The present invention provides novel polynucleotides encoding HGPRBMY39 polypeptides, fragments and homologues thereof. Also provided are vectors, host cells, antibodies, and recombinant and synthetic methods for producing said polypeptides. The invention further relates to diagnostic and therapeutic methods for applying these novel HGPRBMY39 polypeptides to the diagnosis, treatment, and/or prevention of various diseases and/or disorders related to these polypeptides. The invention further relates to screening methods for identifying agonists and antagonists of the polynucleotides and polypeptides of the present invention.

Regulation of cell proliferation, differentiation, and migration is important for the formation and function of tissues. Regulatory proteins such as growth factors control these cellular processes and act as mediators in cell-cell signaling pathways. Growth factors are secreted proteins that bind to specific cell surface receptors on target cells. The bound receptors trigger intracellular signal transduction pathways which activate various downstream effectors that regulate gene expression, cell division, cell differentiation, cell motility, and other cellular processes. Some of the receptors involved in signal transduction by growth factors belong to the large superfamily of G-protein coupled receptors (GPCRs) which represent one of the largest receptor superfamilies known.
GPCRs are biologically important as their malfunction has been implicated in contributing to the onset of many diseases, which include, but are not limited to, Alzheimer's, Parkinson, diabetes, dwarfism, color blindness, retinal pigmentosa and asthma. Also, GPCRs have also been implicated in depression, schizophrenia, sleeplessness, hypertension, anxiety, stress, renal failure and in several cardiovascular, metabolic, neuro, oncology and immune disorders (F Horn, G Vriend, J. Mol. Med. 76: 464-468, 1998.). They have also been shown to play a role in HIV infection (Y Feng, C C Broder, P E Kennedy, E A Berger, Science 272:872-877, 1996).
GPCRs are integral membrane proteins characterized by the presence of seven hydrophobic transmembrane domains which together form a bundle of antiparallel alpha (a) helices. The 7 transmembrane regions are designated as TM1, TM2, TM3, TM4, TM5, TM6, and TM7. These proteins range in size from under 400 to over 1000 amino acids (Strosberg, A. D. (1991) Eur. J. Biochem. 196: 110; Coughlin, S. R. (1994) Curr. Opin. Cell Biol. 6: 191-197). The amino-terminus of a GPCR is extracellular, is of variable length, and is often glycosylated. The carboxy-terminus is cytoplasmic and generally phosphorylated. Extracellular loops of GPCRs alternate with intracellular loops and link the transmembrane domains. Cysteine disulfide bridges linking the second and third extracellular loops may interact with agonists and antagonists. The most conserved domains of GPCRs are the transmembrane domains and the first two cytoplasmic loops. The transmembrane domains account for structural and functional features of the receptor. In most G-protein coupled receptors, the bundle of a helices forms a ligand-binding pocket formed by several G-protein coupled receptor transmembrane domains.
The TM3 transmembrane domain has been implicated in signal transduction in a number of G-protein coupled receptors. Phosphorylation and lipidation (palmitylation or farnesylation) of cysteine residues can influence signal transduction of some G-protein coupled receptors. Most G-protein coupled receptors contain potential phosphorylation sites within the third cytoplasmic loop and/or the carboxy terminus. For several G-protein coupled receptors, such as the b adrenoreceptor, phosphorylation by protein kinase A and/or specific receptor kinases mediates receptor desensitization. In fact, phosphorylation of an activated G-protein coupled receptor is a common mechanism for desensitizing signaling to a G-protein.
The extracellular N-terminal segment, or one or more of the three hydrophilic extracellular loops, have been postulated to face inward and form polar ligand binding sites which may participate in ligand binding. Ligand binding activates the receptor by inducing a conformational change in intracellular portions of the receptor. In turn, the large, third intracellular loop of the activated receptor interacts with an intracellular heterotrimeric guanine nucleotide binding (G) protein complex which mediates further intracellular signaling activities, including the activation of second messengers such as cyclic AMP (cAMP), phospholipase C, inositol triphosphate, or ion channel proteins. TM3 has been implicated in several G-protein coupled receptors as having a ligand binding site, such as the TM3 aspartate residue. TM5 serines, a TM6 asparagine and TM6 or TM7 phenylalanines or tyrosines have also been implicated in ligand binding (See, e.g., Watson, S. and S. Arkinstall (1994) The G-protein Linked Receptor Facts Book, Academic Press, San Diego Calif., pp. 2-6; Bolander, F. F. (1994) Molecular Endocrinology, Academic Press, San Diego Calif., pp. 162-176; Baldwin, J. M. (1994) Curr. Opin. Cell Biol. 6: 180-190; F Horn, R Bywater, G Krause, W Kuipers, L Oliveira, ACM Paiva, C Sander, G Vriend, Receptors and Channels, 5:305-314, 1998).
Recently, the function of many GPCRs has been shown to be enhanced upon dimerization and/or oligomerization of the activated receptor. In addition, sequestration of the activated GPCR appears to be altered upon the formation of multimeric complexes (AbdAlla, S., et al., Nature, 407:94-98 (2000)).
Structural biology has provided significant insight into the function of the various conserved residues found amongst numerous GPCRs. For example, the tripeptide Asp(Glu)-Arg-Tyr motif is important in maintaining the inactive confirmation of G-protein coupled receptors. The residues within this motif participate in the formation of several hydrogen bonds with surrounding amino acid residues that are important for maintaining the inactive state (Kim, J. M., et al., Proc. Natl. Acad. Sci. U.S.A., 94:14273-14278 (1997)). Another example relates to the conservation of two Leu (Leu76 and Leu79) residues found within helix II and two Leu residues (Leu 128 and Leu131) found within helix III of GPCRs. Mutation of the Leu128 results in a constitutively active receptor—emphasizing the importance of this residue in maintaining the ground state (Tao, Y. X., et al., Mol. Endocrinol., 14:1272-1282 (2000); and Lu. Z. L., and Hulme, E. C., J. Biol. Chem., 274:7309-7315 (1999). Additional information relative to the functional relevance of several conserved residues within GPCRs may be found by reference to Okada et al in Trends Biochem. Sci., 25:318-324 (2001).
GPCRs include receptors for sensory signal mediators (e.g., light and olfactory stimulatory molecules); adenosine, bombesin, bradykinin, endothelin, y-aminobutyric acid (GABA), hepatocyte growth factor, melanocortins, neuropeptide Y, opioid peptides, opsins, somatostatin, tachykinins, vasoactive intestinal polypeptide family, and vasopressin; biogenic amines (e.g., dopamine, epinephrine and norepinephrine, histamine, glutamate (metabotropic effect), acetylcholine (muscarinic effect), and serotonin); chemokines; lipid mediators of inflammation (e.g., prostaglandins and prostanoids, platelet activating factor, and leukotrienes); and peptide hormones (e.g., calcitonin, C5a anaphylatoxin, follicle stimulating hormone (FSH), gonadotropic-releasing hormone (GnRH), neurokinin, and thyrotropin releasing hormone (TRH), and oxytocin). GPCRs which act as receptors for stimuli that have yet to be identified are known as orphan receptors.
GPCRs are implicated in inflammation and the immune response, and include the EGF module containing, mucin-like hormone receptor (Emrl) and CD97p receptor proteins. These receptors contain between three and seven potential calcium-binding EGF-like motifs (Baud, V. et al. (1995) Genomics 26: 334-344; Gray, J. X. et al. (1996) J. Immunol. 157: 5438-5447). These GPCRs are members of the recently characterized EGF-TM7 receptors family. In addition, post-translational modification of aspartic acid or asparagine to form erythro-p-hydroxyaspartic acid or erythro-p-hydroxyasparagine has been identified in a number of proteins with domains homologous to EGF. The consensus pattern is located in the N-terminus of the EGF-like domain. Examples of such proteins are blood coagulation factors VII, IX, and X; proteins C, S, and Z; the LDL receptor; and thrombomodulin.
One large subfamily of GPCRs are the olfactory receptors. These receptors share the seven hydrophobic transmembrane domains of other GPCRs and function by registering G protein-mediated transduction of odorant signals. Numerous distinct olfactory receptors are required to distinguish different odors. Each olfactory sensory neuron expresses only one type of olfactory receptor, and distinct spatial zones of neurons expressing distinct receptors are found in nasal pasages. One olfactory receptor, the RAlc receptor which was isolated from a rat brain library, has been shown to be limited in expression to very distinct regions of the brain and a defined zone of the olfactory epithelium (Raming, K. et al., (1998) Receptors Channels 6: 141-151). In another example, three rat genes encoding olfactory-like receptors having typical GPCR characteristics showed expression patterns exclusively in taste, olfactory, and male reproductive tissue (Thomas, M. B. et al. (1996) Gene 178: 1-5).
Another group of GPCRs are the mas oncogene-related proteins. Like the mas oncogenes themselves, some of these mas-like receptors are implicated in intracellular angiotensin II actions.
Angiotensin II, an octapeptide hormone, mediates vasoconstriction and aldosterone secretion through angiotensin II receptor molecules found on smooth vascular muscle and the adrenal glands, respectively.
A cloned human mas-related gene (mrg) mRNA, when injected into Xenopus oocytes, produces an increase in the response to angiotensin peptides. Mrg has been shown to directly affect signaling pathways associated with the angiotensin II receptor, and, accordingly, affects the processes of vasoconstriction and aldosterone secretion (Monnot, C. et al. (1991) Mol. Endocrinol. 5: 1477-1487).
GPCR mutations, which may cause loss of function or constitutive activation, have been associated with numerous human diseases (Coughlin, supra). For instance, retinitis pigmentosa may arise from mutations in the rhodopsin gene. Rhodopsin is the retinal photoreceptor which is located within the discs of the eye rod cell. Parma, J. et al. (1993, Nature 365: 649-651) reported that somatic activating mutations in the thyrotropin receptor cause hyperfunctioning thyroid adenomas and suggested that certain GPCRs susceptible to constitutive activation may behave as protooncogenes.
Purines, and especially adenosine and adenine nucleotides, have a broad range of pharmacological effects mediated through cell-surface receptors. For a general review, see Adenosine and Adenine Nucleotides in The G-Protein Linked Receptor Facts Book, Watsonetal. (Eds.) Academic Press 1994, pp. 19-31.
Some effects of ATP include the regulation of smooth muscle activity, stimulation of the relaxation of intestinal smooth muscle and bladder contraction, stimulation of platelet activation by ADP when released from vascular endothelium, and excitatory effects in the central nervous system. Some effects of adenosine include vasodilation, bronchoconstriction, immunosuppression, inhibition of platelet aggregation, cardiac depression, stimulation of nociceptive afferants, inhibition of neurotransmitter release, pre- and postsynaptic depressant action, reducing motor activity, depressing respiration, inducing sleep, relieving anxiety, and inhibition of release of factors, such as hormones.
Distinct receptors exist for adenosine and adenine nucleotides. Clinical actions of such analogs as methylxanthines, for example, theophylline and caffeine, are thought to achieve their effects by antagonizing adenosine receptors. Adenosine has a low affinity for adenine nucleotide receptors, while adenine nucleotides have a low affinity for adenosine receptors.
There are four accepted subtypes of adenosine receptors, designated A1, A2A, A2B, and A3. In addition, an A4 receptor has been proposed based on labeling by 2 phenylaminoadenosine (Cornfield et al. (1992) Mol. Pharmacol. 42: 552-561).
P2x receptors are ATP-gated cation channels (See Neuropharmacology 36 (1977)). The proposed topology for PZX receptors is two transmembrane regions, a large extracellular loop, and intracellular N and C-termini.
Numerous cloned receptors designated P2y have been proposed to be members of the G-protein coupled family. UDP, UTP, ADP, and ATP have been identified as agonists. To date, P2Y1-7 have been characterized although it has been proposed that P2Y7 may be a leukotriene B4 receptor (Yokomizo et al. (1997) Nature 387: 620-624).
It is widely accepted, however, that P2Y1, 2, 4, and 6 are members of the G-protein coupled family of P2y receptors.
At least three P2 purinoceptors from the hematopoietic cell line HEL have been identified by intracellular calcium mobilization and by photoaffinity labeling (Akbar et al. (1996) J. Biochem. 271: 18363-18567).
The Ai adenosine receptor was designated in view of its ability to inhibit adenylcyclase. The receptors are distributed in many peripheral tissues such as heart, adipose, kidney, stomach and pancreas. They are also found in peripheral nerves, for example intestine and vas deferens. They are present in high levels in the central nervous system, including cerebral cortex, hippocampus, cerebellum, thalamus, and striatum, as well as in several cell lines. Agonists and antagonists can be found on page 22 of The G-Protein Linked Receptor Facts Book cited above, herein incorporated by reference. These receptors are reported to inhibit adenylcyclase and voltage-dependent calcium chanels and to activate potassium chanels through a pertussis-toxin-sensitive G-protein suggested to be of the G/Go class. Ai receptors have also been reported to induce activation of phospholipase C and to potentiate the ability of other receptors to activate this pathway.
The A2A adenosine receptor has been found in brain, such as striatum, olfactory tubercle and nucleus accumbens. In the periphery, A2 receptors mediate vasodilation, immunosuppression, inhibition of platelet aggregation, and gluconeogenesis. Agonists and antagonists are found in The G-Protein Linked Receptor Facts Book cited above on page 25, herein incorporated by reference. This receptor mediates activation of adenylcyclase through Gs.
The A2B receptor has been shown to be present in human brain and in rat intestine and urinary bladder. Agonists and antagonists are discussed on page 27 of The G-Protein Linked Receptor Facts Book cited above, herein incorporated by reference. This receptor mediates the stimulation of cAMP through Gg.
The A3 adenosine receptor is expressed in testes, lung, kidney, heart, central nervous system, including cerebral cortex, striatum, and olfactory bulb. A discussion of agonists and antagonists can be found on page 28 of The G-Protein Linked Receptor Facts Book cited above, herein incorporated by reference. The receptor mediates the inhibition of adenylcyclase through a pertussis-toxin-sensitive G-protein, suggested to be of the Gi/Go class.
The P2Y purinoceptor shows a similar affinity for ATP and ADP with a lower affinity for AMP. The receptor has been found in smooth muscle, for example, and in vascular tissue where it induces vasodilation through endothelium-dependent release of nitric oxide. It has also been shown in avian erythrocytes.
Agonists and antagonists are discussed on page 30 of The G-Protein Linked Receptor Facts Book cited above, herein incorporated by reference. The receptor function through activation of phosphoinositide metabolism through a pertussis-toxin insensitive G-protein, suggested to be of the Gi/Go class.
N-formyl peptide receptors are another family of G-protein coupled receptors. N-formyl peptide receptors are known to bind to N-formyl peptides and mediate a number of host defensive responses of human neutrophils that result in chemotaxis, secretion of hydrolytic enzymes, and superoxide generation. Inappropriate activation or defective regulation of these responses can result in pathogenic states responsible for inflammatory disease. The receptor is a 50 to 70-kD, integral plasma membrane glycoprotein with intracellular and surface localization. Its abundance in the membrane is regulated by membrane flow and recycling processes. Cytoskeletal interactions are believed to control its organization in the plane of the membrane and interaction with other proteins. The receptor's most important interaction is with guanyl nucleotide binding proteins that serve as signal transduction partners ultimately leading to activation of effector responses. Because the interaction of the receptor with G proteins is necessary for transduction, control of this interaction may be at the root of understanding the molecular control of responses in these cells (Jesaitis, A, J., Allen, R, A, J. Bioenerg, Biomembr., 20(6):679-707, (1988)).
Two particular proteins, Formyl Peptide Receptor (FPR) and Formyl Peptide Receptor-Like 1 (FPRL1) belong to the seven-transmembrane, GPCR superfamily. Because of the capacity of FPR and FPRL1 to interact with bacterial chemotactic formylated peptides, these receptors are thought to play a role in host defense against microbial infection. In addition, a variety of novel agonists have been identified for these receptors, including several endogenous molecules that are involved in proinflammatory responses. Most notably, FPRL1 has been found to be used by at least three amyloidogenic protein and peptide ligands, the serum amyloid A (SAA), the 42 amino acid form of □ amyloid (A beta42), and the prion peptide PrP106-126, to chemoattract and activate human phagocytic leukocytes (Su et al., J. Exp. Med., 189:395-402 (1999), Le et al. J. Neurosci., 21(RC123):1-5 (2000), Le et al., J. Immunol., 166:1448-1451 (2001), Chiang et al., J. Exp. Med., 191:1197-1207 (2000), Yang et al., J. Exp. Med., 192:1069-1074 (2000)). These findings have greatly expanded the functional scope and role in pathophysiological conditions for the formyl peptide receptors.
Leukocyte or phagocyte recruitment at sites of infection and inflammation is dependent on the presence of a gradient of chemotactic factors or chemoattractants. Chemoattractants such as N-formyl-methionyl-leucyl-phenylalanine (fMLF), activated complement component 5 (C5a), leukotriene B4 (LTB4), platelet-activating factor (PAF) and chemokines activate GPCRs on both hematopoietic and non-hematopoietic cells (Hwang, J. Lipid Med., 2:123-158 (1990); Oppenheim et al., Annu. Rev. Immunol., 9:617-648 (1991), Rollins, Blood, 90:909-26 (1997), Zlotnik et al., Crit. Rev. Immunol., 19:1-47 (1999)). Synthetic fMLF was one of the first identified leukocyte chemoattractants. Natural fMLF was subsequently purified and identified in supernatants of gram negative bacteria. fMLF activates FPR on leukocytes to increase cell migration, phagocytosis and the release of proinflammatory mediators. Since picomolar to nanomolar amounts of fMLF can activate FPR, and high concentrations of fMLF can only elicit a limited response upon FPRL1, FPR is considered to be a high-affinity receptor, while FPRL1 is considered to be a low-affinity receptor (Ye et al., Biochem. Biophys. Res. Commun., 184:582-589 (1992), Durstin et al, Biochem. Biophys. Res. Commun., 201:174-179 (1994)).
FPRL1 possesses 69% identity at the amino acid level with FPR (Boulay et al., Biochem. Biophys. Res. Commun., 168:1103-1109 (1990), Boulay et al., Biochemistry, 29:11123-11133 (1990)). FPR is expressed on phagocytic leukocytes, and FPRL1 is expressed on phagocytic leukocytes and hepatocytes, epithelial cells, T lymphocytes, astrocytoma cells, neuroblastoma cells, and microvascular endothelial cells (Prossnitz et al., Pharmacol. Ther., 74:73-102 (1997), Le et al., J. Neuroimmunol., 111:102-108 (2000), Ye et al., Biochem. Biophys. Res. Commun., 184:582-589 (1992), Gronert et al., J. Exp. Med., 187:1285-1294 (1998)).
A variety of ligands have been identified for formyl peptide receptors. In addition to bacterial fFML, a number of synthetic peptides activate FPR and FPRL1, such as the hexapeptide WKYMVM (SEQ ID NO:99) (Bae et al., J. Leuko. Bio, 65:241-248 (1999)). Also, HIV envelope proteins contain domains that interact with formyl peptide receptors (Su et al, J. Immunol., 162:5924-5930 (1999)). Lastly, a great variety of endogenous ligands interact with FPRL1, such as serum amyloid A (SAA), the 42 amino acid form of beta amyloid (A beta42), prion peptide PrP106-126, mitochondria peptide fragment MYFINILTL (SEQ ID NO:100) from NADH dehydrogenase subunit 1, and LL-37, an enzymatic cleavage fragment of the neutrophil granule-derived cathelicidin (Su et al., J. Exp. Med., 189:395-402 (1999), Le et al. J. Neurosci., 21(RC123):1-5 (2000), Le et al., J. Immunol., 166:1448-1451 (2001), Chiang et al., J. Exp. Med., 191:1197-1207 (2000), Yang et al., J. Exp. Med. 192:1069-1074 (2000)). All of these ligands are chemotactic and illicit proinflammatory responses in human leukocytes. LL-37 is also an antimicrobial peptide.
SAA, A beta42 and PrP106-126 are endogenous proteins that tend to precipitate when aggregated and result in amyloid deposition in pathologic states such as systemic amyloidosis (SAA), Alzheimer's disease (A beta42) and prion disease (PrP106-126). Thus the recent identification of novel and host-derived ligands for both FPR and FPRL1 suggests that these receptors may contribute to the proinflammatory aspects of systemic amyloidosis and neurodegenerative diseases.
Using the above examples, it is clear the availability of a novel cloned G-protein coupled receptor provides an opportunity for adjunct or replacement therapy, and are useful for the identification of G-protein coupled receptor agonists, or stimulators (which might stimulate and/or bias GPCR action), as well as, in the identification of G-protein coupled receptor inhibitors. All of which might be therapeutically useful under different circumstances.
The present invention also relates to recombinant vectors, which include the isolated nucleic acid molecules of the present invention, and to host cells containing the recombinant vectors, as well as to methods of making such vectors and host cells, in addition to their use in the production of HGPRBMY39 polypeptides or peptides using recombinant techniques. Synthetic methods for producing the polypeptides and polynucleotides of the present invention are provided. Also provided are diagnostic methods for detecting diseases, disorders, and/or conditions related to the HGPRBMY39 polypeptides and polynucleotides, and therapeutic methods for treating such diseases, disorders, and/or conditions. The invention further relates to screening methods for identifying binding partners of the polypeptides.

Human G-protein coupled receptor, HGPRBMY39


A method, apparatus, and computer implemented instructions for ordering multiple elements within a set of elements in a list in a data processing system. The set of elements are presented in a list format in a graphical user interface. The present invention waits for a first user input selecting the elements within the set of elements. In response to detecting the first user input, monitoring is performed for a second user input indicating a movement of the selected elements within the set of elements. In response to detecting the second user input, the selected elements are automatically reordered within the set of elements based on the user input. In this manner, the elements may be manipulated within the list using a single user input rather that requiring a user input to manipulate each element individually.

Data manipulation is a commonly performed process in a data processing system. The data manipulation may take many forms. For example, text may be copied, deleted, inserted, or saved. In other instances, data presented on a graphical user interface (GUI) may be displayed in the form of a list. The list may be ordered in many different ways. For example, the list for a set of files may be alphabetical, by date of modification, by file extension, or by file size. With a list of functions or topics, the elements within this type of list may be placed in alphabetical order, the order in which elements are added, or by categories.
Oftentimes, a user may be allowed to move elements within the element list. This movement of elements within the list is also referred to as ordering or reordering. List reordering is present in many applications. Two examples of applications, which provide list reordering, are Internet Explorer and Netscape Navigator. Internet Explorer is a browser program available from Microsoft Corporation, and Netscape Navigator is a browser program available from Netscape Communications Corporation. Both of these programs have lists of languages for the user to prioritize the language in which Web pages are to be displayed. However, these lists only allow single selection. As a result, the user has to move each list element individually to reorder them. Oftentimes, having to reorder multiple elements one at a time can be time consuming and tedious.
Therefore, it would be advantageous to have an improved method and apparatus for reordering elements in a list.

Method and apparatus in a data processing system for list ordering with multiple selection

International Business Machines Corporation


A delay locked loop that controls a delay time period by using a shifter and an adder includes a master delay locked loop and a slave delay locked loop. The master delay locked loop outputs a first digital value corresponding to one clock cycle of a first input clock signal. The slave delay locked loop receives the first digital value and delays a second input clock signal for a time period smaller than the one clock cycle of the first input clock signal. The slave delay locked loop includes a shifter, an operator, and a variable delay circuit. The shifter shifts the first digital value to generate a second digital value. The operator adds or subtracts an offset value to or from the second digital value to generate a third digital value, wherein the offset value varies according to a process, a voltage, and a temperature (PVT). The variable delay circuit delays the second input clock signal for a time period corresponding to the third digital value.

1. Technical Field
The present disclosure relates to a delay locked loop and, more particularly to a delay locked loop that controls a delay time period by using a shifter and an adder.
2. Discussion of Related Art
Delay locked loops (DLLs) remove a skew between an external clock signal input to an internal circuit and an internal clock signal used in the internal circuit. DLLs detect a difference between phases of the external clock signal and the internal clock signal and compensate for the detected phase difference, thereby removing a skew between the external clock signal and the internal clock signal.

Delay locked loop for controlling delay time using shifter and adder and clock delaying method


A method of producing an angiotensin converting enzyme inhibitor-containing composition, which is of value as an antihypertensive agent or diet, from natural resources. According to the method, proteins are hydrolyzed with a protease elaborated by a microorganism of the genus Bacillus, Aspergillus or Rhizopus or a protease of papaya origin.

Angiotensin converting enzyme (ACE) is an enzyme which is chiefly present in the lung, vascular endothelial cells and renal proximal tubules and acts on angiotensin I (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-His-Leu) to cleave a dipeptide (His.sup.9 -Leu.sup.10) off its C-terminus to give rise to angiotensin II which has potent pressor activity.
Furthermore, this enzyme decomposes bradykinin, a physiological hypotensive substance, to inactivate it and, as such, is intimately involved in the pressor system. It has been considered that inhibition of ACE would lower the blood pressure and is, therefore, clinically useful for the prevention and treatment of hypertension.
Recently, since captopril, a proline derivative, was synthesized and found to have hypotensive activity, much research has been undertaken for synthesis of a variety of ACE inhibitors and it has also been attempted to isolate such substances from natural resources.
This is because natural type ACE inhibitors available from foods or food materials may be expected to be of value as antihypertensive agents of low toxicity and high safety.
However, it is rare that a potent ACE inhibitor is found in natural resources and all that are known at present are teprotide (a nonapeptide, SQ 20881) which was isolated from Brazilian and Japanese snake venoms and Metabolite IS83 of a Streptomyces organism. (Japanese Patent Laid-open No. 58-177920). As ACE inhibitors obtainable by enzymatic treatment of a natural material, the peptides obtainable by hydrolysis of milk casein with trypsin (Japanese Patent Laid-open No. 58-109425, No. 59-44323, No. 59-44324, No. 61-36226 and No. 61-36227) are known. Under the circumstances, development of new, more potent ACE inhibitors has been earnestly awaited.

Method for producing an angiotensin converting enzyme inhibitor-containing composition

Nippon Gohsei Kagaku Kogyo Kabushiki Kaisha


An encoder includes a magnet, an optical coded disc, a magnetic sensing assembly, an optical sensing assembly and a signal processing unit. The optical coded disc has a first incremental pattern track and a second incremental pattern track. The magnet and the optical coded disc are structurally coaxial and rotatable. The magnet sensing assembly senses the magnet rotation to obtain an absolute position signal. The optical sensing assembly senses the optical coded disc rotation to obtain a first incremental position signal and a second incremental position signal. The signal processing unit receives and integrates those signals to obtain a high precision absolute position information.

With the advancement of technology, the encoder technology is widely used in the field of precision instrument control such as rotating speed measurement and position detection of motors. For example, the absolute encoder can be used to detect the number of rotations, rotation direction and rotation position of the motor.
Conventionally, Gray code or M-code (also called maximum length sequence or m-sequence code) is used by the optical encoder to obtain information of the absolute position. The main architecture of the optical encoder includes a light emitter, a light receiver, a coded disc and a processing circuit. The light emitter and the light receiver of the reflective optical encoder are disposed on the same side relative to the coded disc, and the desired signal output is obtained by appropriately designing the patterns on the coded disc.
However, since the conventional encoder architecture and encoding method are very sensitive to the positional deviation between sensor and coded disc, the encoder needs to be extremely accurate in the assembling and aligning process of sensor and coded disc. Furthermore, as the precision requirement of the encoder is increased, the area of the corresponding optical sensing region of the light receiver is also greatly reduced, so that the pollution of the external environment such as oil, dirt or microparticles will seriously affect the sensing of the absolute position signal.
For overcoming the drawbacks of the conventional technologies, there is a need of providing an improved encoder and a position detection method thereof to achieve high precision absolute position sensing, obtain higher resistance ability to environmental pollution, improve the robustness of the encoder, be easy for assembling and make the encoder thinner are important issues in the field.

Encoder using a magnetic sensing assembly and an optical sensing assembly and position detection method for a motor


A opening control apparatus for a sliding door of a vehicle, includes a driving source, a clutch arranged to connect the driving source and the sliding door in an engaged state and to disconnect the driving source and the sliding door in a disengaged state, and a control section. The control section brings the clutch from the disengaged state to the engaged state when a measured distance of movement of the sliding door from a stop position to a position in one of an opening direction and a closing direction reaches a first predetermined distance and then a measured distance of movement of the sliding door from the position in the one of the opening and closing directions reaches a second predetermined distance, and drives the sliding door to move in the one of the opening and closing directions by the driving source.

The present invention relates to an opening control apparatus for a sliding door of a vehicle.
Japanese Patent No. 3576483 shows an opening control apparatus for a sliding door of a vehicle. In this control apparatus, when the vehicle is stopped at a slope, a movement sensing section senses a movement of the sliding door stopping at an open position in a slope direction by self weight. Then, the control apparatus controls an electromagnetic clutch to be changed from a disengaged state to an engaged state by energizing the electromagnetic clutch, and simultaneously drives the sliding door in a moving direction at a safety speed by a driving force of a motor so that the sliding door is not moved at a high speed in an opening direction or a closing direction.


Composite bodies of magnetostrictive materials of the type RE-Fe.sub.2, where RE is one or more of the rare earth elements, preferably samarium or terbium, can be suitably hot pressed with a matrix metal selected from the group consisting of aluminum, copper, iron, magnesium or nickel to form durable and machinable magnetostrictive composites still displaying appreciable magnetostrictive strains.

Magnetostriction occurs when a material on exposure to a magnetic field develops significant strain: at room temperature, sample dimensions can change by as much as fractions of a percent. Conversely, the straining of a magnetostrictive material changes its magnetization state.
Magnetostrictive materials have been used with electromagnetic actuators to form transducers which serve as, for example, ultrasonic generators or fine control valves for the metering of fluids. In these applications, variation of the magnetic field is employed to produce varying strains in the magnetostrictive material to produce a mechanical output. Conversely, a suitable magnetostrictive material might be employed as a torque or force sensor. In fact, such materials are being considered as torque sensors in the form of a magnetostrictive ring mounted on a shaft such as an automobile steering shaft. Torque in such a shaft would strain the magnetostrictive ring, giving rise to a detectable change in the ring's axial magnetization.
Maximizing device performance naturally suggests using materials having large saturation magnetostriction, .lambda..sub.s, which is a dimensionless measure of the field-induced strain frequently expressed in units of parts per million (ppm). Extremely high values of .lambda..sub.s are found in rare earth-iron compounds such as the terbium-iron compound, TbFe.sub.2, where .lambda..sub.s equals 1750 ppm for a polycrystalline sample. Unfortunately, the rare earth-iron compounds are very brittle materials having little tensile strength, an unpropitious characteristic for automotive applications requiring good mechanical properties. On the other hand, stronger and tougher materials such as steels have very limited magnetostriction: T250 maraging steel, which is currently being evaluated in torque sensors, has a .lambda..sub.s of only .about.30 ppm. The wide gulf between these two extremes offers ample opportunity and challenge for developing new magnetostrictors combining good magnetostriction with satisfactory mechanical properties.
The prospect of embedding magnetostrictive powder in a strengthening matrix has been sporadically explored as follows.
The Clark and Belson patent, U.S. Pat. No. 4,378,258, entitled "Conversion Between Magnetic Energy and Mechanical Energy," reported sintering cold-pressed pellets of ErFe.sub.2 with nickel and TbFe.sub.2 with iron. Few details of the properties of these materials were provided. They retain some magnetostriction, but as it turns out, the sintered bodies are brittle and of insufficient strength for many applications such as automotive sensor applications. Clark and Belson also produced resin-bonded composites of the RE-Fe.sub.2 (RE=rare earth) magnetostrictive compounds, but these materials also are of insufficient mechanical strength for automotive applications.
Peters and Huston of the International Nickel Company attempted to prepare composites of SmFe.sub.2 in nickel by sintering, by extrusion and by hot pressing, but they obtained values of magnetostriction which were only modestly larger than that of the nickel alone and did not recommend the practices. See D. T. Peters and E. L. Huston, "Nickel Composite Magnetostrictive Material Research for Ultrasonic Transducer," January 1977, Naval Electronic Systems Command Contract No. N00039-76-C-0017, US Department of Commerce National Technical Information Service, ADA 040336; and D. T. Peters, "Production and Evaluation of ReF(2)-Nickel Composite Magnetostrictive Materials," Final Report, January 1979, Naval Electronic Systems Command Contract No. N00039-77-C-0108, US Department of Commerce National Technical Information Service, ADA 066947.
Others have also made magnetostrictive composites of RE-Fe.sub.2 materials in epoxy binders. However, none of the above-referenced attempts have produced composites of suitable magnetostriction and mechanical properties to serve as, for example, torque sensors in demanding environments such as automotive applications.
An example of a torque sensor such as might be used in an automotive application is found in I. J. Garshelis, IEEE Trans. Magn. 28, 2202 (1992). Garshelis describes a magnetostrictive ring in which circumferential magnetization is maintained by a large static hoop stress, the hoop stress also serving to rigidly attach the ring to the shaft carrying the torque. Stresses in the ring associated with the torque tilt the magnetization away from the circumferential direction. An axial component of magnetization develops and in turn produces a magnetic field in the space around the ring which is detected by a magnetic field intensity sensor; the magnetic field intensity is used to measure the torque in the shaft. An example of the application of such a shaft in an automobile, of course, is a steering column shaft. However, the stresses on the magnetostrictive ring can be quite high, and none of the above-described magnetostrictive materials provide a desirable combination of mechanical strength and large magnetostriction. Accordingly, there remains a need for the development of materials suitable for such applications.


In some embodiments, a configurable multiphase coupled magnetic structure may include a four-sided pot core defining an interior space, one or more cylindrical cores disposed within the interior space of the four-sided pot core, and at least two windings respectively wound around the one or more cylindrical cores, wherein the at least two windings are connected in a multiphase power delivery configuration. The windings may be multi-turn windings. The four-sided pot core may be a rectangular-shaped pot core. The cylindrical cores may be I-cores. Other embodiments are disclosed and claimed.

Many electronic systems require or benefit from the use of power delivery devices. For example, electronic systems such as microprocessor-based systems or digital signal processor based systems may require substantial power consumption. Power supply designs with smaller size and higher efficiency are generally more desirable. One type of voltage regulator topology that may meet the high output current demand of some electronic systems is the multiphase interleaved DC-DC converter.
For example, a DC-to-DC converter may include a switch and a low pass filter. Control circuitry may control a duty cycle of the switch so that the output voltage is regulated within a certain range. Typically a free wheeling diode or synchronous switch may be connected between ground and an inductor to provide a current path when the switch is opened. When higher current is required, multiple interleaved phases may be used.
Multiphase interleaving structures may require many inductors. To reduce components count, a coupled magnetic structure may be adopted. Even though the coupled magnetic structure has many advantages, manufacturing some coupled magnetic structures may be relatively complex and some coupled magnetic structures may provide limited design flexibility.
For example, a two-phase converter may be constructed with a toroidal core coupled magnetic structure. Even though the structure is simple, manufacturing may require a special winding tool. A multiphase converter may also be constructed with an H-core coupled magnetic structure. Although manufacturing may be easier than the toroidal approach, design flexibility is limited because the structure uses only a single turn winding (which may make it difficult to provide a high inductance value).

Configurable multiphase coupled magnetic structure


Nucleated fetal cells such as nucleated fetal red blood cells are separated from maternal blood with a discontinuous triple gradient gel and centrifugation. Nucleated fetal red blood cells are collected at an interface between a gel layer having a density in the range of from 1.105 to 1.110 g/mL and the second layer having a density in the range of from 1.075 to 1.085 g/mL, and maternal granulocytes are collected at an interface between a gel layer having a density in the range of from 1.115 to 1.125 g/mL and a layer having a density in the range of from 1.105 to 1.110 g/mL. This allows separation of fetal cells for testing from the maternal blood rather than the placenta or amniotic fluid, reducing the risk of sample collection and facilitating routine testing of fetal cells for evidence of genetic defects.

The examination of fetal cells for early detection of fetal diseases and genetic abnormalities is undertaken in approximately one out of every thirty pregnant women. The main indication is maternal age (over 35 years). The tests may involve DNA gene typing or, more commonly, the use of live fetal cells for chromosomal karyotyping.
Fetal cells are usually obtained by amniocentesis, the removal of amniotic fluid from the amniotic cavity within the amniotic sac or placenta. The procedure presents a risk of harm to the fetus, particularly after the first trimester of pregnancy. The risk to the fetus together with the high cost of the procedure have prevented the establishment of examination of fetal cells for early detection of abnormalities as a routine procedure in pregnancy.
In the late 1970s and early 1980s, Herzenberg and his colleagues reported that fetal cells were present in maternal blood as early as 15 weeks gestation. The authors separated maternal and fetal cells using fluorescence-activated cell sorting (FACS) by staining maternal blood for a distinguishing paternal HLA antigen. The authors state that the demonstration that fetal cells enter maternal circulation and can be isolated by FACS-enrichment procedures could have practical significance in enabling karyotyping without the need for amniocentesis. The authors state that this would be possible if the frequency of successful isolation of cells at 15 weeks is sufficiently high and the cells could be induced to divide (enter metaphase). Furthermore, extensive HLA typing reagents, or other cell surface reagents would need to be developed to distinguish maternal and fetal cells. To date, the technique has not been successfully adapted for use as a clinical technique for either karyotyping or fetal DNA analysis.
Recently, fetal cells present in maternal blood have been used to perform analysis of genes present in the fetus. In one technique, the maternal and fetal cells were not separated and the DNA from the cell mixture is amplified with Y chromosome-specific primers to determine whether the fetus is male. It has been suggested that DNA amplification techniques can also be performed to detect gene sequences associated with disease in this manner. 0f course, the method cannot be used where the mother is a carrier for the trait.
Prior to this invention, amniotic fluid has been the only source of antenatal cells to provide a sufficient number of live cells for karyotyping. Furthermore, DNA analysis methods have only been possible in relatively limited situations which depend on particular differences in maternal and fetal cells, e.g. presence of the Y chromosome in the fetus or presence of HLA-A2 antigen on fetal, but not maternal, cells.

Triple gradient process for recovering nucleated fetal cells from maternal blood

The Board of Trustees of the Leland Stanford Junior University


A centralized location system includes a location update application programming interface (API) to receive varying types of location inputs for a user from at least one location-providing application. A memory stores a location of the user and the location inputs, wherein the location update API periodically updates in the memory the location inputs when location updates are received from the at least one location-providing application. A location export API, upon request from a location-based service application, processes the location inputs to estimate a location of the user, which location estimate replaces the stored location in memory and is sent to the location-based service application. A user interface enables the user to specify a location granularity for at least one of the at least one location-providing application and the location-based service application.

1. Technical Field
The disclosed embodiments relate to a system and its methods for centralizing location updates, and more particularly, for centralizing location updates for location-based applications based on receipt of location inputs from location-providing applications.
2. Related Art
Consumers are becoming increasingly mobile. This increase in mobility creates many opportunities for organizations to provide consumers with location-based content and services. For example, a consumer may subscribe to a location-based restaurant review service that presents the consumer with a list of popular eateries that are located within driving distance of the consumer's current location. This service may also use the time of day to customize the list based on the type of meal (e.g., breakfast, lunch, or dinner). Consumers generally value this type of location-based content more than traditional content because it is more focused, relevant, and useful. Another service may provide a way that friends can track each other's locations, or other more user-integrated type services. Location-based content is information provided to a consumer that is keyed to a past, present or future geographic location of the consumer. Similarly, location-based services are services keyed to geographic location information for the consumer.
Additionally, the sources of location information related to a user of such applications have grown in recent years. These include devices that supply, for instance, a global positioning satellite (GPS) latitude and longitude coordinate set, a Global System for Mobile Communications (GSM) cell tower identifier, and a location related to a Wi-Fi access point media access control (MAC) address. Applications that integrate location information as part of a service provided to a user have heretofore used a single location source (or type of source) to provide location updates, and generally the location information obtained is destined for a single device or application.


A non-volatile memory system (3) is proposed consisting of a first non-volatile flash memory (5) having a plurality of blocks, each block having a plurality of pages, each block being erasable and each page being programmable, and a second non-volatile random access memory (23) having a plurality of randomly accessible bytes. The second non-volatile memory (23) stores data for mapping logical blocks to physical blocks and status information of logical blocks. Each logical block has an associated physical page pointer stored in the second non-volatile memory (23) that identifies the next free physical page of the mapped physical block to be written. The page pointer is incremented after every page write to the physical block, allowing all physical pages to be fully utilized for page writes. Furthermore, a method of writing and reading data is disclosed whereby the most recently written physical page associated with a logical address is identifiable by the memory system without programming flags into superseded pages, or recording time stamp values in any physical page or block of the first non-volatile memory (5). Furthermore, a method is provided for a logical block to be mapped to two physical blocks instead of one to provide additional space for page writes, resulting in reduction in page copy operations, thereby increasing the performance of the system.

Flash memory is a form of EEPROM (Electrically Erasable and Programmable Read Only Memory) that allows multiple memory locations to be erased or written in one programming operation. The memory is commonly used as a mass data storage subsystem for electronic devices, such as memory cards, USB (Universal Serial Bus) flash drives and solid-state drives as replacements of hard disk drives.
A flash memory device consists of one or more arrays of transistor cells as its data storage units. Each of those cells is capable of keeping one or more bits of data even if the electric power supply is cut off. Therefore, a flash memory is termed a non-volatile memory because it does not require an external power supply to retain stored data. However, this also requires that previously stored data is erased once a new round of programming or data input is required. This process is termed an erase-before-write, which is often time-consuming.
In commercial applications, a large number of transistor cells are divided into physical blocks, pages and sectors for their address management to facilitate data access, storage and programming. A flash memory is generally organized into a plurality of physical blocks. Each of these blocks is divided into a plurality of physical pages. Within each physical page, memory is often divided into two portions for the storage of user data and overhead data. Overhead data is commonly used to store the user data's status and flags, to record logical address information, error correction code, etc. Overhead data is sometimes also termed spare area or redundant data. FIG. 1 shows an example of a flash memory 5 having M blocks 50 (labeled 0 to M−1), each block 50 being organized into G pages 60 (labeled 0 to G−1), and each page 60 being further divided into user data 70 and overhead data 72 portions.
In one commercial implementation, a flash memory device consists of a number of blocks of 16 KB each. Every block is further divided into 32 pages, each page is then able to store 512 bytes of data equal to the size of a host sector. In another commercial implementation, a flash memory device consists of blocks of 128 KB each, a page size of 2 KB, such that a block is composed of 64 pages, and a page is composed of 4 sectors. In addition, each page also contains additional non-volatile cells for storing overhead data. These flash memory devices are herein termed multi-paged block flash memories, since every block is organized into a plurality of pages.
Programming flash memory is usually done in one or more pages, which is typically less than a block size. Moreover, in one commercial implementation (e.g., some NAND flash memories), pages within a block must be programmed in order from the least significant page to the most significant page. Random page programming within the block is prohibited.
To avoid the operation of erase-before-write, the concept of logical and physical addresses has been introduced. The physical address denotes the actual location or address of a group of transistor cells while the logical address means an address recognized by a host and which is logically associated to a physical address. A read/write operation for a logical address requested from a host end is converted into a read/write operation for an actual physical address of a flash memory by several steps of mapping algorithms. This mapping algorithm is often performed by a device termed a flash memory controller. The challenge for such a flash memory controller is how to optimize the flash memory controller system architecture to improve data access speed, to utilize the flash memory blocks and pages more efficiently and to improve on the reliability and usage life of the flash memories.
FIG. 2 shows a flash memory controller attached to the host at one interface and flash memories at another interface. The flash memory controller and its attached flash memories are semiconductor devices and they form a non-volatile semiconductor mass storage system together. FIG. 2 shows internal blocks of a typical flash memory controller with only major blocks shown for clarity. A host 1 communicates with a flash memory controller 3, which is arranged to access a non-volatile memory consisting of one or more physically-separate flash memory devices 5. The communication between the flash controller 3 and the host 1 is via a host interface 7. The communication between the controller 3 and the memory devices 5 is via a flash interface 9. The controller 3 further includes a ECC logic unit 13, a buffer RAM 11 and a processor 15. The processor 15 operates making use of temporary memory provided by a system volatile RAM 17 and a processor RAM 19, and software stored in a ROM 21.
In a typical process of operation for the device illustrated in FIG. 2, the host 1 initiates a data transfer operation by sending commands to the flash controller 3. A host write command specifies the starting logical address to write along with the number of sectors to write. A host read command specifies the starting logical address to read from along with the number of sectors to read.
User data is typically transferred between host and flash memories through the buffer RAM 11. The host uses logical addresses to read or write data. One of the functions of the controller 3 is to translate the host logical addresses into flash memory physical addresses so that data can be stored in proper storage cells/transistors.
The host logical address is often translated into intermediate terms of logical block and logical page addresses, where a logical block comprises a plurality of logical pages. There are various methods to perform this translation based on different flash memory controller implementations and algorithms. For example, the controller may map the upper host logical address bits to a logical block, and the rest of the lower host logical address bits to logical pages. The controller then maps the logical block and logical pages to physical block and physical pages. As an example, a logical block may be organized into 64 logical pages in sequential address order, such that logical block 0 is page-addressable from logical address 0 to 63, logical block 1 is page-addressable from logical address 64 to 127, logical block 2 is page-addressable from logical address 128 to 191, and so on. A logical block may be mapped to one or more physical blocks, and each logical page of this logical block may be mapped to a physical page of the mapped physical block(s). The controller then issues a sequence of low-level commands and control signals to read or write to flash memories using the mapped physical addresses. Host logical addresses and their corresponding terms of logical blocks and logical pages are virtual concepts, whereas physical blocks and physical pages are the real physical locations within flash memories.
Typically, the system volatile RAM 17 incorporated into the controller is used for storing the logical to physical address mapping and other system information. On power up, the controller is required to read mapping information from the flash memory 5 (typically in flash overhead data) and initialize the system volatile RAM 17 prior to any data transfer operation.
Other functions performed by the controller includes ECC (error correcting codes) generation and checking, error recovery, erasing blocks that contain obsolete data, performing wear-leveling function to improve on flash block usage, and others.
When a flash memory having multi-paged blocks is used, data in less than all the pages of a block is usually required to be updated by programming the new data in unused pages of either the same or another block. However, an efficient mapping algorithm for flash memories having multi-paged blocks has still not been satisfactorily developed. The following explains some of the fundamental challenges faced by a flash memory controller design for multi-paged block flash memory.
When a host writes N number of pages (where N≧1) of user data starting at a specific logical address to the storage device, the controller must implement some methods for mapping the logical address to flash physical address. The flash physical address is a function of the physical block number and physical page number. This address pair is herein denoted as {physical block, physical page}. The controller has to decide, for each of the N pages, in which {physical block, physical page} to store the user data. When the host subsequently reads data from the logical address previously written to, the controller must be able to translate the logical address to its mapped physical address, which is used to access specific location in flash memory and return the user data to the host.
Secondly, when the host updates M number of pages to the same logical address (where M≦N), the controller has to map the logical address to physical address for each of the M pages. The challenge is that a flash physical page must be erased before it can be written to again. Most present controllers implement methods to write user data to a different {physical block, physical page} than was previously written to for the same logical address. This requires the controller to re-map the logical address to a different {physical block, physical page} for each of the M pages for updates. When host subsequently reads data from the logical address, the controller must be able to translate the logical address to the physical address of the most recently written location to retrieve valid data, such that the older user data mapped to the same logical address are superseded.
Thirdly, host may be required to update to the same logical address multiple times, and each time with different user data from the previous writes.
Finally, when power for the non-volatile mass storage system is turned off and subsequently turned on again, the controller must be able to retain all the mapping information.
There are many controller designs to fulfill these functional requirements in order to make data access, storage, and transfer efficiently.
In a very early design, a host logical block is always mapped to a fixed flash physical block. In other words, every time the host writes to the same logical block, user data is always stored to the same flash physical block. However, prior to writing to the flash block, the flash block must first be erased. The disadvantage of this scheme is that any write is always slowed down by the time-consuming erase operation.
To address this, one prior art proposal was to avoid the "erase-before-write" scheme by re-writing user data to an erased physical block, and recording its associated logical block in the overhead data with a new flag. The previous data in the old block is marked using an old flag. In this scheme, the logical block number may be different from its mapped physical block number. However, for a flash memory having multi-paged blocks, the logical pages are always mapped to fixed physical pages within the block.
One disadvantage of this scheme is when host updates one or more pages of a logical block, a new erased physical block must be allocated for storing new data. Next, the valid pages of user data that were not over-written must be copied from the original block to the assigned erased physical block. The original physical block must then be invalidated by writing an old flag in its overhead data. Both the copying of pages and invalidating original block demand additional operation and time. Often times, the original block is invalidated even when not all the pages have been fully used, resulting in less efficient block usage. The more frequent block erase due to less efficient block usage will cause a drop in reliability since each flash block has limited program/erase cycles beyond which failure may occur. Additionally, the time consuming block erase may cause a performance penalty, even though it may be mitigated by performing erase in the background.
An improvement was made to avoid the copying of valid pages during updates. This is done by tagging the newly assigned erased physical block as a "moved" block. In fact, up to two physical blocks are used, one is the original block, and another is a moved block. Additional information is used to indicate whether a valid page is located in the original block, or the moved block. However, in this scheme, the logical pages are still associated with fixed physical pages within the blocks. Since the scheme has only one level of "moved" block, the process of copying valid pages and invalidating the "moved" block is still required when there are more than two updates to the same logical page. As before, this demands additional operation and time, results in less efficient block usage and more erase cycles to be performed.
In another attempt for flash controller design, the logical pages can be mapped to any physical pages within the mapped physical block. Hence, the logical to physical address mapping is done on a finer granularity. Tags in the overhead data associate a {logical block, logical page} with a {physical block, physical page}. To handle updates, instead of marking the original superseded page as old, the controller uses a time stamp written in the overhead data as an indication of which is the most recently written data. Two implementations are outlined. In both implementations, a physical block may be shared for data of different logical blocks.
In the first implementation, a time stamp is recorded in every physical page that was written. If a logical page is updated multiple times, user data will be stored in physical pages whose overhead data will have the same {logical block, logical page} tag but with different time stamps. On power up, for the controller to locate the most recently written page, it is expected that the controller reads the overhead data of all the flash physical pages, compares the logical addresses and time stamps to identify most recently written pages containing valid data.
In the second implementation, the controller is only required to record a time stamp for physical blocks instead of recording in every physical page. The time stamp is required to identify the one valid page, since, in its generalized form, data updates for same {logical block, logical page} may be written to pages of different physical blocks, and each physical block may also be shared with data of other logical blocks. The most recently written physical page is determined by the relative physical location within a block. The implementation requires a reverse reading technique to dynamically identify if a logical page has been re-written and generally requires a large buffer to re-assemble the user data prior to transferring them to the host in the correct order.
In both implementations, a real time clock or a modulo counter is required to generate a time value that is to be recorded in flash memory blocks or pages. This time stamping operation is expected to add complexity to the flash memory controller, such as having to generate time-stamp values, handling of wrap around cases, and to perform time-stamp comparison among pages having common logical addresses.
Another type of non-volatile memory that attracts much research attention is Non-Volatile Random Access Memory (NVRAM). Random Access Memory (RAM) is classified as volatile memory and has faster data access speed as it is based on a different type of technology and does not require erase-before-write operation. Currently, NVRAM is created by attaching a backup battery to a volatile random access memory. In this case, unlike a normal Random Access Memory (RAM), the data stored in a NVRAM is kept even if the external electric power supply (other than the battery) is switched off because the backup battery holds the electric charges required. RAM has much faster data transfer speed than ROM and the same applies to NVRAM.
Recently developed NVRAMs based on various technologies do not require the aid of a battery to keep stored data. These include Magneto-Resistive Random Access Memory (MRAM), Ferroelectric Random Access Memory (FRAM), Ovonic Unified Memory (OUM), and others currently under development. These solid-state memories are sometimes referred to as "next generation" or "universal" or "nano-technology" non-volatile memories and have properties similar to SRAM with additional feature of being non-volatile.
Similar to flash memory, these NVRAMs do not require power to retain data. There are however, major functional differences between flash memory and Non-Volatile Random Access Memory that provide NVRAM with advantages over flash memory as follows:                Contents in NVRAM are randomly addressable for read and write in minimum unit of a byte.        The process of writing and reading data in NVRAM is faster and it completes in one short read or write cycle. For flash memory, programming data will incur a long busy period during which time the state of the non-volatile memory cells are changed. For some flash implementation (e.g. NAND flash), reading data will incur a long busy period during which time the data from non-volatile memory cells are read.        Updating a specific byte location in NVRAM can be performed multiple times and it does not require erasing that byte prior to the update.        Writing any byte is allowed at any address with no limitations on the allowable address due to prior history of writes, unlike some flash memory (e.g. NAND flash) that imposes restrictions on programming in sequential page addresses within a block.
The term NVRAM as used here encompasses any solid-state non-volatile random access memory having at least some functional characteristics (preferably all) as described above, including MRAM, FRAM, OUM and others based on various technologies, some of which are still under research and development. The disadvantage of NVRAM is that at the current time, it is still more expensive than flash memory in terms of cost per MB. Hence, it is not expected to completely replace flash memory as the non-volatile memory of choice in mass storage applications in the near future.
Ongoing design and manufacturing improvements are bringing NAND flash memory to the next level of performance. Process shrinks are providing flash memory devices with multi-gigabit storage densities as well as faster read access. In addition, architectural innovations are boosting the speeds of erasure and programming as well as read access. These improvements have provided a roadmap that will bring NAND flash performance to new levels that further increase their utility in modern computing system designs.

Controller for non-volatile memories and methods of operating the memory controller


Monitoring scattered gamma rays is used to identify substances disposed between coaxial tubulars disposed in a subterranean wellbore. Gamma rays are strategically directed from within an inner most tubular and into the annulus, some of the gamma rays scatter from the substance between the tubulars and are detected with detectors set a designated axial distance from the gamma ray source. Gamma rays also scatter from fluid within the tubular, a ratio of the gamma rays detected that scatter from the fluid in the tubular and from the substance can be used to determine the substance.

1. Field of Invention
The invention relates generally to investigating an annulus between tubulars disposed in a subterranean wellbore. More specifically, the present invention relates to a device and method that uses a radiation source for inspecting a subterranean annulus and a radiation detector for identifying a substance or substances in the annulus.
2. Description of Prior Art
Subterranean wellbores used for producing hydrocarbons typically are lined with a string of casing that is cemented to the formation intersected by the wellbore. Often an inner casing string is inserted within the casing string cemented in place. Fluid produced from the well flows to the surface within production tubing that is inserted into the inner casing string. Over the life of a typical well the production tubing may be removed so that remediation, repair, or flow enhancement operations may be commenced in the well. There may also be a need at some time for removal of a portion or for all of the casing.
Generally drilling fluids fill the annular space between the concentric tubulars. Particulates within the drilling fluids may settle out or precipitate over time and form a cement like substance that couples together the concentric tubulars and prevents the removal of the inner tubular from the wellbore. While cutting tools can sever the tubulars to enable removing the unstuck portion, the tubular cannot be removed if the cut is made at a depth below where the tubulars are adhered together. Alternatively, too shallow a cut can leave an undesirably long portion of free pipe extending above the point of adhesion.

Method and apparatus for interrogating a subterranean annulus


An electrochemical sensor has a sensor housing and an ion-sensitive field effect transistor (ISFET) with a source connection (S) and a drain connection (D). An ion-sensitive surface area (IS) on the front surface of the ISFET is immersible in a measuring medium. A clamping element serves to clamp the ISFET with its rear surface against an end surface of the sensor housing. The clamping element has a central opening leaving the ion-sensitive surface area (IS) exposed. A leak-tight circular connection between the clamping element and the sensor housing is formed by vibratory, preferably ultrasonic, welding. The ISFET is sandwiched between two rubber-elastic elements, at least one of which forms a leak-tight seal against penetration of the measuring medium from the ion-sensitive surface area (IS) to the source- and drain connections (S) and (D).

Among the widely used electrochemical sensors with a sensor element and/or sensor housing consisting of glass, so-called non-glass sensors are gaining in importance. An application for non-glass sensors is for example the measurement of concentrations in production processes in the food industry. In particular the measurement of pH values that were previously measured primarily with glass electrodes is or will become outlawed in many industrial situations. The purpose of the new legislation is to avoid the dangers associated with a possible breakage of glass parts, e.g., in a production chain in the food industry.
The design of a glass-free electrochemical sensor poses on the one hand a problem that instead of a sensor housing made of glass, an enclosure of a different material is to be selected. As a solution, there are a variety of suitable polymer materials available. The material should meet application-specific requirements, i.e., adequate mechanical stability and chemical resistance, and it should be a good electrical insulator. On the other hand, there is a problem of finding a glass-free alternative for the sensor membrane, in particular for pH-sensors which usually contain a membrane of pH glass as a essential component of the measuring system. This makes it appropriate to use a different measuring principle.
To provide glass-free ion-sensitive elements that can in particular be configured as glass-free pH-sensitive elements, ion-sensitive field effect transistors, hereinafter referred to by the customary acronym ISFET, present themselves as a solution. For example, a method and a circuit for measuring ion activity in liquids involving the use of an ISFET are described in DE 3116884 A1. The ISFET in this case contains an insulating layer acting as transistor gate. The insulating layer, which has the function of an ion-sensitive surface area, is arranged between a source electrode and a drain electrode. A pH-measuring device with an electrode including an ISFET is described, e.g., in EP 63213 B1.
The aforementioned documents give only a schematic indication of the arrangement of the ISFET in the sensor. However, when attempting to implement this concept in practice, it becomes evident that the positioning, mounting and the electrical connections of the ISFET are of importance for a functional sensor. As a ground rule, it should be ensured that certain parts of the sensor are sealed tightly against leaks and moreover that the ISFET is protected against excessive mechanical stress, e.g., in applications involving increased pressure.
Sensors which belong generically to the same type are presented in U.S. Pat. No. 6,117,292 and U.S. Pat. No. 6,153,070. They have a sensor housing containing an ISFET in the shape of a small disc. A source connection and a drain connection are arranged on the rear side of the disc. At the front side, the disc has an ion-sensitive surface area for immersion into a measuring medium. The sensors have a stacked configuration in which the ISFET is clamped against a plate-shaped base that serves as a mechanical seat and at the same time as a lead-off element. The latter function is achieved through a design with direction-specific electrical conductivity due to a laminated structure of the plate-shaped base with alternating insulating- and conducting layers running substantially perpendicular to the main plane of the plate-shaped base. As a result, the base is electrically conductive in the direction perpendicular to its main plane and at the same time electrically insulating in one direction of the main plane. This arrangement provides the electrical connections to the source- and drain contacts on the rear side of the ISFET. Drawbacks of these sensors lie in their complexity and high manufacturing cost. In addition, the desire to arrange the source- and drain connections on the rear side of the ISFET represents a particular disadvantage, because it does not conform to the customary design of ISFETs and thus adds to the cost and limits the selection of available types of ISFETs.
A reference electrode is described in NL 1003458 C, which instead of the customary Ag/AgCl half cell with glass frit and conductive gel uses an Ag platelet coated with an AgCl film, with a thin SiO2 film arranged on top of the AgCl film. A clamping element serves to clamp the Ag platelet against an end surface of a sensor housing, so that the rear surface of the platelet, which faces away from the AgCl-coated side bears against the end surface of the sensor housing. The clamping element has a central opening leaving a mid-portion of the AgCl film exposed. A substantially ring-shaped sealing element is arranged between the clamping element and the AgCl platelet, surrounding the mid-portion of the AgCl as a tight seal against leakage of the measuring medium. It is mentioned in NL 1003458 C that the clamping element (referred to in Dutch as "kopdeel", meaning "head part") is attached to the sensor housing (referred to as "huls", meaning "casing") by means of an adhesive bond, but preferably by ultrasonic welding. However, this reference gives no indication regarding the spatial arrangement of the ultrasonic welding bond and in particular whether it forms a leak-tight seal running in a closed circle. There is furthermore no indication on how to perform the welding procedure. The ultrasonic welding process as well as other kinds of vibratory welding present a problem that in addition to the components to be bonded together, adjacent components are also subjected to some degree of vibration. This may be tolerable in the case of the Ag platelet of the aforementioned reference. However, if an ISFET were to be installed instead of the Ag platelet, the vibrations reaching the ISFET would cause cracks or separation of the film layer. Furthermore, the wire bonds of the lead-off wires to the source- and drain contacts of some types of ISFETs are particularly prone to getting damaged by vibrations. These kinds of problems do not exist in the reference electrode described in NL 1003458 C and accordingly this reference offers no suggestion whatsoever for a solution. Furthermore, the arrangement described in NL 1003458 C is designed with electrical contacts arranged on the rear side, analogous to the arrangements of U.S. Pat. No. 6,117,292 and U.S. Pat. No. 6,153,070, and is therefore not suitable for the particularly common type of ISFETs with electrical leads on the front side.


A liquid fuel power plant (100) including an open-ended combustion chamber (102) and a first mechanism (110) for delivering a combustible liquid fuel to the combustion chamber (102). A second mechanism (118) is included for delivering compressed air to the combustion chamber (102) to provide a pressurized air-fuel mixture. A third mechanism (130) ignites the pressurized air-fuel mixture in the combustion chamber (102) and a fourth mechanism (134) is provided for extending the length of the combustion chamber (102) for decomposing the pressurized air-fuel mixture to provide an exhaust gas comprised of fundamental elements. Finally, a fifth mechanism (142) is provided for using the exhaust gas to perform useful work. The air inlet line (116) delivers compressed air from a turbocharger (118) which is preheated in an air passageway (128) and thereafter mixed with the fuel in the combustion chamber (102). The residue of the combustion is thereafter forced by the compressed air into a spiral-shaped extension (134) which forms a reaction region (138) of the combustion chamber (102). The reaction region (138) becomes sufficiently hot to ensure complete decomposition of the mixture.

1. Field of the Invention
The present invention relates to power plants. More specifically, the present invention relates to methods and apparatus for a non-polluting turbo-charged power plant having a liquid fuel burning chamber for the combustion of hydrocarbon based fuels.
While the present invention is described herein with reference to illustrative embodiments for particular applications, it should be understood that the invention is not limited thereto. Those having ordinary skill in the art and access to the teachings provided herein will recognize additional modifications, applications and embodiments within the scope thereof and additional fields in which the present invention would be of significant utility.
2. Description of the Related Art
Many different types of liquid fueled power plants are known in the art for providing thrust to, for example, propel a projectile or drive a generator. Examples include liquid fueled jet engines, piston engines and rocket motors of various designs. Each of these liquid fueled power plant designs suffer from a number of problems during the launch and flight stages of the projectile or when driving the generator. The problems common to liquid fueled power plant designs include the generation of excessive amounts of noise and heat. Also, in the case of a liquid fueled rocket motor, large amounts of smoke can be generated which results in increased levels of atmospheric pollution.
Low detectability of a projectile during target approach is necessary in stealth operations. However, the generation of excessive noise during the launch and flight stages increases the probability that the projectile will be detected upon approach. Likewise, generation of large amounts of heat by the projectile can be detected by infrared sensors such as the forward looking infrared devices utilized by aircraft. The heat generated by the projectile can also be detected visually by utilizing night vision goggles. The smoke generated by certain liquid fueled rocket motors creates a visual smoke trail. Thus, the projectile is easier to track and the origin of the launch point is easier to determine. The density of the smoke trail is dependent upon the type of rocket motor fuel employed. Each of these problems increase the probability of projectile detection during approach to the target. Likewise, when driving a generator with, for example, a liquid fueled piston engine, the smoke exhaust from the engine increases the atmospheric pollution level.
The use of a turbocharger or supercharger in combination with a liquid fueled power plant is known. In particular, the use of a turbocharger in combination with a turbine jet engine, piston engine or turbine rocket motor capable of providing thrust to propel a projectile is also known. In general, the use of a turbocharger in combination with any of the above mentioned power plants affords control of the direction of the hot expanding exhaust gases of the power plant, increases the volume of the hot expanding exhaust gases, and provides oxidation of the liquid fuel under pressure.
A turbine jet engine has a long cylindrical body and includes one or more liquid fuel burning chambers. The burning chambers are located at the center of the long cylindrical body and normally burn at temperatures in excess of three-thousand degrees Fahrenheit. The turbine jet engine includes multiple compression stages comprising a turbine or turbocharger located in the forward section of the jet engine. The turbocharger produces a very high pressure in the burning chambers. When the liquid fuel is injected into the burning chamber, the fuel is combusted to provide hot, high pressure gases. A high percentage of the output gases are fed back and utilized in a control loop to drive the turbine wheel. The balance of the output gases are used to perform useful work such as driving an aircraft or missile.
The outer walls of the jet engine burning chamber are at a lower temperature than that of the flame at the center of the burner. Because of the temperature differential between the flame and the outer wall and the operating temperature of the burning chamber, the liquid fuel, which is generally a hydrocarbon based fuel, is not totally combusted. When particles of a hydrocarbon based fuel are not totally burned, hydrocarbon based pollutants are produced. Further, since the liquid fuel is not totally combusted, the turbine jet engine is not fuel efficient. Additionally, the turbine jet engine is very noisy, expensive to build and produces excessive heat. Each of these characteristics of turbine jet engines increases the detectability of a projectile and the pollution level of the atmosphere.
Liquid fueled piston engines employing turbochargers are used in air vehicles while liquid fueled piston engines utilizing turbochargers or superchargers are used in stationary drive applications. As an example, the turbine associated with a turbocharger is located external to the piston engine block in a position normally occupied by a carburetor. Hot exhaust gases and ambient air are each fed to the turbine which compresses the gas mixture. The compressed gas mixture enables a higher volume of air to be fed to the designated piston chamber. The compressed air (e.g., greater than one atmosphere) is mixed with liquid fuel and ignited to provide a greater force then otherwise available to the crankshaft of a piston engine. Use of a turbocharger in a liquid fueled turbine rocket motor (e.g., a turbine jet engine in a rocket) is also known. The turbocharger is employed to generate and feed high volume compressed air to one or more combustion chambers. The pressurized air forces a higher volume of air into the fixed volume combustion chamber. The higher pressure exhaust gas of the combustion chamber is used to drive the turbine wheel in a feedback control loop. Both the liquid fueled piston engine and the turbine rocket motor are very noisy. Therefore, a projectile propelled by either power plant can be tracked by an audible sensor. Further, depending upon the type of liquid fuel employed in the piston engine and the rocket motor, large amounts of smoke can be generated which results in increased levels of atmospheric pollution.
Another example of a liquid fuel power plant design of the prior art is an incinerator employed for destroying hazardous waste. The incinerator includes a cylindrical combustion chamber joined by a flat circular plate to a smaller inlet pipe. Fuel nozzles protrude through the flat plate into the combustion chamber. The incinerator includes a blower air input which can be comprised of an impeller blade type air compressor. The function of the blower air input is to provide an oxidizer to mix with the liquid fuel to promote combustion. The oxidizer can also be provided by a turbocharger, a supercharger or similar device.
The air and fuel are not premixed but instead are injected into the incinerator combustion chamber at the point of flame stabilization. The fuel is ignited and the combustion chamber is heated to operating temperature. The hazardous waste material to be combusted is then delivered to the combustion chamber by fuel injectors. Total combustion of the fuel is ensured by recirculation of the gas and air mixture. Thus, low nitrous oxide (NO.sub.x) levels are produced. The heat generated by the combustion is released to the atmosphere through a long exhaust tube. The incinerator is intended only to destroy hazardous waste material and thus, is not a power plant capable of providing thrust to propel a projectile or otherwise performs useful work. Another device suitable for use with the incinerator for providing the oxidizer to mix with the liquid fuel is a motor driven radial outflow compressor. The radial outflow compressor is not driven by the exhaust gases of the combustion chamber. Normally, an alternative power source such as an electric motor or a piston or rotary engine is employed to drive the radial outflow compressor.
Thus, there is a need in the art for improvements in the design of liquid fueled power plants to reduce the detectability of and the exhausted pollutants from the power plants.

Liquid fuel turbocharged power plant and method


An electrolytic capacitor is disclosed. In an embodiment an electrolytic capacitor includes a housing having a base and an opening arranged opposite the base and a closure element being at least partly introduced into the opening, wherein the closure element is configured to close the housing, wherein the closure element includes a sealing element for electrically insulating a connection between closure element and housing, and wherein the closure element comprises at least one first contact element for electrically conductive connecting a second contact element.

Electrolytic capacitors consist of at least two layers of electrode films, the anode and the cathode. A spacer impregnated with an operating electrolyte is arranged between said electrode films. In the case of aluminum electrolytic capacitors, aluminum films are used as electrodes. In general, the electrode films with the spacer situated therebetween are wound up to form a capacitor winding.
Securing elements that serve as mechanical and electrical contacting can be welded on axial electrolytic capacitors. However, it has thereby been possible hitherto only to enable the negative contacting (cathode). The positive contacting can only be effected via a wire (anode wire).
By means of suitable welded-on contact plates or contact laminae, designs such as press-fit or SMD (surface-mounted device) are possible, but hitherto only with the negative pole. The positive pole remains as a wire that has to be laboriously reworked to form a press-fit or SMD contact.
Axial electrolytic capacitors having a large-area positive pole (aluminum sheet) are known. However, since said sheet is mounted in a recessed manner, directly welding a contact plate onto the aluminum sheet, and hence an anodal contacting by means of a contact plate, is very laborious.


A device for administering a cannula (14), having a basic element (10),the cannula (14), a tip (16) of which protrudes beyond the basic element (10) in a ready to use position of the device, a traction element (12), which is movable with respect to the basic element (10), and a releasable pretensioning device (36, 38, 40) for pretensioning the traction element (12) with respect to the basic element (10) in the ready to use position of the device, wherein the traction element (12) interacts with the cannula (14) so that, when the pretensioning device (36, 38, 40) of the traction element (12) is released, the tip (16) of the cannula (14) retracts into the basic element (10).

The invention relates to a device for administering a cannula.
In particular, the invention relates to a device for the percutaneous introduction of a cannula into an implanted port of a port catheter system. Such a port typically has a closing element, for example, of silicone, which is pierced by the cannula. The port catheter system may, for example, be a venous catheter for chemotherapy.
A device for administering a cannula is known, for which, after the port of a catheter is punctured with the cannula and after a drug, for example, has been injected through the cannula, the device for pulling out the cannula is restrained at the patient in order to retract the cannula into the device. The cannula is retracted into the device in order to hide the tip of the cannula and, by so doing, to decrease the risk of injury. The counter pressure, exerted on the device during this procedure, may cause the tip of the cannula to become slightly curved before it is pulled out, so that the closing element of the port is damaged by the deformed tip during the retraction. For example, small parts of the closing element could be cut out so that, after being punctured repeatedly, the closing element may start to leak.


A prosthetic socket liner. A liner of the prosthetic socket liner has an inner and outer surface, the inner surface configured to engage skin of a user's residual limb and the outer surface configured to engage a surface of a socket of a prosthesis. An air channel coupled to the liner and to a valve extends downwardly towards a closed end of the liner and is configured to transfer air between an outer surface of the liner and ambient air through the valve. In implementations the air channel is configured to channel air between an inside of a cavity and a location outside the cavity. A method of donning a socket of a prosthesis includes donning a liner of a prosthetic socket liner over a residual limb, opening a valve on the liner, inserting the liner into a socket of a prosthesis with the valve open, and closing the valve.

1. Technical Field
Aspects of this document relate generally to liners used in relation to prosthetic limbs.
2. Background Art
Liners are used in the field of prosthetic limbs. In instances a liner is placed over a residual limb prior to donning a socket of a prosthetic limb, and the liner forms a layer at least partially between the residual limb and the socket of the prosthetic limb. An example of a conventional liner may be found in U.S. Pat. No. 6,544,292 to Aldo A. Laghi entitled "Prosthetic liner with integral air expulsion valve," issued Apr. 8, 2003, the disclosure of which is incorporated entirely herein by reference.


In a control method of a refrigerator having a storage chamber for aging of meat, an operation to keep the storage chamber at an aging temperature and an operation to cool the storage chamber to a cooling temperature lower than the aging temperature are repeated. This enables optimal aging of meat via an aging time and aging temperature suitable for meat.

1. Field
Embodiments relate to a refrigerator and a control method thereof, which enable aging and storage of meat at appropriate temperatures.
2. Description of the Related Art
Generally, after decapitation, poultry experiences rigor mortis characterized by stiffness of muscles or joints. While undergoing rigor mortis, poultry meat becomes stiff and has an unpleasant taste, having poor market quality.
However, once the muscle stiffness peaks, meat begins to undergo self-digestion by protease, etc. and becomes tender. Self-digestion increases the PH and exudation of muscles, and involves, e.g., digestion of proteins into constituent amino acids by the action of enzymes, improving taste.
For this reason, meat in rigor mortis may be kept at a predetermined temperature to reach maximum stiffness. This is called "aging".
Although the aged meat has superior tenderness, excessively long aging may deteriorate the quality of the meat due to propagation of microorganisms and acidification of fat, and in the worst case, may become inedible. Therefore, it may be important to select an appropriate aging method and aging period.

Refrigerator and control method for aging of meat