART RNA. The nucleic acid duplex formed between the probe and a nucleic acid sequence coding for an hWART polypeptide may be used in the identification of the sequence of the nucleic acid detected (for example see, Nelson et al., in Nonisotopic DNA Probe Techniques, p. 275 Academic Press, San Diego (Kricka, ed., 1992) hereby incorporated by reference herein in its entirety, including any drawings). Kits for performing such methods may be constructed to include a container having disposed therein a nucleic acid probe.
The invention also features a nucleic acid molecule as set forth in SEQ ID NO:l or SEQ ID NO:2 or fragments thereof, comprising one or more regions that encode an hWART polypeptide or an hWART domain polypeptide, where the hWART polypeptide or the hWART domain polypeptide is fused to a non-WART polypeptide. Such fused polypeptides include, for example, but are not limited to, a GST-fusion protein.
The invention also features recombinant nucleic acid, preferably in a cell or an organism. The recombinant nucleic acid may contain a sequence set forth in SEQ ID NO:1, SEQ ID NO:2, or a functional derivative thereof and a vector or a promoter effective to initiate transcription in a host cell. The recombinant nucleic acid can alternatively contain a transcriptional initiation region functional in a cell, a sequence complimentary to an RNA sequence encoding an hWART polypeptide and a transcriptional termination region functional in a cell.
Another aspect of the invention relates to a recombinant cell or tissue comprising a nucleic acid molecule encoding an hWART polypeptide. The recombinant cell may comprise a nucleic acid molecule encoding either an hWART polypeptide; an hWART domain polypeptide; or an hWART polypeptide or hWART domain polypeptide fused to a non-WART polypeptide.
The term xe2x80x9crecombinant organismxe2x80x9d refers to an organism that has a new combination of genes or nucleic acid molecules. A new combination of genes or nucleic acid molecules can be introduced to an organism using a wide array of nucleic acid manipulation techniques available to those skilled in the art.
The term xe2x80x9corganismxe2x80x9d relates to any living being comprised of a least one cell. An organism can be as simple as one eukaryotic cell or as complex as a mammal. Therefore, a recombinant organism can also be a recombinant cell.
The recombinant cell can be a eukaryotic or prokaryotic organism.
The term xe2x80x9ceukaryotexe2x80x9d refers to an organism comprised of cells that contain a nucleus. Eukaryotes are differentiated from xe2x80x9cprokaryotesxe2x80x9d which do not have a nucleus and lack other cellular structures found in eukaryotes, such as mitochondria and endoplasmic reticulum. Prokaryotes include unicellular organisms, such as bacteria while eukaryotes are represented by yeast, invertebrates, and vertebrates.
The recombinant cell can harbor a nucleic acid vector that is extragenomic. The term xe2x80x9cextragenomicxe2x80x9d refers to a nucleic acid vector which does not insert into the cell genome. Many nucleic acid vectors are designed with their own origins of replication allowing them to utilize the recombinant cell replication machinery to copy and propagate the vector nucleic acid sequence. These vectors are small enough that they are not likely to harbor nucleic acid sequences homologous to genomic sequences of the recombinant cell. Thus these vectors replicate independently of the host genome and do not recombine with or integrate into the genome.
A recombinant cell can harbor a portion of a nucleic acid vector in an intragenomic fashion. The term xe2x80x9cintragenomicxe2x80x9d defines a nucleic acid construct that is incorporated within the cell genome. Multiple nucleic acid vectors available to those skilled in the art contain nucleic acid sequences that are homologous to nucleic acid sequences in a particular organism""s genomic DNA. These homologous sequences will result in recombination events that integrate portions of the vector into the genomic DNA. Those skilled in the art can control which nucleic acid sequences of the vector are integrated into the cell genome by flanking the portion to be incorporated into the genome with homologous sequences in the vector.
Another aspect of the invention features an isolated, enriched, or purified hWART polypeptide.
By xe2x80x9chWART polypeptidexe2x80x9d it is meant an amino acid sequence substantially similar to the sequence shown in SEQ ID NO:3, SEQ ID NO:4, or fragments thereof. A sequence that is substantially similar will preferably have at least 90% identity (more preferably at least 95% and most preferably 99-100%) to the sequence of SEQ ID NO:3 or SEQ ID NO:4.
The hWART polypeptides of the present invention preferably have a substantially similar biological activity to the proteins encoded by the full length nucleic acid sequence set forth in SEQ ID NO:1 or SEQ ID NO:2, or to the proteins with amino acid sequence set forth in SEQ ID NO:3 or SEQ ID NO:4. By xe2x80x9cbiological activityxe2x80x9d it is meant an activity of the hWART protein in a cell. The biological activity of the hWART is related to some of the activities of the cell which include, but are not limited to, cell proliferation motogenesis, metastasis, tumor escape, cell adhesion, transformation, or apoptosis.
By xe2x80x9cidentityxe2x80x9d is meant a property of sequences that measures their similarity or relationship. Identity is measured by dividing the number of identical residues in the two sequences by the total number of residues and multiplying the product by 100. Thus, two copies of exactly the same sequence have 100% identity, but sequences that are less highly conserved and have deletions, additions, or replacements have a lower degree of identity. Those skilled in the art will recognize that several computer programs are available for determining sequence identity.
By xe2x80x9cisolatedxe2x80x9d in reference to a polypeptide is meant a polymer of 6, 12, 18 or more amino acids conjugated to each other, including polypeptides that are isolated from a natural source or that are synthesized. The isolated polypeptides of the present invention are unique in the sense that they are not found in a pure or separated state in nature. Use of the term xe2x80x9cisolatedxe2x80x9d indicates that a naturally occurring sequence has been removed from its normal cellular environment. Thus, the sequence may be in a cell-free solution or placed in a different cellular environment. The term does not imply that the sequence is the only amino acid chain present, but that it is essentially free (about 90-95% pure at least) of material naturally associated with it.
By the use of the term xe2x80x9cenrichedxe2x80x9d in reference to a polypeptide it is meant that the specific amino acid sequence constitutes a significantly higher fraction (2-5 fold) of the total of amino acids present in the cells or solution of interest than in normal or diseased cells or in the cells from which the sequence was taken. This could be caused by a person by preferential reduction in the amount of other amino acids present, or by a preferential increase in the amount of the specific amino acid sequence of interest, or by a combination of the two. However, it should be noted that xe2x80x9cenrichedxe2x80x9d does not imply that there are no other amino acid sequences present, just that the relative amount of the sequence of interest has been significantly increased. The term significant here is used to indicate that the level of increase is useful to the person making such an increase, and generally means an increase relative to other amino acids of about at least 2 fold, more preferably at least 5 to 10 fold or even more. The term also does not imply that there is no amino acid from other sources. The other source amino acid may, for example, comprise amino acid encoded by a yeast or bacterial genome, or a cloning vector such as pUC19. The term is meant to cover only those situations in which a person has intervened to elevate the proportion of the desired nucleic acid.
It is also advantageous for some purposes that an amino acid sequence be in purified form. The term xe2x80x9cpurifiedxe2x80x9d in reference to a polypeptide does not require absolute purity (such as a homogeneous preparation); instead, it represents an indication that the sequence is relatively purer than in the natural environment (compared to the natural level this level should be at least 2-5 fold greater, e.g., in terms of mg/mL. Purification of at least one order of magnitude, preferably two or three orders, and more preferably four or five orders of magnitude is expressly contemplated. The substance is preferably free of contamination at a functionally significant level, for example 90%, 95%, or 99% pure.
In another aspect, the invention features an isolated, enriched, or purified hWART polypeptide fragment.
By xe2x80x9chWART polypeptide fragmentxe2x80x9d it is meant an amino acid sequence that is less than the full-length amino acid sequence. The full-length amino acid sequences of hWART1 and hWART2 are shown in SEQ ID NO:3 and SEQ ID NO:4. Examples of fragments include hWART domains, hWART mutants and hWART-specific epitopes.
By xe2x80x9chWART domainxe2x80x9d it is meant a portion of the hWART polypeptide having homology to amino acid sequences from one or more known proteins wherein the sequence predicts some common function, interaction or activity. Well known examples of domains are the SH2 (Src Homology 2) domain (Sadowski, et al, Mol. Cell. Biol. 6:4396, 1986; Pawson and Schlessinger, Curr. Biol. 3:434, 1993), the SH3 domain (Mayer, et al, Nature 332:272, 1988; Pawson and Schlessinger, Curr. Biol. 3:434, 1993), and pleckstrin (PH) domain (Ponting, TIBS 21:245, 1996; Haslam, et al, Nature 363:309, 1993), all of which are domains that mediate protein:protein interaction or protein:lipid interaction, and the kinase catalytic domain (Hanks and Hunter, FASEB J 9:576-595, 1995). Computer programs designed to detect such homologies are well known in the art. The relative homology is at least 20%, more preferably at least 30% and most preferably at least 35%.
By xe2x80x9chWART mutantxe2x80x9d it is meant an hWART polypeptide which differs from the native sequence in that one or more amino acids have been changed, added or deleted. Changes in amino acids may be conservative or non-conservative. By xe2x80x9cconservativexe2x80x9d it is meant the substitution of an amino acid for one with similar properties such as charge, hydrophobicity, structure, etc. Examples of polypeptides encompassed by this term include, but are not limited to, (1) chimeric proteins which comprise a portion of an hWART polypeptide sequence fused to a non-hWART polypeptide sequence, for example, a polypeptide sequence of hemmaglutinin (HA), (2) hWART proteins lacking a specific domain, for example the catalytic domain, and (3) hWART proteins having a point mutation. An hWART mutant will retain some useful function such as, for example, binding to a natural binding partner, catalytic activity, or the ability to bind to an hWART specific antibody (as defined below).
By xe2x80x9chWART-specific epitopexe2x80x9d it is meant a sequence of amino acids that is both antigenic and unique to an hWART polypeptide. An hWART-specific epitope can be used to produce hWART-specific antibodies, as more fully described herein. Particularly preferred epitopes are shown in the Examples section below.
By xe2x80x9crecombinant hWART polypeptidexe2x80x9d it is meant to include a polypeptide produced by recombinant DNA techniques such that it is distinct from a naturally occurring polypeptide either in its location (e.g., present in a different cell or tissue than found in nature), purity or structure. Generally, such a recombinant polypeptide will be present in a cell in an amount different from that normally observed in nature.
The polypeptide of the invention comprises an amino acid sequence having (a) the full length amino acid sequence set forth in SEQ ID NO:3 or SEQ ID NO:4; (b) the full length amino acid sequence of the sequence set forth in SEQ ID NO:3 or SEQ ID NO:4, except that it lacks one or more of the following segments of amino acid residues:12-45, 55-151, 236-377, 404-520, 555-559, 601-702, 691-998, 1011-1086 of SEQ ID NO:3, or 1-33, 43-139, 342-466, 467-480, 514-518, 974-1048 of SEQ ID NO:4; (c) the amino acid sequence set forth in SEQ ID NO:3 or SEQ ID NO:4 from amino acid residues 12-45, 55-151, 236-377, 404-520, 555-559, 601-702, 691-998, 1011-1086 of SEQ ID NO:3, or 1-33, 43-139, 342-466, 467-480, 514-518, 974-1048 of SEQ ID NO:4; or (d) the full length amino acid sequence set forth in SEQ ID NO:3 or SEQ ID NO:4 except that it lacks one or more of the domains selected from the group consisting of an N-terminal domain, a catalytic domain, and a C-terminal domain.
In yet another aspect, the invention features an antibody (e.g., a monoclonal or polyclonal antibody), or antibody fragment, having specific binding affinity to an hWART polypeptide or hWART polypeptide fragment.
By xe2x80x9cspecific binding affinityxe2x80x9d is meant that the antibody binds to target (hWART) polypeptides with greater affinity than it binds to other polypeptides under specified conditions. Antibodies having specific binding affinity to an hWART polypeptide may be used in methods for detecting the presence and/or amount of an hWART polypeptide in a sample by contacting the sample with the antibody under conditions such that an immunocomplex forms and detecting the presence and/or amount of the antibody conjugated to the hWART polypeptide. Diagnostic kits for performing such methods may be constructed to include a first container containing the antibody and a second container having a conjugate of a binding partner of the antibody and a label, such as, for example, a radioisotope. The diagnostic kit may also include notification of an FDA approved use and instructions therefor.
The term xe2x80x9cpolyclonalxe2x80x9d refers to antibodies that are heterogenous populations of antibody molecules derived from the sera of animals immunized with an antigen or an antigenic functional derivative thereof. For the production of polyclonal antibodies, various host animals may be immunized by injection with the antigen. Various adjuvants may be used to increase the immunological response, depending on the host species.
xe2x80x9cMonoclonal antibodiesxe2x80x9d are substantially homogenous populations of antibodies to a particular antigen. They may be obtained by any technique which provides for the production of antibody molecules by continuous cell lines in culture. Monoclonal antibodies may be obtained by methods known to those skilled in the art. See, for example, Kohler, et al., Nature 256:495-497 (1975), and U.S. Pat. No. 4,376,110.
The term xe2x80x9cantibody fragmentxe2x80x9d refers to a portion of an antibody, often the hypervariable region and portions of the surrounding heavy and light chains, that displays specific binding affinity for a particular molecule. A hypervariable region is a portion of an antibody that physically binds to the polypeptide target.
In another aspect, the invention features a hybridoma which produces an antibody having specific binding affinity to an hWART polypeptide. By xe2x80x9chybridomaxe2x80x9d is meant an immortalized cell line which is capable of secreting an antibody, for example an hWART antibody. In preferred embodiments the hWART antibody comprises a sequence of amino acids that is able to specifically bind an hWART polypeptide.
The invention features a method for identifying human cells containing an hWART polypeptide, or a related sequence. The method involves identifying the novel polypeptide in human cells using techniques that are routine and standard in the art, such as those described herein for identifying hWART polypeptides (e.g., cloning, Southern or Northern blot analysis, in situ hybridization, PCR amplification, etc.).
The invention also features methods of screening cells for natural binding partners of hWART polypeptides. By xe2x80x9cnatural binding partnerxe2x80x9d it is meant a protein that interacts with an hWART polypeptide. Binding partners include ligands, agonists, antagonists and downstream signaling molecules such as adaptor proteins and may be identified by techniques well known in the art such as co-immunoprecipitation or by using, for example, a two-hybrid screen. (Fields and Song, U.S. Pat. No. 5,283,173, issued Feb. 1, 1994 and, incorporated be reference herein.) The present invention also features the purified, isolated or enriched versions of the polypeptides identified by the methods described above.
In another aspect, the invention provides a method for identifying a substance capable of modulating hWART activity comprising the steps of (a) contacting an hWART polypeptide with a test substance; and (b) determining whether the substance alters the activity of said polypeptide.
The invention also features another method of identifying substances capable of modulating the function of an hWART polypeptide. The method comprises the following steps: (a) expressing an hWART polypeptide in cells; (b) adding a compound to the cells; and (c) monitoring a change or an absence of a change in cell phenotype, cell proliferation, catalytic activity of the hWART polypeptide, and binding a natural binding partner.
The term xe2x80x9ccompoundxe2x80x9d includes small organic molecules including, but not limited to, oxindolinones, quinazolines, tyrphostins, quinoxalines, and those contained within extracts from natural sources. Examples of such compounds are included in section XIII, below.
The term xe2x80x9cfunctionxe2x80x9d refers to the cellular role of a serine-threonine protein kinase. The serine-threonine protein kinase family includes members that regulate many steps in signaling cascades, including cascades controlling cell growth, migration, differentiation, gene expression, muscle contraction, glucose metabolism, cellular protein synthesis, and regulation of the cell cycle.
The term xe2x80x9cmodulatesxe2x80x9d refers to the ability of a compound to alter the function of a protein kinase. A modulator preferably activates the catalytic activity of a protein kinase, more preferably activates or inhibits the catalytic activity of a protein kinase depending on the concentration of the compound exposed to the protein kinase, or most preferably inhibits the catalytic activity of a protein kinase.
The term xe2x80x9ccatalytic activityxe2x80x9d, in the context of the invention, defines the ability of a protein kinase to phosphorylate a substrate. Catalytic activity can be measured, for example, by determining the amount of a substrate converted to a product as a function of time. Phosphorylation of a substrate occurs at the active-site of a protein kinase. The active-site is normally a cavity in which the substrate binds to the protein kinase and is phosphorylated.
The term xe2x80x9csubstratexe2x80x9d as used herein refers to a molecule that is phoshorylated by or directly interacts with the protein kinase. The substrate is preferably a peptide and more preferably a protein. In relation to the protein kinase RAF, preferred substrates are MEK and the MEK substrate MAPK.
The term xe2x80x9cactivatesxe2x80x9d refers to increasing the cellular function of a protein kinase. The protein kinase function is preferably the interaction with a natural binding partner or catalytic activity.
The term xe2x80x9cinhibitxe2x80x9d refers to decreasing the cellular function of a protein kinase. The protein kinase function is preferably the interaction with a natural binding partner or catalytic activity.
The term xe2x80x9cmodulatesxe2x80x9d also refers to altering the function of a protein kinase by increasing or decreasing the probability that a complex forms between a protein kinase and a natural binding partner. A modulator preferably increases the probability that such a complex forms between the protein kinase and the natural binding partner, more preferably increases or decreases the probability that a complex forms between the protein kinase and the natural binding partner depending on the concentration of the compound exposed to the protein kinase, and most preferably decreases the probability that a complex forms between the protein kinase and the natural binding partner.
The term xe2x80x9ccomplexxe2x80x9d refers to an assembly of at least two molecules bound to one another. Signal transduction complexes often contain at least two protein molecules bound to one another, either transiently or in succession. For instance, a receptor protein tyrosine kinase, GRB2, SOS, and RAF sequentially interact in response to a mitogenic ligand.
The term xe2x80x9cexpressingxe2x80x9d as used herein refers to the production of an hWART polypeptide from a nucleic acid vector containing an hWART gene within a cell. The nucleic acid vector is transfected into cells using well known techniques in the art as described herein.
The term xe2x80x9caddingxe2x80x9d as used herein refers to administering a solution comprising a compound to the medium bathing cells. The solution comprising the compound can also comprise an agent, such as dimethyl sulfoxide, which facilitates the uptake of the compound into the cells.
The term xe2x80x9cmonitoringxe2x80x9d refers to observing the effect of adding the compound to the cells of the method. The effect can be manifested in a change in cell phenotype, cell proliferation, protein kinase catalytic activity, or in the interaction between a protein kinase and a natural binding partner.
The term xe2x80x9ccell phenotypexe2x80x9d refers to the outward appearance of a cell or tissue or the function of the cell or tissue. Examples of cell or tissue phenotype are cell size (reduction or enlargement), cell proliferation (increased or decreased numbers of cells), cell differentiation (a change or absence of a change in cell shape), cell survival, apoptosis (cell death), or the utilization of a metabolic nutrient (e.g., glucose uptake). Changes or the absence of changes in cell phenotype are readily measured by techniques known in the art.
The term xe2x80x9ccell proliferationxe2x80x9d refers to the rate at which a group of cells divides. The number of cells growing in a vessel can be quantitated by a person skilled in the art when that person visually counts the number of cells in a defined area using a comon light microscope. Alternatively, cell proliferation rates can be quantitated by laboratory apparatae that optically measure the density of cells in an appropriate medium.
The method can utilize any of the molecules disclosed in the invention. These molecules include nucleic acid molecules encoding hWART polypeptides, nucleic acid vectors, recombinant cells, polypeptides, or antibodies of the invention.
Substances identified as modulators of hWART activity can be used to study the effects of hWART modulation in animal models of cell proliferative disorders. For example, inhibitors of hWART activity can be tested as treatments for cell proliferative disorders such as leukemia or lymphoma using subcutaneous xenograph models in mice.
In a preferred embodiment, the invention provides a method for treating or preventing an abnormal condition by administering a compound which is a modulator of hWART function in vitro. The abnormal condition preferably involves abnormality in hWART signal transduction pathway, and most preferably is cancer. Such compounds preferably show positive results in one or more in vitro assays for an activity corresponding to treatment of the disease or disorder in question (such as the assays described in example 9 below). Examples of substances that can be screened for favorable activity are provided in section XIII below.
The summary of the invention described above is non-limiting and other features and advantages of the invention will be apparent from the following detailed description, and from the claims.


The present disclosure discloses a data push method and device, a storage medium, and an electronic device. The method includes: acquiring to-be-pushed data and identifier information of the to-be-pushed data, the identifier information of the to-be-pushed data uniquely identifies the to-be-pushed data; and pushing the to-be-pushed data if indication information is not stored at a target storage location in a storage space, the target storage location comprising a storage location corresponding to the identifier information of the to-be-pushed data, and the indication information indicating identifier information of data that had been pushed.

Identifier information (docId) of articles is cached directly in existing solutions for storing data push history. Internet users have increasingly demanded for latest feeds in this era of information explosion. Data push applications attract users by the important factors of efficiency and real-time performance of pushing relevant data to the users. The retention rate of users decreases if users keep seeing same feeds repetitively when refreshing data or failing to refresh data. Therefore, when data is pushed to users, efficient filtering of historical pushed data is critical to retention of users.

Data push method and device, storage medium, and electronic device

TENCENT TECHNOLOGY (SHENZHEN) COMPANY LIMITED


EL light emitting device includes a cylindrical EL light emitting unit and a columnar power feeding unit. EL light emitting unit is composed such that a cylindrical receiver coil is arranged and connected along an inner circumferential face of the cylindrical EL light emitting element and integrated into a single body by an outer cover member. The power feeding unit is formed in a columnar shape whose diameter is smaller than an inner diameter of EL light emitting unit so that the power feeding unit can be inserted into the cylindrical EL light emitting unit. When the power feeding unit is inserted into EL light emitting unit and the power feeding unit is impressed with an alternating voltage, a high alternating voltage corresponding to the turn rate of both coils is generated in the receiver coil, so that light can be emitted from EL light emitting element.

1. Field of the Invention
The present invention relates to an EL light emitting device for driving an EL light emitting element so that the EL light emitting element can emit light when electric power is electromagnetically induced in a receiver coil by supplying an electric current to a feeder coil. Further, the present invention relates to an EL light emitting unit having a receiver coil and an EL light emitting element effectively used for the EL light emitting device. Furthermore, the present invention relates to a power feeding unit having a feeder coil and a power feeding section.
2. Description of Related Art
The EL light emitting element is a self-light-emitting element characterized in that the thickness is small and the visibility is high. Therefore, it is expected that the EL light emitting element will be applied to various uses. In fact, the EL light emitting element is put into practical use in some technical fields.
For example, Japanese Patent Publication No. JP-A-2002-215069 discloses an electric decoration poster on which displaying is conducted by the combination of an EL element light emitting body with a film. In this electric decoration poster, the EL element light emitting body and the film are combined with each other, and an image on the film is distinctly seen when light is emitted from the EL element light emitting body.
In general, in some cases, the use of the EL element in the open air, which includes the electric decoration poster disclosed in JP-A-2002-215069, is limited, and further the use of the EL element to a toy is limited for the reasons of safety.
Specifically, the problems are described as follows. Since a high voltage is required for driving the EL element and the driving is conducted by AC power, it is necessary to pay the maximum attention to the prevention of an electric shock caused by an imperfect circuit, wiring or connecting section.
Concerning the means for supplying power to the EL element, it is common to use the means of using a connector or socket or the means of soldering, that is, it is common to use the means of supplying power by a mechanical contact. When the above means are adopted, mechanical stress is concentrated on the connecting portion in which the EL element is connected to the electrode section.

EL light emitting unit, power feeding unit and EL light emitting device


A transfer system for food products (P) having a product conveyor (11); a first support conveyor (13) suitable for moving supports (12) in equicurrent with the food products (P); a plurality of pickers (R1, R2, R3) situated in series along the run of the products (P) and supports (12) for individually collecting the products (P) from the product conveyor (11) to arrange them on the supports (12) translated from the first support conveyor (13); presence and position surveying devices (C1, C2) of which at least one is situated upstream with respect to the food products (P), of a first picker (R1) of the plurality of pickers (R1, R2, R3) suitable for detecting the presence, number, position and orientation of each product (P); an electronic image with a presence and position surveying device (C3), also connected to an electronic image identification and data processing system (34), wherein the pickers (R1–R4) are equipped with handlers (22) with an individual grip of the sucker type, with an anti-crash system and a suction circuit.

The present invention relates to a food product transfer system by means of pickers.
More specifically, the invention relates to a transfer system of food products using pickers which collect the products moving along a line to transfer them to supports also running on transport lines.
Product handling systems and equipment of this type are known in the technique of canning plants, as they allow the automation of canning operations.
A plant of the above-mentioned type is the object of European patent 0 856 465 in the name of Gerhard Schubert GmbH.
The equipment object of European patent 0 856 465 belongs to the area of product handling systems by means of pickers for transferring the same from a feeding line to a support system.
Object of the invention, according to the Schubert patent, is to provide a process and related equipment for reducing the time lost for handling supports to be filled, without jeopardizing the plant efficiency.
This object is achieved, according to the patent disclosure, thanks to the fact that                supports and products move in counter-current; and        the support velocity is adjusted according to the products in movement.
The above-mentioned Schubert European patent asserts the impossibility of transferring the disclosure of technological control measures for equicurrent transport systems to counter-current systems: as the diminishing of products on the conveyor belt, on one side, and the filling level of supports on the conveyor belt, on the other side, develop in a reciprocally inverse way.
Even if the equipment according to the Schubert patent provides a rational solution to the problem of product transfer, it has various drawbacks.
First of all, the handling of the transfer in counter-current, from the point of view of the concomitant optimisation of high productivity and minimum waste, both in terms of partially filled supports and non-collected products, appears rather problematical in the regulation, and cannot be used in the case of different products.
Another drawback of a logistic type is linked to the arrangement of the equipment and machinery which, in the case of the counter-current system, can create ties which may not fit in with the planimetry of the facility housing the plant.
A general objective of the present invention is, therefore, to provide a system for the transfer of food products by means of pickers, running in equicurrent, suitable for operating at high speeds, with minimum or null waste products.
Another objective of the present invention is to allow a simple control and management of the system.
Also within the objectives of the present invention, is the provision of a packaging plant which makes use of the transfer system of food products by means of pickers.

Transfer system of food products by means of pickers


An information processing device includes a memory, and a processor coupled to the memory and configured to acquire a plurality of data from first databases, where the data are stored in the first databases in a first period, and identifiers are stored in the first databases in association with the data, where the first databases correspond to servers that perform manipulations on a plurality of records containing the data stored in a second database, and the identifiers indicate order of the manipulations, and store the data in a third database in order indicated by the identifiers.

To distribute the load when a database is referenced, a database to which the contents of the database are replicated may be created. In this case, the replication source database is called a master database (DB), and the replication destination database is called a replica DB.
When there are multiple client terminals referencing the database, the load distribution of the master DB can be achieved by having the client terminals reference not only the master DB but also the replica DB.
However, in the system using the replica DB, there is room for improvement in reduction in the response time when replicating the master DB to the replica DB. Note that the technique related to the present disclosure is also disclosed in Japanese Laid-Open Patent Publication Nos. H11-167510 and H10-49416.

Information processing device and information processing system


The invention relates to a vibration generator which is used in devices, such as mobile phones, requiring a vibration mode. More specifically, the invention relates to a horizontal vibration type vibration generator which includes a casing that is open on one surface thereof, a vibration part having a weight provided inside the casing, and a spring mounted inside the casing, and which produces horizontal vibration by using the phenomenon of resonance which occurs by causing oscillation in an electromagnetic force having the same frequency as the intrinsic vibration frequency of the spring, and which solves the problem of a reduction in the life span of the vibration generator due to mechanical friction as seen in existing mechanical vibration generators, and generates a large vibration force despite having a thin construction unachievable in a vertical moving type vibration generator. The invention also relates to a production method of the vibration generator.

In the related art, examples of vibration generators used in devices, such as mobile phones, requiring a vibration mode are a vibration motor in which an eccentric type or eccentric mass type weight is installed in a brush DC motor, a BLOC vibration motor in which an eccentric type weight is installed in a rotor, a coin type vibration motor, a vertical vibration motor using resonance, etc. However, the related art vibration generators are problematic in that they cannot efficiently realize certain requirements, such as long life span, reliability, thinness, and high vibration force that are required by devices such as mobile phones.
For example, the vibration generators using the brush DC motors are problematic in that when a brush passes through a gap between segments of a commutator, the brush induces mechanical friction, electric sparks, and abrasion, thereby producing impurities and reducing the expected life span of the vibration generators.
Further, in an effort to overcome the problems of the vibration generators using the brush DC motors, the vertical vibration motors that move upward and downward using resonance can generate resonance vibration in a moving assembly having both a spring and a weight by causing oscillation in an electromagnetic force due to a mutual interaction between the electromagnetic force and a magnetic field. However, the vertical vibration motors are mechanically problematic in that they have a vertically moving mechanism using an elastic body, and so they inevitably require a mechanical space in which the vibration generators can move upward and downward, and this hinders any efforts to reduce the height of the vibration generator.
Further, in the related art, to install various types of vibration motors in limited spaces of devices such as mobile phones, it is required to form an additional space in the devices for receiving a power supply unit provided in a protruding terminal of the vibration motor. Another problem of the related art vibration motor resides in that it is required to connect a lead wire to an external power supply. Here, to electrically connect the lead wire to the external power supply, soldering is used. However, the connection using soldering is problematic in that it may be poorly soldered, a wire may be broken, or a short may occur. Another problem of the connection using soldering resides in that wiring is difficult to be use because of a limited space.

Vibrator for generating horizontal vibration


A single piece of pipe connectable to a similar adjacent pipe and including a female end that is reinforced with a band. The pipe includes in one embodiment a male end having external threads, a female end having an enlarged exterior diameter, a first section at the female end having an interior diameter to receive a male end of the similar adjacent pipe, a second section at the female end having internal threads to mate with the external threads of the male end of the similar adjacent pipe. The first section is positioned to funnel the male end of the similar adjacent pipe to the second section, and the second section is positioned between an intermediate section and the first section. At least one reinforcement band is positioned circumferentially around at least a portion of the female end. The pipe is disconnectable from the similar adjacent pipe and reusable.

1. Field of the Invention
The present invention relates generally to threaded, submersible pump drop pipe and casing assembly connection and method of manufacture for use in water well and related systems.
2. Description of the Related Art
Piping systems with threaded connections are well known in the art. Threaded connections connect lengths of pipe using internal threads on the female end of a pipe that interlock with external threads on the male end of a similar adjacent pipe.
During manufacturing of the pipe, external threads are machined into the male end of the pipe and internal threads are machined into the female end of the pipe, typically through automated cutting processes. The shape of the threads, or "thread profile," can vary greatly and often depends on the particular application of the pipe. For example, triangular threads, square threads, rounded threads, and even trapezoidal threads are well known in the art.
Another thread characteristic that depends on the application of the pipe is whether the threads are machined on a pitch as the threads extend away from the leading edge of the pipe. Threads cut on a pitch, called "tapered threads," create a pipe with a gradually changing circumference as the threads extend away from the leading edge of the pipe. As such, for example, the outer circumference of a male end of a pipe with tapered threads increases as the threads extend away from the male leading edge of the pipe, causing the male end of the pipe to be generally shaped as a truncated cone.
Pipes with tapered threads are well known in the art and offer certain advantages over pipes with non-tapered threads (i.e., threads not cut on a pitch). For example, specific types of tapered threads such as NPTF threads (also known as Dryseal threads) are used in many piping applications to create watertight (or fluid tight) connections without requiring a sealing compound. The watertight connection is formed through a mechanical seal when the internal threads of the female end of a pipe deform into the external threads of the male end of an adjacent pipe (and vice versa) during tightening of the threaded connection.
Tapered threads also have a disadvantage in that care must be taken not to apply too much torque so as to overtighten the connection. Threaded connections with tapered threads are considered "hand-tight" (also known as "finger-tight") at the point when the male end of the pipe can no longer thread into the female end of an adjacent pipe by hand because the taper on the threads has caused the male end to become jammed within the female end. From hand-tight, a wrench is used to turn at least one of the connected pipes, making the connection "wrench-tight." Wrench-tight is generally accepted as being a maximum of two turns past hand-tight.
If one is not careful the threaded connection can be overtightened past wrench-tight and threaten the integrity of the connection. Overtightening the connection causes hoop stress on the female end of the pipe which, when large enough, will split the female end and cause a failed connection. Hoop stress is a problem with tapered threads that is well known in the art and often occurs near the last internal threads—i.e., the internal threads furthest away from the female leading edge of the pipe—although the failure can occur elsewhere on the female end.
Another problem for threaded connections is lateral stress failure of the connection due to lateral forces on the pipe and/or the connection. Although pipes with tapered threads are susceptible to lateral stress failure, this type of failure most frequently occurs on pipes with non-tapered internal threads (i.e., threads that are not cut on a pitch) within the female end of the pipe. Lateral stress failure usually occurs because the manufacturing process for forming the internal threads weakens the pipe wall. Non-tapered internal threads, as well as tapered internal treads, are typically formed in the interior wall of the pipe at the female end by cutting out a portion of the pipe wall. Removing material from the pipe wall decreases the wall thickness and makes the female end of the pipe more prone to lateral stress failure.
Lateral stress failure often occurs near the first internal threads—i.e., where the internal threads begin, near the female leading edge of the pipe—but can also occur elsewhere on the female end. In addition, the amount of threads cut into the female end of a pipe can increase its susceptibility to failure from lateral forces and pipes with more threads have a greater tendency to fail. As a result, a need also exists for strengthening pipes that use threaded connections to increase their resistance against lateral stress failure.


A compact chromatic display system to be used by a viewer to view a virtual image including: (a) an output optical device, which enables the viewer to see through it a chromatic virtual image. (b) an input optical device. (c) an optical arrangement for directing light from the input optical device to the output optical device and (d) a Shift Adjusted Display (SAD) device that radiates chromatic image.

The present invention relates to a holographic planar optic display system and, in particular, to a multi chromatic holographic planar optic display system, which employs a planar optic approach, and which include a Shift Adjusted Display (SAD) device.
As used herein the specifications and claims, the term Shift Adjusted Display (SAD) device refers to a device that performs electronic diversion of input image pixels to the Chromatic Planar Optic Display System, for the purpose of improving the output display image as a result of distorted optic transformation, which is unwanted in the optic display system.
There are a wide variety of display systems for visual radiation of a video image to the user's eyes. The video image can reach the display system from a wide range of sources, such as video cameras, DVD, VCR, computers, and receiver antennas, as a video signal in wire or wireless communication.
These video signals are command signals for the recreation of the image display using a light-radiating device. Light-radiating display devices are based on technologies such as: Cathode Ray Tube (CRT), Light Emitting Diode (LED), Liquid Crystal Display (LCD), Passive Matrix LCD (PMLCD), Active Matrix LCD (AMLCD), Active Matrix Electro-Luminescent display (AMEL), Micro-Electro Mechanical display (MEM), Thin Film Transistors (TFT), Light Doped Drain (LDD), Liquid Crystal On Silicon (LCOS), Ferroelectric LCD (FLC).
Examples of application of these devices are television sets, computer screens, billboards, wristwatches, handheld computers, cellular phones, etc. However, there still are certain situations in which looking directly at a display screen is insufficient. Such situations include Head Up Display (HUD) and Visor Display, in aircraft and other vehicles in which the outer world is seen through image display, or in Head Mounted Display (HMD), in which the system is small to the extent that the eye is unable to focus on the image, on account of the distance between the eye and the screen being too short.
A displayed image may be either a real image or a virtual image. A real image refers to an image, which is observed directly by the unaided human eye, displayed by a viewing surface positioning at a given place. Compact display devices, due to their small size, have a limited surface area on which a real image can be provided. Since the amount of detail that the human eye can resolve per unit of area is limited, devices, which provide a real image, are only capable to providing a limited amount of legible information per display screen.
Due to current technological trends and developments, there is a growing demand for a mobile and compact display device that is capable of displaying an increasing number of visual data to the viewer, which is expressed in a growing demand for a display device with a small surface area and an increasing number of display pixels.
One approach to reduce the size of an image display and yet retain image quality is through the formation of a virtual image instead of a real image. A virtual image can exist at a place where no display surface exists.
A virtual image is seen through an optical device. An example of a virtual image is the image viewed through a magnifying glass, a three-dimensional hologram, a mirror-reflected image, the image viewed through a combiner of head up display and the image viewed through an output diffractive optical element of planar optic visor display. Virtual image displays can provide an image, which appears to be larger than the source object from which the virtual image emerges, and at a distance suitable for the focus ability of the eye.
Creation of the image in Compact Display Sources can be performed in one of several methods, such as scanning a screen with an electron ray in CRT monitors in parallel lines at a high speed, or radiation of light from Chip Laser Emitted Diodes (LED) serving as backlights in flat screen Liquid Crystal Displays (LCD). The result is an image displayed to the viewer's eyes, which is comprised of many light-radiating pixels, aligned in most devices as a two dimensional array of pixels. A light-radiating pixel of this type is also known as a dot.
A dot or pixel is an element that forms a character or symbol when combined in a matrix, or an array. In monochromatic displays, every such pixel can either project light or not, and in more advanced systems the light radiation can be at several grades of intensity, which allows for pixel gray level.
Color display systems have the option of creating a pixel referred to as a full-color pixel, as a combination of several light-radiating pixels, which are in close proximity to each other, while each radiates light in an additive primary color, at the necessary intensity. The combination of these additive primary colors at the necessary division of intensities gives the feel of a color pixel of the desired hue and brightness. The term "additive" refers to the addition of several primary colors, usually three: red, blue, and green. at the appropriate ratios to create the sense of a color of any hue and brightness within the color vision spectrum. Color addition is suitable for creation of a color image from light-radiating sources
Another method of creating color images is "subtraction". In this method, the source of light can be white sunlight, which is blocked with three filters at the necessary filtering intensity, usually yellow, red, and blue filters. An example of use of the subtraction method is in watercolor paintings.
Another option is radiating light in primary colors in the sequential color method. In this method, each pixel in the display array radiates the additive primary colors (red, green, and blue) at a high rate that gives the eye the sense of simultaneous radiation, and the end result of a color pixel of the desired hue and brightness.
An example of a Compact Display Source on the market nowadays is the AMLCD CyberDisplay 640 Color, manufactured by the Kopin Corporation, 695 Myles Standish Blvd., Taunton, Mass. USA. Its active display area measures 5.76 mm×7.68 mm with VGA resolution 640×480 pixels and a video rate of up to 180 frames per second, with three primary colors: red, green, and blue, and a filed of view of 32 degrees. This compact display source is based on Kopin's field color sequential technology in which time division multiplexing produces color by rapidly creating a repetitive sequence of red, green and blue sub-images which the human eye integrates into a full color image.
There are several standards of display arrays, in which one of the primary characteristics is the increase in number of pixels, for example:
Color Graphics ArrayCGA200 × 640 pixelsEnhanced Graphics ArrayEGA350 × 640 pixelsVideo Graphics ArrayVGA480 × 640 pixelsSuper Video Graphics ArraySVGA600 × 800 pixels
As noted above, the present invention relates to holographic planar optic display system. The holographic planar optic display device is a highly efficient display device, as it is both compact and inexpensive. The general structure of the holographic planar optic display device is described in FIG. 1.
This basic structure uses two Diffractive Optical Elements (DOE). Structures of holographic planar optic display devices can include a higher number of DOE's. In display systems based on geometrical optics, the diversion of light rays is made by use of lenses, beam splitters, and mirrors, which cause a relatively thick display system. In planar optic display systems on the other hand, which are based on diffractive optics, the DOE serves as an optical grating that diverts the light coming through it (or reflected from it) by taking advantage of the diffraction phenomenon.
The light is diverted by the input element at a sufficiently large angle to enable it, upon hitting the transparent substrate plate, to be reflected in full internal reflection and move in the substrate until it reaches the output element, which diverts it out of the substrate. The gratings can be light-transmissive gratings or light-reflective gratings. The thickness of the grating is negligible in comparison to those of geometrical optical elements, and the transparent substrate plate thickness is small, approximately 1–3 mm. therefore, display systems based on diffractive planar optics can be extremely compact.
These systems are particularly good when the display is in monochromatic light, namely light with only one wavelength or frequency. In this case, use of simple linear gratings is sufficient, as described in U.S. Pat. No. 4,711,512 of Upatnieks, the contents of which are hereby incorporated by reference.
The light is radiated from the image source in several angles; each pixel radiates a beam of light, as a cone with a certain angle of opening. In planar optic systems, the light radiated from the image source usually undergoes collimation by a geometrical lens placed between the image source and the input element or within the input element. Another possibility is partial collimation in the geometrical lens or the input element and additional collimation by additional gratings between the input element and the output element. After collimation the rays of light are parallel to each other.
The light diversion angle in the grating depends on the structure of the grating, the ratio between the index of refraction of the transparent substrate and the index of refraction of the environment and the light's wavelength. A simple linear grating diverts each wavelength at a different angle. Therefore a system with a linear input grating will create lateral chromatic aberration at its output.
When planning the grating spacing of the input grating, in use of linear gratings, the light must pass through it or be reflected from it at the appropriate angle, which is called the critical angle βC, which assures that the light will be reflected from the inner side of the transparent substrate plate in total internal reflection.
The minimal angle, which is called the critical angle βC that assures total internal reflection of the light within the substrate, can be calculates using Snell's law, that states that for a system in air, βC=sin−1(1/np), np being the plate index of refraction. For example, in glass this index is approximately 1.51.
In color display systems this calculation will be made for the light with the shortest wavelength. For blue light with a wavelength of λB, the angle βB will be calculated, as it is diverted at the smallest angle. The desired grating spacing (gs) can be calculated using the equation: np sin βB−na sin βi=λB/gs or when βi=0, when light hits the input grating at a perpendicular angle: np sin βB=λB/gs
Now, the diversion angles of the other light beams can be calculated, and we can find, for example, the diversion angle for green light, βG, and the diversion angle for red light, βR, and the cycle distance (cd) of each of the light's color  components. Obviously, the light rays will each arrive to the output grating at a different distance from the substrate input point and after a different number of cycles.
Over the past few years, many efforts to solve the problem of chromatic aberration in planar optic display systems. The solutions offered also include the use of more than two gratings or use of a complex input grating. Examples of this are described in U.S. Pat. No. 5,966,223 of Friesem et al, which describes the use of a complex input grating, as illustrated in FIG. 4a; in PCT International Publication No. WO 99/52002 to Amitai et al, which describes the use of at least three gratings, and the second grating diverts the light on the substrate by 90° as illustrated in FIG. 4b; in PCT International Publication No. WO 01/09663 to Friesem et al, which describes the addition of at least one additional diffractive optical element being positioned between the input and the output diffractive optical elements, as illustrated in FIG. 4c; and in PCT International Publication No. WO 01/95027 to Amitai, which describes the installment of a reflecting surface in the input and the installment of a parallel array of partially reflecting surfaces, as illustrated in FIG. 4d, which necessitates thickening the transparent substrate. The contents of these four examples are hereby incorporated by reference.
These solutions are limited in their ability to solve the problem of chromatic dispersion, and mostly the problem of chromatic aberration, and also complicate the production process of the display systems.
There is therefore a need for, and it would be highly advantageous to have a compact multichromatic display system in which the image is displayed to the viewer without unwanted chromatic aberration and/or chromatic dispersion.


A mold for molding a UV cured article in an inner volume thereof, the mold including a mold wall surrounding the inner volume, the mold including a UV-transparent polymer and UV radiation deflecting particles immersed in or adhered to a surface of the mold wall. Also provided is an apparatus including the mold and a process for molding a UV cured article.

Molding methods include those which involve injection molding and extrusion methods where a polymer is heated to a plastic state, then formed in a mold or die, then cooled to form a finished product. As such, the mold is made from a substrate that is able to withstand these pressure and temperature changes. Often, molds are made of high strength steels and are expensive to produce.
For the solution of these problems, UV curing methods have been proposed in the last four decades. According to these methods, ultraviolet radiation is applied to resins such as coatings, adhesives, marking ink and photo-resists, and photocurable substances etc., to cause photo polymerization. UV curing methods can show inter alia the following advantages: i) in the curing reaction, a liquid monomer changes to a solid polymer within a few seconds, ii) since the entire material is basically cured by solvent-free photo polymerization, it can be very effective to fulfil the requirements of environment-related regulations and orders such as PRTR (Pollutant Release and Transfer Register) Law or ISO 14000, iii) the UV curable material does not cure unless exposed to light and, unlike heat-curable material, it does not get cured gradually during preservation, hence, its pot-life is short enough for it to be used in automation processes, iv) a great number of resins are available for use in such UV-curing processes.
However, regarding the manufacture of articles having a more or less complex shape, the following problems can arise.
The resins can be characterized in that they are cured only in regions which are exposed to more than a certain amount of energy radiation. On the other hand, energy radiation typified by UV radiation can be characterized in that it is attenuated while it passes through a resin. As a result, it can be either difficult for energy radiation to penetrate the resin deep enough and at every location, or energy radiation is greatly attenuated or absorbed. Thus, photo-curable resins are cured only in a surface layer having a thickness of several micrometers to several millimeters through which energy radiation can pass, and the deep part and the parts which cannot be reached by the radiation which is emitted in a linear manner from the UV-source remain uncured. Consequently, it can be difficult or partially impossible to apply photo-curable resins to thick-walled materials and/or having a more or less complex shape.
Thus, it is not surprising that UV cure resins have in fact been used to form coatings and adhesives, but they have not generally been used in molding applications. This can, inter alia, be seen from the following examples.
U.S. Pat. No. 5,916,509 entitled "Actinic irradiation and curing of plastic composites within a material forming die" states that uncured thermoset composite reactants containing ultraviolet curable reagents may be effectively cured by pultrusion using a unique molding die, which uniformly irradiates the uncured composites contained within the die.
DE Patent Document No. 197 05 303 entitled "Production of small and micro parts" is concerned with the production of small and micro-parts made of a molding composition and which comprises: (a) evacuating the mold with integrated mold insert; (b) placing the molding composition into the mold under pressure where a low viscosity molding composition is used, which contains a component hardenable by short wave light; (c) irradiating with short wave light while maintaining a post pressure to completely harden the composition; and (d) opening the mold and removing the molding.
In U.S. Pat. No. 5,885,514 entitled "Ambient UV-L-curable elastomer mold apparatus," a process for molding parts such as gaskets using an injection molding machine is described. According to this document, the molding machine includes upper and lower mold plates, which are transparent to UV light, have pattern recesses of differing sizes, a UV light source, a low pressure injection system for delivering elastomers to the mold plates and are located spaced apart from one another.
In a molding apparatus according to JP Patent Document No. 59215838, an ultraviolet ray hardening molding material is injected into a die from an injection molding machine to fill the space in a cavity core. Then ultraviolet rays irradiate the cavity and the cavity core separately via an optical fiber from an ultraviolet ray irradiation source.

Apparatus, mold and method for producing shaped articles from a UV-curable composition


A wireless network gateway for transmitting data between a wireless network and a packet data network. The wireless network gateway comprises: 1) N input-output processors for transmitting and receiving data packets to and from the wireless network and the packet data network; 2) M service processors for performing packet data serving node (PDSN) functions associated with data sessions between the packet data network and mobile stations communicating with the wireless network; 3) a switch fabric for the N input-output processors and the M service processors; and 4) P switch modules. Each of the P switch modules transfers data packets between the switch fabric and at least one input-output processors. A first switch module stores session bindings information associated with a first data session between a first mobile station and the packet data network.

A packet data serving node (PDSN) provides packet data services that support high-speed two-way data communications in wireless networks. The new 3G networks that are now being developed and deployed utilize Simple IP and Mobile IP to allow a mobile subscriber to use a mobile station (e.g. personal computer (PC), personal digital Assistant (PDA), web browsing cell phone) transparently, whether the subscriber is accessing information on a corporate LAN, the Internet or other IP-based network. A PDSN provides these capabilities to the wireless network.
In particular, 3G packet data serving node provides users with the following:
1) Two-way mobile communications utilizing packet segmentation of the user data stream;
2) Mobile IP or Simple IP to data networks such as the Internet, corporate Intranets and Extranets;
3) Secure access to corporate data networks;
4) Transport for support of all applications available to the user over corporate networks and public services such as the Internet; and
5) Raw data rates from 1.2 Kbps to 153.6 Kbps to over 1 Mbps as 3G evolves.
The PDSN is a network element whose primary function is interworking 3G wireless mobile packet sessions with other IP packet data networks (e.g., the Internet). A PDSN performs two basic functions: 1) the exchange of packets with the mobile station over the radio network and 2) the exchange of packets with other IP networks. To perform these functions, the PDSN interfaces with the base station controller (BSC), the Authentication Authorization and Accounting (AAA) servers, Home Agent servers, and packet data networks.
The PDSN communicates to the mobile station (MS) using a point-to-point protocol (PPP) session originated by the mobile station. The PDSN must also communicate with the radio network (i.e., BSC) during handoffs to maintain the PPP session. While the mobile station is exchanging information, the PDSN collects accounting information, which it forwards to an AAA server. It also interacts with the AAA server to receive user profiles to authenticate the mobile user. When Mobile IP is supported in a wireless network, the PDSN performs the necessary Foreign Agent functions to communicate with Home Agents to locate and authenticate mobile users. This includes establishing a secure tunnel to Home Agents for receiving and sending subscriber information.
The PDSN provides the following functions in a typical 3G wireless network architecture:
1) Terminating PPP sessions and forwarding IP packets to the Packet Data Network (PDN);
2) Facilitating Mobile IP session operating as a Foreign Agent (FA);
3) Maintaining communication with the Home Agent (HA) by keeping IP sessions active when mobile users move from a first cell serviced by a first PDSN to a second cell serviced by a second PDSN;
4) Supporting the user Authentication Authorization and Accounting (AAA) services by collecting this information and forwarding it to the appropriate end device and terminating the connection upon authentication failure;
5) Supporting static and dynamic IP addressing schemes;
6) Supporting Simple IP and Mobile IP protocols; and
7) Supporting Virtual Private Networking (VPN).
For a variety of reasons, however, session information associated with a data session can be lost by a failure of a network element. In particular, a failure of a PDSN service processor located in a wireless network gateway router can cause all session information associated with a data call to be lost. This decreases network reliability and increase use of network resources as a subscriber reconnects to the wireless network and reestablishes a session with a network server via a PDSN.
Therefore, there is a need in the art for an improved packet data serving nodes for use in wireless networks. In particular, there is a need for a massively parallel router having a distributed architecture that implements an efficient apparatus and method for recovering a communication session in a wireless network gateway.

Apparatus and method for recovering communication sessions in a wireless network gateway


A memory card drive is provided which can record a large amount of digital information. A plurality of memory card slots is provided in a memory card drive body having a memory interface. A plurality of memory cards is detachably accommodated in the memory card slots. Digital information is recorded into and played back from the memory cards through the memory interface.

1. Field of the Invention
The present invention relates to a memory card drive and a portable memory card drive which can record (write) and playback (read) digital information into and from memory cards.
2. Description of the Related Art
Conventionally, a memory card, which is a card-type recording medium such as a memory stick, in which a flash memory is incorporated, has been widely applied to digital equipment including a personal computer, digital camera, disk drive, pet robot, portable telephone, etc., due to its small-size, low-profile shape, and versatility.
In general, in such digital equipment, a slot for the insertion of the memory card is formed, so that the memory card inserted is electrically connected with the digital equipment and energized to record (write) and playback (read) digital information into and from the memory card.
However, for recording a large amount of digital information, a single memory card has a disadvantage such as a need for replacing the memory card with another one, due to its small storage capacity.

Memory card drive and portable memory card drive


A combined actuator and bottle for storing a fluid and applying the fluid, includes a container having an opening; an elongated tube having a longitudinal axis, the tube being located in the opening, and the tube being slidable along the longitudinal axis relative to the container and being sealed against the container so that an intake end of the tube is located within the container and an outlet end of the tube is located outside the container; the tube having a duct extending in the direction of the longitudinal axis of the tube, the duct forming a fluid connection between the outlet end of the tube and the intake end that is situated within the container; an applicator head mounted at the outlet end of the tube and having an applicator member receiving the fluid from the outlet end of the tube and supplying the fluid to a dispensing opening thereof having an axis which is substantially transverse to a sliding direction of the tube; and a valve assembly mounted in the applicator head, the valve assembly including a hollow area in the applicator head which slidably receives the outlet end of the tube therein, and a flange at the outlet end of the tube which forms a seal with walls of the applicator head in the hollow area for one of selectively (a) blocking flow of the fluid to the dispensing opening, and (b) permitting flow of the fluid to the dispensing opening.

Various containers, spouts, pullout spouts and applicator systems, such as those described below, are known.
Containers having pullout spouts for pouring a liquid are known, for example, from U.S. Pat. Nos. 1,473,295 (Dryer), 1,797,676 (Baker), 2,040,625 (Myers), 3,372,846 (Berkus), 4,461,406 (Vannucci), 4,726,491 (Moon). In such case, the pullout spout is generally located within an opening of, and sealingly connected with, the container. The pullout spout is movable like a telescope between a fully retracted position where its outlet is within the opening of the container and a fully protruded position. In many instances, the container opening as well as the pullout spout are provided with threads for threadedly connecting a sealing cap. When attached, the sealing cap engages the pullout spout and the thread of the opening, to close the container opening to prevent leakage of the contents of the container. Alternatively, the threads can be provided on the end of the pullout spout.
However, such devices merely dispense the liquid out from a relatively large opening in order to pour the liquid. There is no means for dispensing the liquid in a slow, uniform flow, for example, for scrubbing an external surface or a body part.
Although applicator heads are known which are fixed to an opening of a bottle or other container, for example, as disclosed in U.S. Pat. Nos. 3,261,515 (Luedtke) and 4,961,661 (Sutton et al), valves for preventing liquid flow are formed in the bottle opening and not in the applicator heads. For example, in U.S. Pat. No. 4,961,661 to Sutton et al, a plug connected with the inner wall of the tube that supports the applicator head, is provided within the duct of the tube, which plug closes the bore when the tube is tightly screwed onto the cap. A similar arrangement is provided in U.S. Pat. No. 3,261,515 to Luedtke. However, it is desirable to provide the valve in the applicator head mounted to a telescoping tube for better control, which is not shown by these references.
Applicator heads, such as sponges and the like, are known to be secured to the end of a telescoping tube. See, for example, U.S. Pat. Nos. 1,047,852 (Strickland), 2,119,646 (Pidel), 3,106,741 (Stoner) and 4,135,274 (Freeman), as well as Danish Patent No. 104,197. However, no valves are provided in the applicator heads to prevent fluid flow when the applicator heads are extended.

Bottle with built-in telescoping applicator head and valve therein


The invention features derivatives of R(−)-11-hydroxyaporphines and methods of treating Parkinson's disease, sexual dysfunction, and depressive disorders therewith.

The invention relates to the treatment of Parkinson's disease, sexual dysfunction, and depressive disorders.
Parkinson's disease is a progressive neurodegenerative disorder of the basal ganglia of the brain, which most often becomes apparent after the age of 55. It is a prevalent and prototypic hypokinetic disorder, with akinesia, bradykinesia, rigidity and tremor as the most prominent features. The neurological and psychiatric symptoms, including depression and psychosis, with late dementia, usually worsen with time. The neuropathology of Parkinson's disease reveals a striking and selective loss of the dopaminergic neurons of the nigrostriatal pathway of the brain.
As Parkinson's disease is associated with a loss of the neurotransmitter dopamine, it is commonly treated with drugs which replace or mimic the actions of dopamine. Since dopamine itself cannot pass the blood-brain diffusion barrier, the most commonly used therapy is levodopa (L-DOPA), the immediate precursor of dopamine which is readily decarboxylated by remaining dopaminergic neurons and other amine-producing neurons. A complication of long-term treatment with L-DOPA is the development of rapid fluctuations in clinical state such that the patient changes, often abruptly, between mobility and immobility; this phenomenon is known as the 'on-off' effect.
An alternative approach to treatment with L-DOPA is the use of drugs (dopamine agonists and partial-agonists) that mimic the actions of dopamine. Treatment with dopamine receptor agonists has some advantages over treatment with L-DOPA. Unlike L-DOPA, dopamine agonists are effective in patients with advanced stages of Parkinson's disease because their action at postsynaptic receptors is unaffected by the lack of dopamine producing nerve cells that decarboxylate L-DOPA to produce dopamine locally, whereas the denervated dopamine receptors are supersensitive to agonists. Furthermore, there is an increasing interest in the potential of dopamine receptor agonists to provide a neuroprotective effect. Theoretically, such a protective effect might result from (i) a decreased need for the use of L-DOPA, a substance that may cause oxidative stress and perhaps even contribute to further damage of dopamine neurons, (ii) stimulation of dopamine autoreceptors resulting in decreased dopamine synthesis, release, and turnover, resulting in reduced metabolism of dopamine to reactive oxygen species, and (iii) by direct anti-oxidant effects.
R(−)-Apomorphine is a directly acting dopamine agonist at both D1 and D2 receptors, and dopamine autoreceptors, without opiate-like or addictive properties. Apomorphine therapy has led to sustained improvements in Parkinson's disease patients with refractory motor oscillations (on-off phenomena). However, it is difficult to administer owing to its poor bioavailability and extensive first-pass metabolism to inactive metabolites. Therefore, apomorphine is usually administered either by intermittent subcutaneous injection or continuous subcutaneous infusion. Following a single dose, apomorphine has an onset of action of 5-15 minutes, and its effects last for 40-60 minutes.
Direct dopamine agonists, including R(−)-apomorphine, are also effective in the treatment of a number of forms of sexual dysfunction, primarily, but not limited to erectile dysfunction. See Martinez et al., J. Urology 170:2352 (2003).
New compounds that overcome the practical problems associated with apomorphine therapy, particularly its lack of oral bioavailability and short half-life, are needed for the treatment of diseases, such as Parkinson's disease and erectile dysfunction.

R(−)-11-hydroxyaporphine derivatives and uses thereof