Disclosed are therapeutic treatment methods, compositions and devices for maintaining neural pathways in a mammal, including enhancing survival of neurons at risk of dying, inducing cellular repair of damaged neurons and neural pathways, and stimulating neurons to maintain their differentiated phenotype. In one embodiment, the invention provides means for stimulating CAM expression in neurons. The invention also provides means for evaluating the status of nerve tissue, including means for detecting and monitoring neuropathies in a mammal. The methods, devices and compositions include a morphogen or morphogen-stimulating agent provided to the mammal in a therapeutically effective concentration.

The mammalian nervous system comprises a peripheral nervous system (PNS) and a central nervous system (CNS, comprising the brain and spinal cord), and is composed of two principal classes of cells: neurons and glial cells. The glial cells fill the spaces between neurons, nourishing them and modulating their function. Certain glial cells, such as Schwann cells in the PNS and oligodendrocytes in the CNS, also provide a myelin sheath that surrounds neural processes. The myelin sheath enables rapid conduction along the neuron. In the peripheral nervous system, axons of multiple neurons may bundle together in order to form a nerve fiber. These, in turn, may be combined into fascicles or bundles.
During development, differentiating neurons from the central and peripheral nervous systems send out axons that grow and make contact with specific target cells. In some cases, axons must cover enormous distances; some grow into the periphery, whereas others are confined within the central nervous system. In mammals, this stage of neurogenesis is complete during the embryonic phase of life and neuronal cells do not multiply once they have fully differentiated.
A host of neuropathies have been identified that affect the nervous system. The neuropathies, which may affect neurons themselves or associated glial cells, may result from cellular metabolic dysfunction, infection, exposure to toxic agents, autoimmunity, malnutrition, or ischemia. In some cases, the cellular neuropathy is thought to induce cell death directly. In other cases, the neuropathy may induce sufficient tissue necrosis to stimulate the body""s immune/inflammatory system and the immune response to the initial injury then destroys neural pathways.
Where the damaged neural pathway results from CNS axonal damage, autologous peripheral nerve grafts have been used to bridge lesions in the central nervous system and to allow axons to make it back to their normal target area. In contrast to CNS neurons, neurons of the peripheral nervous system can extend new peripheral processes in response to axonal damage. This regenerative property of peripheral nervous system axons is thought to be sufficient to allow grafting of these segments to CNS axons. Successful grafting appears to be limited, however, by a number of factors, including the length of the CNS axonal lesion to be bypassed, and the distance of the graft sites from the CNS neuronal cell bodies, with successful grafts occurring near the cell body.
Within the peripheral nervous system, this cellular regenerative property of neurons has limited ability to repair function to a damaged neural pathway. Specifically, the new axons extend randomly, and are often misdirected, making contact with inappropriate targets that can cause abnormal function. For example, if a motor nerve is damaged, regrowing axons may contact the wrong muscles, resulting in paralysis. In addition, where severed nerve processes result in a gap of longer than a few millimeters, e.g., greater than 10 millimeters (mm), appropriate nerve regeneration does not occur, either because the processes fail to grow the necessary distance, or because of misdirected axonal growth. Efforts to repair peripheral nerve damage by surgical means has met with mixed results, particularly where damage extends over a significant distance. In some cases, the suturing steps used to obtain proper alignment of severed nerve ends stimulates the formulation of scar tissue which is thought to inhibit axon regeneration. Even where scar tissue formation has been reduced, as with the use of nerve guidance channels or other tubular prostheses, successful regeneration generally still is limited to nerve damage of less than 10 millimeters in distance. In addition, the reparative ability of peripheral neurons is significantly inhibited where an injury or neuropathy affects the cell body itself or results in extensive degeneration of a distal axon.
Mammalian neural pathways also are at risk due to damage caused by neoplastic lesions. Neoplasias of both the neurons and glial cells have been identified. Transformed cells of neural origin generally lose their ability to behave as normal differentiated cells and can destroy neural pathways by loss of function. In addition, the proliferating tumors may induce lesions by distorting normal nerve tissue structure, inhibiting pathways by compressing nerves, inhibiting cerbrospinal fluid or blood supply flow, and/or by stimulating the body""s immune response. Metastatic tumors, which are a significant cause of neoplastic lesions in the brain and spinal cord, also similarly may damage neural pathways and induce neuronal cell death.
One type of morphoregulatory molecule associated with neuronal cell growth, differentiation and development is the cell adhesion molecule (xe2x80x9cCAMxe2x80x9d), most notably the nerve cell adhesion molecule (N-CAM). The CAMs are members the immunoglobulin super-family. They mediate cellxe2x80x94cell interactions in developing and adult tissues through homophilic binding, i.e., CAMxe2x80x94CAM binding on apposing cells. A number of different CAMs have been identified. Of these, the most thoroughly studied are N-CAM and L-CAM (liver cell adhesion molecules), both of which have been identified on all cells at early stages of development, as well as in different adult tissues. In neural tissue development, N-CAM expression is believed to be important in tissue organization, neuronal migration, nerve-muscle tissue adhesion, retinal formation, synaptogenesis, and neural degeneration. Reduced N-CAM expression also is thought to be associated with nerve dysfunction. For example, expression of at least one form of N-CAM, N-CAM-180, is reduced in a mouse demyelinating mutant. Bhat, Brain Res. 452: 373-377 (1988). Reduced levels of N-CAM also have been associated with normal pressure hydrocephalus, Werdelin, Acta Neurol. Scand. 79: 177-181 (1989), and with type II schizophrenia. Lyons, et al., Biol. Psychiatry 23: 769-775 (1988). In addition, antibodies against N-CAM have been shown to disrupt functional recovery in injured nerves. Remsen, Exp. Neurobiol. 110: 268-273 (1990).
Currently no satisfactory method exists to repair the damage caused by traumatic injuries of motor neurons and diseases of motor neurons.
There are 15,000 to 18,000 new cases of spinal cord injury each year in the United States. In addition, there are approximately 200,000 survivors of spinal cord injury. The annual cost of care for these patients exceeds $7 billion. The pathophysiology following acute spinal cord trauma is a complex and not fully understood mechanism. The primary tissue damage caused by mechanical trauma occurs immediately and is irreversible. Allen, J. Am. Med. Assoc. 57: 878-880 (1911). Experimental evidence indicates that much of the post-traumatic tissue damage is the result of a reactive process that begins within minutes after the injury and continues for days or weeks. Janssen, et al., Spine 14: 23-32 (1989) and Panter, et al., (1992). This progressive, self-destructive process includes pathophysiological mechanisms such as hemorrhage, post-traumatic ischemia, edema, axonal and neuronal necrosis, and demyelinization followed by cyst formation and infarction. For review, see Tator, et al., J. Neurosurg, 75: 15-26 (1991) and Faden, Crit. Rev. Neurobiol. 7: 175-186 (1993). Proposed injurious factors include electrolyte changes whereby increased intracellular calcium initiates a cascade of events (Young, J. Neurotrauma 9, Suppl. 1: S9-S25 (1992) and Young, J. Emerg. Med 11: 13-22 (1993)), biochemical changes with uncontrolled transmitter release (Liu, et al., Cell 66: 807-815 (1991) and Yanase, et al., J. Neurosurg 83: 884-888 (1995), arachidonic acid release, free-radical production, lipid peroxidation (Braughler, et al., J. Neurotrauma 9, Suppl. 1: S1-S7 (1992), eicosanoid production (Demediuk, et al., J. Neurosci. Res. 20: 115-121 (1988), endogenous opioids (Faden, et al., Ann Neurol. 17: 386-390 (1985), metabolic changes including alterations in oxygen and glucose (Faden, Crit. Rev. Neurobiol. 7: 175-186 (1993)), inflammatory changes (Blight, J. Neurotrauma 9, Suppl. 1: S83-S91 (1992), and astrocytic edema (Kimelberg, J. Neurotrauma 9, Suppl. 1: S71-S81 (1992). For the past 400 years surgical approaches including laminectomy and decompression, accompanied by fusion, have been the most commonly practiced treatment strategies. Hansebout, xe2x80x9cEarly Management of Acute Spinal Cord Injuryxe2x80x9d, pp. 181-196 (1982) and Janssen, et al., Spine 14: 23-32 (1989). However, these procedures have not involved the application of techniques to augment the regenerative properties of spinal cord tissue.
A host of diseases of motor neurons have been identified, including demyelinating diseases, myelopathies, and diseases of motor neurons such as amyotrophic lateral sclerosis (ALS). INTERNAL MEDICINE, ch. 121-123 (4th ed., J. H. Stein, ed., Mosby, 1994). Multiple sclerosis (MS) is the most common demyelinating disorder of the central nervous system, causing patches of sclerosis (i.e., plaques) in the brain and spinal cord. MS has protean clinical manifestations, depending upon the location and size of the plaque. Typical symptoms include visual loss, diplopia, nystagmus, dysarthria, weakness, paresthesias, bladder abnormalities, and mood alterations. Myriad treatments have been proposed for this long-term variable illness. The list of proposed treatments encompasses everything from diet to electrical stimulation to acupuncture, emotional support, and various forms of immunosupressive therapy. None have proved to be satisfactory.
Progressive loss of lower and upper motor neurons occurs in several diseases (e.g., primary lateral sclerosis, spinal muscular atrophy, benign focal amyotrophy). However, ALS is the most common form of motor neuron disease. Loss of both lower and upper motor neurons occur in ALS. Symptoms include progressive skeletal muscle wasting, weakness, gasciculations, and cramping. Some cases have predominant involvement of brainstem motoneurons (progressive bulbar palsy). Unfortunately, treatment of motor neuron and related diseas is largely supportive at this time. INTERNAL MEDICINE, ch. 123 (4th ed., J. H. Stein, ed., Mosby, 1994).
Accordingly, there is a need in the art for treatments of motor neurons disorders and injuries, and related deficits in neural functions.
The present invention provides methods and compositions for maintaining neural pathways in a mammal in vivo, including methods for enhancing the survival of neural cells.
In a preferred embodiment, methods of the invention for treating motor neuron defects, including amyotrophic lateral sclerosis, multiple sclerosis, and spinal cord injury comprise administering a morphogen comprising a dimeric protein having an amino acid sequence selected from the group consisting of a sequence have 70% homology with the C-terminal seven-cysteine skeleton of human OP-1 (amino acids 330-341 of SEQ ID NO:2), a sequence having greater than 60% amino acid sequence identity with human OP-1; generic sequence 7 (SEQ ID NO:4); generic sequence 8 (SEQ ID NO:6); generic sequence 10 (SEQ ID NO:7); and OPX (SEQ ID NO:3); wherein the morphogen stimulates production of N-CAM or L1 isoforms by an NG108-15 cell in vivo. Spinal cord injuries include injuries resulting from a tumor, mechanical trauma, and chemical trauma. The same or similar methods are contemplated to restore motor function in a mammal having amyotrophic lateral sclerosis, multiple sclerosis, or a spinal cord injury. Administering one of the aforementioned morphogens also provides a prophylactic function. Such administration has the effect of preserving motor function in a mammal having, or at risk of having, amyotrophic lateral sclerosis, multiple sclerosis, or a spinal cord injury. Also according to the invention, morphogen administration preserves the integrity of the nigrostriatal pathway.
Specifically, methods of the invention for treating (pre- or post-symptomatically) amyotrophic lateral sclerosis, multiple sclerosis, or a spinal cord injury comprise administering a morphogen selected from the group consisting of human OP-1, mouse OP-1, human OP-2, mouse OP-2, 60A, GDF-1, BMP2A, BMP2B, DPP, Vg1, Vgr-1, BMP3, BMP5, and BMP6. Such morphogens are capable of stimulating production of N-CAM or L1 isoform by an NG108-15 cell in vivo.
In a particularly-preferred embodiment, the morphogen is a soluble complex, comprising at least one morphogen pro domain, or fragment thereof, non-covalently attached to a mature morphogen.
In one aspect, the invention features compositions and therapeutic treatment methods comprising administering to a mammal a therapeutically effective amount of a morphogenic protein (xe2x80x9cmorphogenxe2x80x9d), as defined herein, upon injury to a neural pathway, or in anticipation of such injury, for a time and at a concentration sufficient to maintain the neural pathway, including repairing damaged pathways, or inhibiting additional damage thereto.
In another aspect, the invention features compositions and therapeutic treatment methods for maintaining neural pathways. Such treatment methods include administering to the mammal, upon injury to a neural pathway or in anticipation of such injury, a compound that stimulates a therapeutically effective concentration of an endogenous morphogen. These compounds are referred to herein as morphogen-stimulating agents, and are understood to include substances which, when administered to a mammal, act on tissue(s) or organ(s) that normally are responsible for, or capable of, producing a morphogen and/or secreting a morphogen, and which cause endogenous level of the morphogen to be altered.
In particular, the invention provides methods for protecting neurons from the tissue destructive effects associated with the body""s immune and inflammatory response to nerve injury. The invention also provides methods for stimulating neurons to maintain their differentiated phenotype, including inducing the redifferentiation of transformed cells of neuronal origin to a morphology characteristic of untransformed neurons. In one embodiment, the invention provides means for stimulating production of cell adhesion molecules, particularly nerve cell adhesion molecules (N-CAM). The invention also provides methods, compositions and devices for stimulating cellular repair of damaged neurons and neural pathways, including regenerating damaged dendrites or axons. In addition, the invention also provides means for evaluating the status of nerve tissue, and for detecting and monitoring neuropathies by monitoring fluctuations in morphogen levels.
In one aspect of the invention, the morphogens described herein are useful in repairing damaged neural pathways of the peripheral nervous system. In particular, morphogens are useful for repairing damaged neural pathways, including transected or otherwise damaged nerve fibers. Specifically, the morphogens described herein are capable of stimulating complete axonal nerve regeneration, including vascularization and reformation of the myelin sheath. Preferably, the morphogen preferably is provided to the site of injury in a biocompatible, bioresorbable carrier capable of maintaining the morphogen at the site and, where necessary, means for directing axonal growth from the proximal to the distal ends of a severed neuron. For example, means for directing axonal growth may be required where nerve regeneration is to be induced over an extended distance, such as greater than 10 mm. Many carriers capable of providing these functions are envisioned. For example, useful carriers include substantially insoluble materials or viscous solutions prepared as disclosed herein comprising laminin, hyaluronic acid or collagen, or other suitable synthetic, biocompatible polymeric materials such as polylactic, polyglycolic or polybutyric acids and/or copolymers thereof. A preferred carrier comprises an extracellular matrix composition derived, for example, from mouse sarcoma cells.
In a particularly preferred embodiment, a morphogen is disposed in a nerve guidance channel which spans the distance of the damaged pathway. The channel acts both as a protective covering and a physical means for guiding growth of a neurite. Useful channels comprise a biocompatible membrane, which may be tubular in structure, having a dimension sufficient to span the gap in the nerve to be repaired, and having openings adapted to receive severed nerve ends. The membrane may be made of any biocompatible, nonirritating material, such as silicone or a biocompatible polymer, such as polyethylene or polyethylene vinyl acetate. The casing also may be composed of biocompatible, bioresorbable polymers, including, for example, collagen, hyaluronic acid, polylactic, polybutyric, and polyglycolic acids. In a preferred embodiment, the outer surface of the channel is substantially impermeable.
The morphogen may be disposed in the channel in association with a biocompatible carrier material, or it may be adsorbed to or otherwise associated with the inner surface of the casing, such as is described in U.S. Pat. No. 5,011,486, provided that the morphogen is accessible to the severed nerve ends.
Morphogens described herein are also useful in autologous peripheral nerve segment implants, such as in the repair of damaged or detached retinas, or other damage to the optic nerve.
In another aspect of the invention, morphogens described herein are useful to protect against damage associated with the body""s immune/inflammatory response to an initial injury to nerve tissue. Such a response may follow trauma to nerve tissue, caused, for example, by an autoimmune dysfunction, neoplastic lesion, infection, chemical or mechanical trauma, disease, by interruption of blood flow to the neurons or glial cells, or by other trauma to the nerve or surrounding material. For example, the primary damage resulting from hypoxia or ischemia-reperfusion following occlusion of a neural blood supply, as in an embolic stroke, is believed to be immunologically associated. In addition, at least part of the damage associated with a number of primary brain tumors also appears to be immunologically related. Application of a morphogen, either directly or systemically alleviate and/or inhibit the immunologically related response to a neural injury. Alternatively, administration of an agent capable of stimulating morphogen expression and/or secretion in vivo, preferably at the site of injury, may also be used. Where the injury is to be induced, as during surgery or other aggressive clinical treatment, the morphogen or agent may be provided prior to induction of the injury to provide a neuroprotective effect to the nerve tissue at risk.
Generally, morphogens useful in methods and compositions of the invention are dimeric proteins that induce morphogenesis of one or more eukaryotic (e.g., mammalian) cells, tissues or organs. Tissue morphogenesis includes de novo or regenerative tissue formation, such as occurs in a vertebrate embryo during development. Of particular interest are morphogens that induce tissue-specific morphogenesis at least of bone or neural tissue. As defined herein, a morphogen comprises a pair of polypeptides that, when folded, form a dimeric protein that elicits morphogenetic responses in cells and tissues displaying morphogen-specific receptors. That is, the morphogens generally induce a cascade of events including all of the following in a morphogenically permissive environment: stimulating proliferation of progenitor cells; stimulating the differentiation of progenitor cells; stimulating the proliferation of differentiated cells; and, supporting the growth and maintenance of differentiated cells. xe2x80x9cProgenitorxe2x80x9d cells are uncommitted cells that are competent to differentiate into one or more specific types of differentiated cells, depending on their genomic repertoire and the tissue specificity of the permissive environment in which morphogenesis is induced. An exemplary progenitor cell is a hematopoeitic stem cell, a mesenchymal stem cell, a basement epithelium cell, a neural crest cell, or the like. Further, morphogens can delay or mitigate the onset of senescence- or quiescence-associated loss of phenotype and/or tissue function. Still further, morphogens can stimulate phenotypic expression of a differentiated cell type, including expression of metabolic and/or functional, e.g., secretory, properties thereof. In addition, morphogens can induce redifferentiation of committed cells (e.g., osteoblasts, neuroblasts, or the like) under appropriate conditions. As noted above, morphogens that induce proliferation and/or differentiation at least of bone or neural tissue, and/or support the growth, maintenance and/or functional properties of neural tissue, are of particular interest herein. See, e.g., WO 92/15323, WO 93/04692, WO 94/03200 (providing more detailed disclosures as to the tissue morphogenic properties of these proteins).
As used herein, the terms xe2x80x9cmorphogen,xe2x80x9d xe2x80x9cbone morphogen,xe2x80x9d xe2x80x9cbone morphogenic protein,xe2x80x9d xe2x80x9cBMP,xe2x80x9d xe2x80x9cmorphogenic proteinxe2x80x9d and xe2x80x9cmorphogenetic proteinxe2x80x9d all embrace the class of proteins typified by human osteogenic protein 1 (hOP-1). Nucleotide and amino acid sequences for hOP-1 are provided in SEQ ID NOS:1 and 2, respectively. For ease of description, hOP-1 is considered a representative morphogen. It will be appreciated that OP-1 is merely representative of the TGF-xcex2 subclass of true tissue morphogens and is not intended to limit the description. Other known and useful morphogens include, but are not limited to, BMP-2, BMP-3, BMP-3b, BMP-4, BMP-5, BMP-6, BMP-8, BMP-9, BMP-10, BMP-11, BMP-12, BMP-13, BMP-15, GDF-1, GDF-2, GDF-3, GDF-5, GDF-6, GDF-7, GDF-8, GDF-9, GDF-10, GDF-11, GDF-12, 60A, NODAL, UNIVIN, SCREW, ADMP, and NEURAL, and morphogenically-active amino acid variants of any thereof.
In specific embodiments, useful morphogens include those sharing the conserved seven cysteine skeleton, and sharing at least 70% amino acid sequence homology (similarity), within the C-terminal seven-cysteine skeleton of human OP-1, residues 330-431 of SEQ ID NO:2 (hereinafter referred to as the xe2x80x9creference sequencexe2x80x9d). In another embodiment, the invention encompasses use of biologically active species (phylogenetic) variants of any of the morphogenic proteins recited herein, including conservative amino acid sequence variants, proteins encoded by degenerate nucleotide sequence variants, and morphogenically-active proteins sharing the conserved seven cysteine skeleton as defined herein and encoded by a DNA competent to hybridize under standard stringency conditions to a DNA encoding a morphogenic protein disclosed herein, including, without limitation, OP-1 or BMP-2 or BMP-4. Presently, however, the reference sequence is that of residues 330-431 of SEQ ID NO:2 (OP-1).
In still another embodiment, morphogens useful in methods and compositions of the invention are defined as morphogenically-active proteins having any one of the generic sequences defined herein, including OPX (SEQ ID NO:3) and Generic Sequences 7 and 8 (SEQ ID NOS:4 and 5, respectively), or Generic Sequences 9 and 10 (SEQ ID NOS:6 and 7, respectively). OPX encompasses the observed variation between the known phylogenetic counterparts of the osteogenic OP-1 and OP-2 proteins, and is described by the amino acid sequence presented herein below and in SEQ ID NO:3. Generic Sequence 9 is a 96 amino acid sequence containing the C-terminal six cysteine skeleton observed in hOP-1 (residues 335-431 of SEQ ID NO:2) and wherein the remaining residues encompass the observed variation among OP-1, OP-2, OP-3, BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, BMP-8, BMP-9, BMP-10, BMP-11, BMP-15, GDF-1, GDF-3, GDF-5, GDF-6, GDF-7, GDF-8, GDF-9, GDF-10, GDF-11, 60A, UNIVIN, NODAL, DORSALIN, NEURAL, SCREW and ADMP. That is, each of the non-cysteine residues is independently selected from the corresponding residue in this recited group of known, naturally-sourced proteins. Generic Sequence 10 is a 102 amino acid sequence which includes a five amino acid sequence added to the N-terminus of the Generic Sequence 9 and defines the seven cysteine skeleton observed in hOP-1 (330-431 SEQ ID NO:2). Generic Sequences 7 and 8 are 96 and 102 amino acid sequences, respectively, containing either the six cysteine skeleton (Generic Sequence 7) or the seven cysteine skeleton (Generic Sequence 8) defined by hOP-1 and wherein the remaining non-cysteine residues encompass the observed variation among OP-1, OP-2, OP-3, BMP-2, BMP-3, BMP-4, 60A, DPP, Vg1, BMP-5, BMP-6, Vgr-1, and GDF-1.
Of particular interest are morphogens which, when provided to a specific tissue of a mammal, induce tissue-specific morphogenesis or maintain the normal state of differentiation and growth of that tissue. In preferred embodiments, the present morphogens induce the formation of vertebrate (e.g., avian or mammalian) body tissues, such as but not limited to nerve, eye, bone, cartilage, bone marrow, ligament, tooth dentin, periodontium, liver, kidney, lung, heart, or gastrointestinal lining. Preferred methods may be carried out in the context of developing embryonic tissue, or at an aseptic, unscarred wound site in post-embryonic tissue. Methods of identifying such morphogens, or morphogen receptor agonists, are known in the art and include assays for compounds which induce morphogen-mediated responses (e.g., induction of endochondral bone formation, induction of differentiation of metanephric mesenchyme, and the like). In a preferred embodiment, morphogens of the invention, when implanted in a mammal in conjunction with a matrix permissive of bone morphogenesis, are capable of inducing a developmental cascade of cellular and molecular events that culminates in endochondral bone formation. See, U.S. Pat. No. 4,968,590; Sampath, et al., Proc. Natl. Acad. Sci. USA 80: 6591-6595 (1983), the disclosures of which are incorporated by reference herein.
In an alternative preferred embodiment, morphogens of the invention are also capable of stimulating production of cell adhesion molecules, including nerve cell adhesion molecules (N-CAMs). In a preferred embodiment, the present morphogens are capable of stimulating the production of N-CAM in vitro in NG108-15 cells, which are a preferred model system for assessing neuronal differentiation, particularly motor neuron differentiation.
In still other embodiments, an agent which acts as an agonist of a morphogen receptor may be administered instead of the morphogen itself. An xe2x80x9cagonistxe2x80x9d of a receptor is a compound which binds to the receptor, and for which the result of such binding is similar to the result of binding the natural, endogenous ligand of the receptor. That is, the compound must, upon interaction with the receptor, produce the same or substantially similar transmembrane and/or intracellular effects as the endogenous ligand. Thus, an agonist of a morphogen receptor binds to the receptor and such binding has the same or a functionally similar result as morphogen binding (e.g., induction of morphogenesis). The activity or potency of an agonist can be less than that of the natural ligand, in which case the agonist is said to be a xe2x80x9cpartial agonist,xe2x80x9d or it can be equal to or greater than that of the natural ligand, in which case it is said to be a xe2x80x9cfull agonist.xe2x80x9d Thus, for example, a small peptide or other molecule which can mimic the activity of a morphogen in binding to and activating the morphogen""s receptor may be employed as an equivalent of the morphogen. Preferably the agonist is a full agonist, but partial morphogen receptor agonists may also be advantageously employed. Such an agonist may also be referred to as a morphogen xe2x80x9cmimic,xe2x80x9d xe2x80x9cmimetic,xe2x80x9d or xe2x80x9canalog.xe2x80x9d
Morphogen inducers and agonists can be identified by mutation, site-specific mutagenesis, combinatorial chemistry, etc. Such methods are well known in the art. For example, methods of identifying morphogen inducers or agonists of morphogen receptors may be found in U.S. Pat. No. 08/478,097 filed Jun. 7, 1995 now U.S. Pat. No. 6,040,431 and U.S. Pat. No. 08/507,598 filed Jul. 26, 1995, now U.S. Pat. No. 5,834,188 the disclosures of which are incorporated herein by reference. Candidate morphogen inducers and agonists are then tested for their ability to induce endochondral bone formation and preferably, to stimulate N-CAM production in neurons or in a neuronal model system, such as NG108-15 cells. Morphogen inducers and agonists identified according to the present invention are capable of inducing endochondral bone formation when implanted in a mammal in conjunction with a matrix permissive of bone morphogenesis and are capable of stimulating production of N-CAM in vitro.

Methods and compositions for the treatment of motor neuron injury and neuropathy


A polymer for an electrode protective layer including a polymer (A) including a fluorine-based polymer in which a monomer unit including poly(alkylene oxide) and a monomer unit including a curable functional group (e.g., a thermocurable functional group or a photocurable functional group) are grafted on the fluorine-based polymer, and when preparing an electrode by coating an electrode active material layer using the polymer and curing (e.g., thermally curing or photocuring) the result, excellent lithium ion conductivity is obtained since lithium ion flow is not inhibited, chemical resistance for an electrolyte liquid is high, and voltage stability of a secondary battery may be enhanced by suppressing side reactions with the electrolyte liquid occurring on an electrode active material surface due to properties of a uniform and flexible protective layer.

A secondary battery that is representatively known among electrochemical devices refers to a device storing external electrical energy after converting to a form of chemical energy, and generating electricity when needed. A term "rechargeable battery" is also used in that the battery is able to be charged many times. Commonly used secondary batteries may include a lead storage battery, a nickel-cadmium (Ni—Cd) battery, a nickel hydrogen (NiMH) storage battery, a lithium ion (Li-ion) battery, and a lithium ion polymer (Li-ion polymer) battery. Secondary batteries offer both economic and environmental advantages over one-time-use primary batteries.
With recent gradual development of wireless communication technologies, weight lightening of portable devices or automobile accessories has been required, and demands for secondary batteries used as an energy source for these devices have increased.
High energy density lithium secondary batteries mainly used in laptops and smart phones currently include a positive electrode formed with lithium oxide, a carbon-based negative electrode, a separator, and a liquid-state or solid-state electrolyte. As application areas for lithium secondary batteries expand to electric vehicles (EV) or energy storage systems (ESS), environments for the battery use become severe such that the driving voltage increases to 4.5 V or higher, and metal lithium is used as a negative electrode. A metal lithium negative electrode has received much attention with very high theoretical specific capacity of 3860 mAh/g and lowest electrochemical potential of −3.04 V (vs. standard hydrogen electrode), however, commercialization thereof has been delayed due to problems such as side reactions with an electrolyte liquid or non-uniform deposition/elution of lithium.
Metal lithium continuously forms a solid electrolyte interface (SEI) through a reaction with an organic electrolyte liquid and a lithium salt dissolved therein. The SEI layer continues to undergo destruction and regeneration while a charge and discharge cycle of a battery is repeated, and a newly exposed lithium metal surface reacts again with an electrolyte liquid to induce a decrease in the Coulombic efficiency and a short-circuit through lithium dendrite growth in the battery, which delays commercialization of a secondary battery using a metal lithium electrode.
As a solution to such a problem, attempts to coat a stable artificial SEI layer on an electrode active material surface such as lithium metal, and improve cycle properties therethrough have been made. For example, studies on improving cycle properties through suppressing lithium dendrite formation or side reactions by applying and coating polyacetylene, tetraethoxysilane, lithium phosphorous oxynitride, alumina particles, an ultra-thin alumina film or the like on a lithium film have been actively progressed. However, a phenomenon of reduced electrode protective effect was still observed after continuous battery driving, and this has been analyzed to be due to low lithium ion conductivity of an electrode, low flexibility, and crack occurrences caused by a non-uniform coating film.

Electrode protective layer polymer and secondary battery to which same is applied


A pseudo noise superimposing unit superimposes a pseudo noise (M-sequence) to an audio signal picked up by a microphone and outputs the superimposed signal to an amplifying system. An calculating unit calculates a correlation value between the audio signal picked up by the microphone and the pseudo noise. The calculating unit estimates a gain of a closed loop based on the correlation value. A gain control unit suppresses a gain of the audio signal based on the estimated gain of the closed loop.

Various techniques for preventing howling in a loud speaker system for a lecture, a concert or the like have been provided. In a general howling suppression method, when occurrence of howling is detected, a frequency range causing the howling is attenuated by a filter.
In an audio signal amplifier circuit described in patent document 1, when howling is detected, a low pass filter for removing howling is operated so as to decrease a gain of the audio signal amplifier circuit. The audio signal amplifier circuit checks whether or not the howling is detected by stopping the operation of the low pass filter at every predetermined time interval. The audio signal amplifier circuit decreases the gain in a stepwise manner until the howling is not detected. The audio signal amplifier circuit fixes the gain when the howling is not detected.
Patent document 2 discloses a method in which presence or absence of occurrence of howling is detected based on a frequency characteristic of an input signal and a filter characteristic for suppressing howling is calculated.
Non-patent document 1 proposes a howling canceller with the use of synchronized addition of an M-sequence noise. The howling canceller described in the non-patent document 1 outputs in advance a high level M-sequence noise so as to perform a training of an adaptive filter. The howling canceller outputs the M-sequence noise having a low level during its operation so as to continuously update the adaptive filter. In addition, the howling canceller disclosed in the non-patent document 1 determines that a disturbance level is high and stops the updating of the adaptive filter in a case where an input level of a microphone becomes high, because when the disturbance level becomes high due to continuous speaking of a person or generation of a sound of a musical instrument, the updating of the adaptive filter is inhibited.
Patent Document 1: JP-A-7-15788
Patent Document 2: JP-A-6-327088
Non-patent Document 1: "Inspection relating to removal of howling in an audio system" by Makoto Itami, Mitsutoshi Hatori, Institute of Electronics, Information, and Communication Engineers, Technical Reports EA89-4, in 1989

Loop gain estimating apparatus and howling preventing apparatus


A method provides for producing a cable connection assembly including an electrical cable connected to a cable connector. The cable connector is positioned on a conductor end portion, so that a portion of the insulating layer is at least partially surrounded by the cable connector. The conductor end portion is disposed within a fastening tube, so that a first tube portion of the fastening tube surrounds the cable connector, and a second tube portion of the fastening tube surrounds the cable jacket. The fastening tube is pressed between strip-shaped pressing surfaces which are disposed around a central axis at a constant distance therefrom. During the pressing step, the first tube portion is pressed to a first inner diameter and the second tube portion is pressed to a second inner diameter greater than the first inner diameter.

Today, due to the increasing digitization of components and systems and the associated increasing amount of data to be transmitted, increasingly higher demands are being placed on the electrical cables required for transmission. In particular, a constantly high signal transmission quality over large frequency ranges combined with low, or at least constant attenuation over the respective frequency range plays an increasingly central role.
In order to meet these requirements, use is made of coaxial cables, for example. The coaxial arrangement of the inner conductor, dielectric, and shield largely ensures high signal transmission quality combined with low attenuation and low susceptibility to interference, provided the coaxial configuration and the associated characteristic impedance are maintained substantially constant over the entire length of the electrical cable. However, the cable ends, on which typically connector systems are mounted to communicatively connect the electrical cable to the components between which data is to be transmitted, are problematic in this context. During mounting of the connector system to the electrical cable, it is common that unwanted discontinuities are formed, for example by asymmetrical deformation of the electrical cable during attachment of the connector system to the electrical cable. Such discontinuities can affect the overall transmission quality of signals to be transmitted. For example, the discontinuities can cause frequency-dependent attenuations, also referred to as "notches." However, during mounting of the connector system to the electrical cable, it must be ensured at the same time that the connection between the connector system and the electric cable is sufficiently stable to ensure safe use of the electrical cable and the connector system. However, with the presently known connection methods, it is not possible to connect a connector system to an electrical cable in a reliable process without adversely affecting the transmission quality.

Method and device for producing a cable connection assembly


Disclosed is a consumer processing system for identifying and recognizing a consumer engaged in a transaction with a merchant. The system includes a consumer processing system interface for receiving, from a merchant, a consumer/transaction data set with a plurality of fields. A consumer/transaction database is populated with data sets, and each data set is related to a specific consumer and also includes multiple data fields therein. The consumer/transaction data set is established as part of an initial data set in the consumer/transaction database, and thereafter, during subsequent transactions, compared to an existing data field in an existing data set in the consumer/transaction database. Based upon the establishment or comparison, a consumer activity data set is communicated from the consumer processing system interface to the merchant. A method of identifying and recognizing a consumer engaged in a transaction with a merchant is also disclosed.

1. Field of the Invention
The present invention relates generally to consumer processing and transaction systems and, in particular, to a consumer processing system and method for identifying and recognizing a consumer or customer engaged in a transaction with a merchant, such as the identification and recognition of a repeat customer at a particular point-of-sale.
2. Description of Related Art
In order to enable convenient purchases or goods and services by consumers, the financial service industry has developed many alternative payment methods that allow a consumer to engage in a transaction and receive goods and services on credit. For example, such alternative payment methods may include checks, ATM or debit cards, credit cards, charge cards, etc. In addition, these credit vehicles are able to be used on many platforms and via many communication methods and processes. For example, a credit or charge card may be used over the telephone, by mail or electronically over the Internet or at an in-store location. The benefit of existing payment methods allows a consumer to move the point-of-sale (POS) from an in-store location to one's home. For example, a consumer may place an order from a catalog over the telephone and use a credit card or a charge card to pay for the goods and/or services. A similar process can be used for mail orders.
Virtual commerce and the growth of the Internet as a medium for commerce have placed pressure on the payment options discussed above with respect to both convenience, transactional security and profitability by the credit issuer. However, the consumer's convenience is paramount, and the Internet provides yet another POS, or option, to the consumer for purchasing goods and/or services via an alternative medium. This growth in commerce on the Internet and over the telephone has also placed additional burdens on the merchant, such as identification and recognition of a customer. However, this burden also may lead to certain benefits, such as the ability to identify and recognize customers in not only a negative sense, such as in the identification of fraud or bad credit, but also in a positive sense, such as in the opportunity to offer additional benefit to a repeat customer in good standing.
Moving the POS to the consumer's home, the consumer can use the telephone or otherwise conduct business over the Internet, which provides a tangible benefit to the consumer. Such remote transactions provide the consumer with a certain amount of anonymity, as well as a much greater amount of convenience in making purchases. Likewise, the merchant obtains more business by opening up these lines of communication and allowing for the engagement in such a transaction at remote points-of-sale.
However, both the consumers and the merchants suffer in one important respect. In particular, when operating in a real-time sales environment, the merchant typically has no way of quickly determining whether a consumer is a repeat customer. Accordingly, the merchant may suffer by offering goods and services to a person with a fraudulent history or bad credit characteristics, based upon these previous sales. Such activity is detrimental to the merchant, and could have been avoided had the merchant been able to identify and recognize this repeat consumer. Similarly, both the merchant and consumer may suffer from this lack of identification and recognition on the "positive" side of a previous transaction. For example, a repeat and "good" customer may be offered additional benefits or special merchant offers, which will further engender the consumer to the merchant and provide the merchant with additional business. However, since such repeat consumers cannot be identified or recognized in many cases, the ability to provide such a benefit to the consumer, which indirectly also benefits the merchant, is unavailable.
Therefore, it is the merchant's ability to identify and recognize a consumer using various data transmitted to the merchant that allows for this mutually beneficial and ongoing consumer/merchant relationship. Of course, as discussed above, this relationship may be a potential "negative" relationship (such as in bad credit) or a "positive" relationship (such as in offering "perks" to the best customers). In either case, the merchant must have access to this valuable information and data in order to decide how best to interact with any individual consumer.
According to the prior art, existing merchants have used various approaches in order to overcome the inability to quickly identify repeat customers, such as quickly identifying repeat customers in a real-time sales environment. For example, some merchants attempt to solve this problem by requiring a log-in by the customer prior to purchase. Many times, this approach causes abandonment of shopping carts and reduces the total sales that a merchant will close. Therefore, this log-in process reduces the merchant's aggregate revenue and profit. Other merchants invest in software, purchased externally or internally developed, as well as hardware, to run real-time applications that use various methods to identify existing customers. However, such an approach raises a merchant's capital expenditure and operating costs. Still further, some merchants do neither the log-in process nor invest in any software, and forego the business benefit of knowing who was a repeat customer in real-time. These merchants usually run a monthly or weekly batch process to identify the repeat customers, but this process does not allow them any real-time benefit.


An apparatus for angular positioning of a mirror includes a motor that rotates a mirror, a detector that detects a rotational angle of the mirror, and a controller. The controller supplies current to the motor so that the rotational angle of the mirror reaches a target angle, estimates, based on a model representing a relation between a value of current to be supplied to the motor and an angle of inclination of the mirror, the angle of inclination of the mirror to which current is supplied, and if the estimated angle exceeds a predetermined tolerance, adjusts the supply of current to the motor so that the angle of inclination of the mirror falls within the predetermined tolerance.

Field of the Invention
The present invention relates to a mirror angular-positioning apparatus and a processing apparatus.
Description of the Related Art
A galvano apparatus is used in laser processing apparatuses (machine tools) such as a laser drilling machine, laser trimmer, and laser repairer. The galvano apparatus irradiates a target position with laser light by reflecting it by a mirror attached to the rotating shaft of a motor while controlling the rotational angle of the mirror. To accurately align the laser light irradiation position with the target position, it is necessary to accurately control the rotational angle of the mirror. Therefore, the galvano apparatus includes a detector (for example, a capacitive sensor or an optical or magnetic encoder) for detecting the rotational angle of the mirror. Note that the mirror of the galvano apparatus must be rotated at a high speed because the laser processing apparatus is required to have a high operating speed as well.
Also, in the galvano apparatus, if no dynamic balance is obtained between the motor rotating shaft and mirror or if a force generated by a magnet and coil of the motor contains a component in a direction other than the rotational direction, a vibration mode in which the mirror vibrates in a direction in which the mirror falls toward the motor rotating shaft is excited. To suppress this vibration of the mirror in the falling direction, Japanese Patent Laid-Open No. 61-116632 has proposed a technique of adjusting the dynamic balance to the motor rotating shaft.
In this prior art, however, it is impossible to sufficiently remove the vibration of the mirror in the falling direction when rapidly and accurately positioning the laser irradiation position (that is, the mirror rotational angle). In addition, the detector for detecting the mirror rotational angle in the conventional galvano apparatus cannot detect the vibration of the mirror in the falling direction. Accordingly, an article may be processed with this vibration existing, so a processing error may occur in the article. Especially when continuously positioning a laser in a plurality of irradiation positions, a positioning operation succeeding another positioning operation may be performed before the vibration of the mirror in the falling direction sufficiently attenuates. As a consequence, the waves of the vibrations may superpose each other to generate a large vibration.

Mirror angular-positioning apparatus and processing apparatus


Provided are frame interpolation apparatus and methods in which motion estimation is performed by separation into a static object and a moving object. The frame interpolation apparatus interpolates multiple frames including an nth frame and an (n−1)th frame located adjacent the nth frame in order to generate an interpolation frame. Some embodiments of the apparatus include a static object separation unit, a motion vector (MV) estimation unit, and an interpolation frame generation unit. The static object separation unit may compare a macroblock (MB) of the nth frame with an MB of the (n−1)th frame, which may correspond to the MB of the nth frame, in order to separate each MB of the nth frame into a static object and a moving object. The MV estimation unit may search in the (n−1)th frame for an MB that matches with each of MBs of the nth frame, which may be determined to be the moving object, to estimate an MV. The interpolation frame generation unit may generate the interpolation frame using the estimated MV, the nth frame, and the (n−1)th frame.

The present invention generally relates to electronic display control, and more particularly, to a frame rate conversion apparatus and method in which frames are converted.
Conventionally, in personal computers (PC) or high-definition televisions (HDTV), frame rate conversion may be performed for compatibility between programs having various broadcasting signal standards such as PAL or NTSC. Frame rate conversion may mean conversion of the number of frames that are output per second. In particular, when a frame rate is increased, interpolation of a new frame may be required. The interpolated frame may be referred to as an interpolation frame. To generate the interpolation frame, motion estimation (ME) may be used. ME may include searching for the most similar blocks between a previous frame and a current frame. A motion vector (MV) may indicate a magnitude of block's movement in ME.
A conventional ME method may be used to reduce temporal redundancy of video data and to generate the MV. Among various ME methods for generating the MV, a block matching algorithm (BMA) may be used. The BMA may search for movement in each block and apply a motion vector corresponding to the movement to all pixels included in the block. The BMA may require a small amount of time to be executed and can be easily implemented as hardware. In a general video, motions can be classified into rotation, translation, and zoom-in/out. In this regard, it may be assumed that a motion between frames having a very small interval therebetween is very little. Therefore, the BMA may be performed on the assumption that there is only translation in a video and motions of all pixels in the same block are the same. Thus, the BMA may search for a block that is most similar to a current block of a current frame in a search range of a previous frame and determine a displacement between the two blocks as an MV. This process may be called a full search. Each block may be composed of 16×16 pixels and may be called as a macroblock (MB).
Since the full search may perform comparison with all pixels included in the search range, it can find an MV having the smallest matching error. However, the full search may require significant computation resources. In other words, the conventional BMA may result in unnecessary computation and power consumption because it may perform ME even for a portion having no motion. Moreover, the conventional BMA may perform a wrong ME by not distinguishing between a static object and a moving object. In this regard, degradation in display quality may result when the wrong ME is applied to an interpolated image.

Frame interpolation apparatus and method for motion estimation through separation into static object and moving object


A light fixture includes a converter operable to drive a light source of the light fixture. The buck converter is operable to provide a predetermined average current to the light source or load. A switch of the buck converter is located in the low side of the buck converters such that a controller of the buck converter may drive the switch directly without the use of an isolation transformer. The buck converter controls operation of the switch based on current through the switch and current through the primary inductor of the buck converter.

The present invention relates generally to constant current driver circuits. More particularly, this invention pertains to improved buck converters for driving light emitting diodes (LEDs) to emit light from a light fixture.
Compared to incandescent lamps and fluorescent lamps, LED lighting has a longer useful life and superior dimming capability. That is, dimming an LED light source will not affect the life span of the LED light source. Thus, as the cost of LED lighting decreases, LED lighting is becoming the lighting of choice for most applications.
Referring to FIG. 1, an LED light source 104 needs a constant current driver circuit to provide a consistent level of light output. A buck converter 100 is the basis for most constant current LED driver circuits. The switch 102 (e.g., a MOSFET) in the conventional buck converter 100 is on the high side floating. A controller 106 of the converter 100 is typically an average current control integrated circuit that needs to be referred to the ground of the converter to sense the average current through the load (i.e., the LED light source 104). Thus, an isolation transformer is required for the controller 106 to turn the switch 102 on and off. The primary winding 108 of the isolation transformer is connected between a gate drive output of the controller 106 and a ground of the converter 100. The secondary winding 110 of the isolation transformer is connected between a control terminal of the switch 102 and a low side of the switch 102. A high side of the switch 102 is connected to a positive input of the converter 100. Eliminating the isolation transformer would reduce the cost, size, and complexity of the converter 100.

Constant current driver based on critical condition mode buck converter


There is provided a current sense circuit (134). An exemplary current sense circuit (134) comprises a voltage-to-current converter circuit (218) that is adapted to receive a voltage that is proportional to a load current drawn from a battery (110) by a load (202) and to produce a current proportional to the load current, and a current-to-voltage converter circuit (228) that is adapted to receive the current proportional to the load current and to produce a voltage proportional to the load current based on a regulated voltage source (230).

In many electronic systems, it is desirable to be able to measure the current drawn by one or more components or subsystems. Current drawn is related to the overall energy consumption of the system. If the current drawn by all devices of interest is accurately sensed, an accurate computation of energy being consumed by the system may be performed. If current measurements are not accurate, the accuracy of the overall energy calculation is reduced. Most motorized vehicles (for example, cars, buses and the like) include electronic systems that are subject to adverse conditions that may impact the accuracy of current measurements because of the location of the electronic systems in or on the vehicle. A significant factor that may affect current measurement accuracy is that automotive batteries are typically subject to wide swings in output voltage. Battery voltage swings result from many factors, including loading and state of battery charge. Another factor that is likely to affect measurement accuracy is a wide variation in temperature at the location where current is being measured. For example, an automotive engine compartment is subject to wide temperature variation depending on such factors as operating conditions and seasonal temperature change.
In addition, it may be desirable to provide short circuit protection for a load while the current flow to the load is measured. Another complicating factor is the desire to obtain an accurate current measurement in a manner that utilizes as little battery voltage as possible. In systems in which it is desirable to provide a digital value corresponding current drawn by a load, still another factor complicating current measurement is the desirability of protecting an analog-to-digital converter adapted to produce the digital value from being damaged by an over-voltage condition. For these reasons, it is a challenging problem to obtain accurate current draw measurements for devices and electronic systems that are powered by a battery in a motor vehicle.

Panasonic Automotive Systems Company of America, Division of Panasonic Corporation of North America


A spool valve for controlling the valve operation timing of an Internal combustion engine has its spool moved in accordance with an output duty Td so that an actual relative rotational angle .theta. may approach the target relative rotational angle .theta.a which is determined in accordance with the operating conditions of the engine. Here, the output duty Td is a sum of a learning ignition advance duty Ta and a temperature correcting duty Tthw. When the output duty Td is outputted, the spool is moved to a position where an oil pressure passage starts to be opened. From this position, the spool is further moved toward an ignition advance by the duty according to a deviation (.theta.a-.theta.). When the relative rotational angle .theta. approaches the angle .theta.a, a learning holding duty Th is outputted in place of the duty Ta so that the spool is controlled to a position where the oil pressure passage is closed. Incidentally, in case of movement toward an ignition lag, a learning ignition lag angle duty Tr is outputted in place of the duty Ta.

1. Field of the Invention
The present invention relates to a variable valve operation timing control device (VTT) for varying the valve operation timing of an internal combustion engine in accordance with the operating conditions of the engine.
2. Description of the Prior Art
As a mechanism for controlling the operation timings of intake valves variably in accordance with the operating conditions of an internal combustion engine, there has been known the variable valve operating timing control device for varying the rotational phase of a camshaft relative to a cam pulley rotating in synchronism with a crankshaft.
The variable valve operation timing control device, as disclosed in Japanese Patent Laid-Open No. 134010/1989, for example, is constructed to include: timing varying means having a hydraulic servo valve for varying the operation (or valve) timings of the intake valves of the internal combustion engine; and hydraulic drive means having a hydraulic cylinder for driving the spool of the servo valve.
In this prior art, moreover, two control valves of the hydraulic drive means are opened or closed to move the servo valve at a constant speed thereby to vary the valve timing of the timing varying means.
Thus in the prior art, the variable valve operation timing control device is complicated because its timing changing means and hydraulic drive means have to be equipped with the separate hydraulic system.
In the prior art, moreover, what is controlled by the two ON/OFF valves is to interrupt the individual supplies of the oil pressures. As a result, the prior art has found it difficult to control the movements of the servo valve delicately and its moving speed and to control the valve operation timing only finely and the moving speed to a desired value. Thus, the prior art is accompanied by a problem that it cannot perform finer controls.
It is, therefore, conceivable to adopt not the ON/OFF valve but a valve capable of controlling the quantity of oil by controlling its degree of opening to change the valve operation timing at a desired rate. If, however, this valve is used, the drive signal of the valve and the change of the valve operation timing may fail to be accurately timed, because of the dispersion in the valve manufacture or the oil leakage from the valve.
This results in another problem that the valve operation timing cannot be held as it is or cannot be varied.

Variable valve operation timing control device


A laminate tape that has a bottom layer of aggressive adhesive formulated to have sufficient adhesion to construction materials to as low as 20 degrees F. The adhesive is applied in a layer of about 2 to 5 mils. A second layer that is about 10 to 60 mils thick is made of rubberized asphalt, which provides self-sealing capabilities. In one embodiment, the first layer has strips of adhesive and sections of rubberized asphalt. The third layer is a film, which can be a thin, contiguous polymer, fabric or particulate. The laminate can be used where a strong adhesive is needed that will adhere to construction materials at or near 20 degrees Fahrenheit, while still retaining self-sealing characteristics.

1. Field of the Invention
This invention relates generally to a self-adhesive laminate and a method for using the laminate to seal around windows, doors, roofing, roof flashing and in other construction environments, and a method of constructing the laminate.
2. Description of the Related Art
In building construction generally, there are many areas of the building in which two materials do not seal perfectly. Even if materials seal well when installed, it is known that buildings settle and, with extremes in temperatures and humidity, buildings expand and contract. When these occur, two contacting materials will separate. Separation in materials that are designed to keep out air, moisture and pests can lead to inefficiency, damage and infestation.
In particular, prefabricated windows are supplied with a metal or polymer flange along their perimeter. This flange is typically nailed or screwed to the building sheathing, such as oriented strand board (OSB), during installation of the window in a rough opening formed in the wall for the window. The finish siding is applied over the sheathing and the flange, and commonly abuts a protruding portion of the window.
The flange is not typically sealed against the sheathing in a water-tight manner, and therefore wind-driven rain can leak around the flange. Leaks can be prevented if a tape is applied to seal the joint between the flange and sheathing before the finish siding is applied. Such tapes attach to at least part of the width of the flange, bridging over any gap between the flange and sheathing, and attaching to the sheathing. The laminate's adhesive forms a seal along the entire outer perimeter of the flange and along the sheathing directly adjacent the flange, thereby providing the water-tight seal needed to prevent inefficiency, damage and pest infestation.
Various types of adhesive tapes or laminates have been used to seal these flanges, and these laminates generally include a polyethylene or polyester film adhered to a bitumen layer, which is commonly rubberized asphalt. Such tapes and related materials are described in U.S. Pat. No. 4,936,938 to Simpson et al.; U.S. Pat. No. 5,096,759 to Simpson et al.; U.S. Pat. No. 5,142,837 to Simpson et al.; U.S. Pat. No. 6,103,356 to Messenger; U.S. Pat. No. 6,627,017 to Simpson; and U.S. Pat. No. 6,479,119 to Simpson. The foregoing patents are incorporated herein by reference.
Although the laminates discussed in the foregoing patents are advantageous over previous technology, they have some disadvantages under extreme conditions. For example, the bitumen layer that is self-sealing around fasteners that penetrate the laminate also has acceptable adhesive properties at temperatures greater than 60 degrees Fahrenheit. Thus, such bitumen layers provide the adhesion to window flanges and sheathing under optimal conditions. However, construction work often must be performed when temperatures fall to as low as 20 degrees Fahrenheit. Conventional laminates may not adhere acceptably in such circumstances, especially when the surfaces to which laminates must adhere have non-ideal textures to which adhesives do not readily adhere even under ideal temperature conditions. Because OSB is made with a waxy coating that provides release from forming molds, it is often difficult to adhere to OSB, even in warm weather.
Two types of adhesives are typically used on flashings for windows and doors: rubber modified asphalt and butyl rubber. A disadvantage of rubberized asphalts is that they have a relatively high temperature (such as 50 degrees F.) below which they lose sufficient adhesion. Butyl rubber adhesives retain their adhesive characteristics at lower temperatures, but are relatively expensive compared to asphalt based adhesives. Typically butyl rubber layers are not thick enough to provide nail-sealing capabilities without being prohibitively expensive.
The present invention solves these and other problems present in the prior art by providing a number of features. These features result in the present invention being a significant improvement over the prior art.


In order to manufacture an innerspring unit (31) comprising pocketed springs and having an increased stability at its edge regions, in a first step, an innerspring main body (30) comprising a plurality of first strings (14) of pocketed springs is provided. In a subsequent second step, at least one second string (13c, 13d) of pocketed springs is attached to a lateral surface of the innerspring main body (30), so that the at least one second string (13c, 13d) of pocketed springs extends in a longitudinal direction of the innerspring main body (30). The springs (13) of the at least one second string (13c, 13d) of pocketed springs have a spring characteristic or a spring geometry different from the springs of the plurality of first strings of the innerspring main body (30). The at least one second string (13c, 13d) of pocketed springs forms together with the innerspring main body (30) the innerspring unit (31).

The present invention relates to a method and an apparatus for manufacturing an innerspring unit comprising a plurality of pocketed or encased springs as well as a corresponding innerspring unit.
Innerspring units are typically used in innerspring mattresses. Conventional innerspring configurations include innerspring units in which coil springs are encased in welded pockets of a fabric material. Individual strings of such pocketed springs are connected to one another so as to form an array of a plurality of pocketed springs arranged in rows and columns.
Such innerspring units may be manufactured by innerspring unit assembly machines which make innerspring units from endless strings of pocketed springs. Conventional innerspring unit assembly machines produce innerspring units in which all of the springs have the same or very similar spring characteristics, e.g., spring diameter, wire diameter or spring material, resulting in a uniform spring stability across the entire innerspring unit, or in which the strings of pocketed springs only extend in one direction of the corresponding innerspring unit.
It is an object of the present invention to provide a manufacturing method and a manufacturing apparatus, which allow to manufacture innerspring units with an increased flexibility. In particular, it is an object of the present invention to provide a manufacturing method and a manufacturing apparatus, which allow to manufacture innerspring units having an increased stability in an edge area of the innerspring units. Moreover, it is an object of the present invention to provide such a manufacturing method and such a manufacturing apparatus, which allow to manufacture innerspring units having different pocketed springs with a different diameter in an edge area of the innerspring units. Finally, it is an object of the invention to provide such a manufacturing method and such a manufacturing apparatus which allow to manufacture innerspring units in an innerspring unit assembly machine using a fully automated process.

Apparatus for manufacturing an innerspring unit comprising pocketed springs


A new and distinct cultivar of an Anthurium andreanum plant named xe2x80x98Anthbnemxe2x80x99, as described and illustrated, and particular characterized by the combined features of compact plant growth and early and very rich flowering; mini-type pot plant, maximum growth to an average of 40 cm; long and erect peduncle, flowers held well above the foliage; full plant habit due to shoot formation, lush plant due to straight but flexible flower and leaf petioles; dark green leaves, compact, durable with light green primary veins; red and very durable flowers, lastingness of the inflorescence up to one year; and large amount of flowers in relation to the amount of leaves, resulting in an excellent leaf to flower size ratio.

Latin name of the genus and species of the plant claimed: Anthurium andreanum L.
Variety denomination: Anthbnem.
xe2x80x98Anthbnemxe2x80x99 is a new and distinct cultivar of Anthurium, botanically known as Anthurium andreanum L. The new cultivar is a product of a planned breeding program, and was obtained from a cross made during such a program in Bleiswijk, The Netherlands, in 1996.
The female or seed parent was a pink-colored Anthurium pot plant designated number 95-634-01 (unpatented). The male or pollen parent was an orange-colored flowering Anthurium pot plant designated number 95-532-02 (proprietary, unpatented). xe2x80x98Anthbnemxe2x80x99 was discovered and selected as a flowering plant within the progeny of the stated cross by the inventor, Jan van Dijk, in March, 1998 in a controlled environment in a glasshouse in Bleiswijk, The Netherlands.
Subsequent asexual reproduction by tissue culture at the same location has demonstrated that the combination of characteristics as herein disclosed for the new cultivar are firmly fixed and are retained through successive generations of asexual reproduction. The new cultivar reproduces true to type through successive generations of asexual reproduction.
The following traits have been repeatedly observed and in combination distinguish xe2x80x98Anthbnemxe2x80x99 as a new and distinct cultivar:
1. Compact plant growth and early and very rich flowering;
2. Mini-type pot plant, maximum growth to an average of 40 cm;
3. Long and erect scape, inflorescences held well above the foliage;
4. Full plant habit due to shoot formation, lush plant due to straight but flexible inflorescence and leaf petioles;
5. Dark green leaves, compact, durable with light green primary veins;
6. Red and very durable inflorescences, lastingness of the inflorescence up to one year; and
7. Large amount of inflorescences in relation to the amount of leaves, resulting in an excellent leaf to inflorescence size ratio.


Multiple strain states in epitaxial transistor channel material may be achieved through the incorporation of stress-relief defects within a seed material. Selective application of strain may improve channel mobility of one carrier type without hindering channel mobility of the other carrier type. A transistor structure may have a heteroepitaxial fin including a first layer of crystalline material directly on a second layer of crystalline material. Within the second layer, a number of defected regions of a threshold minimum dimension are present, which induces the first layer of crystalline material to relax into a lower-strain state. The defected regions may be introduced selectively, for example a through a masked impurity implantation, so that the defected regions may be absent in some transistor structures where a higher-strain state in the first layer of crystalline material is desired.

Demand for higher performance integrated circuits (ICs) in electronic device applications has motivated increasingly complex transistor architectures. Some transistor structures include multiple layers of crystalline semiconductor material engineered to induce strain within a channel layer of the transistor because certain types of strain have been found to increase charge carrier mobility, reducing the time needed for a charge carrier to transit between source and drain terminals, across a channel of a given length.
However, because benefits of channel strain are dependent on the polarity of the charge carrier (e.g., electron vs. hole) it is important to introduce channel strain of a given type (compressive vs. tensile) selectivity to only the subset of transistor structures within a complementary metal-oxide-semiconductor (CMOS) IC that will benefit. For example, one may wish to decrease hole transit times to speed up PMOS transistor structures without negatively impacting electron transit times in adjacent NMOS transistor structures. This goal can be challenging to implement in high volume manufacture of CMOS ICs as it may require PMOS and NMOS transistor structures to have two different channel materials (e.g., one material that is strained and one that is not), and/or two different channel encapsulants (e.g., a high and low or compressive/tensile stressed dielectric), and/or two different source/drain materials (e.g., a high and low or compressive/tensile stressed raised epitaxy), etc. Beyond the complexity of selectively forming or patterning any such materials, the selective incorporation of dissimilar material layers might induce further manufacturing complexities. For example, PMOS transistors may be required to have a different height than NMOS transistors, which sacrifices the simplicity inherent to a highly planar device layer. Transistor architectures and fabrication techniques that can avoid these issues would therefore be advantageous.

Multiple strain states in epitaxial transistor channel through the incorporation of stress-relief defects within an underlying seed material


An acoustic wave device includes a plurality of acoustic wave devices each including a substrate made of a piezoelectric material, a pair of interdigital electrodes formed on the substrate, each of the interdigital electrodes including a plurality of electrode fingers, and an adjustment medium. The adjustment medium includes at least a single layer and is formed on at least a part of the pair of the interdigital electrodes. The adjustment medium further includes at least one thick portion and a thin portion, the thin portion being null or thinner than the thick portion, a total area of the at least one thick portion in a region covering the pair of interdigital electrodes being determined according to a predetermined characteristic value, wherein the plurality of acoustic wave devices include at least two acoustic wave devices that differ from each other with respect to the size of the total area of the at least one thick portion of the adjustment medium.

A surface acoustic wave (SAW) device is well known as a device of application of acoustic waves. A SAW device is utilized in various circuits for processing radio signals across a frequency band ranging from 45 MHz to 2 GHz typically used for cellular phones, etc. Examples of the various circuits include transmission band-pass filters, reception band-pass filters, local oscillation filters, antenna duplexers, IF filters, and FM modulators.
In recent years, the acoustic wave devices are required to improve the characteristics such as high suppression over frequencies out of the band in use and an increase of a temperature stability due to demands of higher performances and downsizing of cellular phones. The method for improving temperature stability has been developed in which a dielectric such as SiO2 is formed on an interdigital electrode of a piezoelectric substrate. Furthermore, boundary-wave devices have been developed to downsize the devices using the boundary-wave devices. The boundary-wave device has an additional dielectric layer on the dielectric layer formed on the interdigital electrode due to trap energy between the surfaces of the additional dielectric layer and the piezoelectric substrate.
Almost of the acoustic wave devices sometimes have a common problem of variations of frequency which is one of the characteristics of the acoustic wave device and the variations of frequency are caused by manufacturing variations. To solve this problem, various methods for adjusting a frequency have been disclosed (e.g., refer to Japanese Open-laid Patent Publication No. 02-301210 and International Publication 2005-083881).
As an example, Japanese Open-laid Patent Publication No. 02-301210 has proposed the method in which the frequency is adjusted by forming a SiN film on an interdigital electrode, a reflector, and a piezoelectric substrate with, for example, plasma CVD. Alternatively, International Publication Pamphlet No. WO 2005/083881 has proposed the method in which the frequency is adjusted by forming a SiN film on an SiO2 film formed on the interdigital electrodes and thinning the thickness of the SiN film by a physical etching method or increasing the thickness by a sputtering method.
Further, International Publication Pamphlet No. WO 2005/093949 has proposed has proposed the frequency adjustment method by adjusting a thickness of second medium in a boundary wave device having inter-digital transducer electrodes disposed at boundary between the first and the second mediums.

Acoustic wave device, transmission apparatus, and acoustic wave device manufacturing method


Arrangements and methods for mounting decorative ornaments and fixtures having decorative ornaments are disclosed. The decorative ornaments may be, for example, beads, crystals, or gems. In one aspect, an arrangement is provided including a frame having an aperture and at least one ornament mounting post projecting from the frame, wherein the ornament is retained by the mounting post when the ornament is mounted on the mounting post. The ornament is mounted to the post by first deflecting the post to a first position, mounting the ornament, and then deflecting the post to its original position whereby the ornament is retained by the post and the aperture. In one aspect, ornaments may be mounted to apertures in a frame by means of one or more wires, for example, a wire passing through a plurality of ornaments. The arrangements and methods may be used for ornamental fixtures, for example, chandeliers and lamps.

The design of chandeliers, lamps, and various other decorative items often involves the need to attach decorative ornaments or crystal components (for example, octagonal or circular beads, pendants, and other ornaments) to supporting metal frames. According to prior art practice, the attachment of these ornaments to the frames typically requires the use of intricate wires, hooks, or other fastening means, and may require special tools. In addition, prior art mounting arrangements and methods typically require multiple fabrication and assembly steps, multiple parts and/or materials, and are labor intensive and costly to perform. Also, many prior art wire mounting methods typically do not generally allow for the desired positioning or orientatating of some components, such as jewels, pendalogs, or pear shaped pendants, though conventional hooks may provide some orientatating of such ornaments, for example, with the aid of gravity. Systems allowing for the orientation of such components other than by gravity generally require complex and expensive brackets, hooks, or other attachment means. Aspects of the present invention overcome these disadvantages of the prior art, among others, when mounting ornaments in decorative fixtures.

Ornamental fixtures having decorative ornaments


A photosensitive circuit is provided. The photosensitive circuit is adapted to a pixel in a pixel array. The photosensitive circuit includes a display element for generating light, transmitting light, or reflecting light, a control circuit coupled to the display element for controlling light intensity of the display element according to a data line and a gate line, and a photosensitive element coupled between the gate line and a read line for generating current at the read line to sense the position of an object according to a reflected light or a shadow from ambient light when light from the display element is reflected by an object or ambient light is shadowed by the object. The control terminal of the photosensitive element is connected to another gate line.

1. Field of the Disclosure
The present disclosure relates to a circuit and a display system, and in particular relates to a photosensitive circuit and a photosensitive display system.
2. Description of the Related Art
Touch panel technology has been widely used in commercial electronic devices such as PDAs, mobile phones and laptop computers etc. Touch panels provide an intuitive user interface and have the multi-touch ability that is not achievable by using conventional mouse input interface. Touch panel technology uses various materials and has various structures and designs. For example, add-on type touch panels with resistive type, capacitive type and other type designs have been developed for many years and are used in commercial applications. Recently, in-cell integrated touch panels have gained much attention due to their simpler structures, and low-cost manufacturing. Of all the in-cell-type touch panels, photo-sensing is an attractive scheme because photo-sensor arrays can be integrated into display panels by leveraging the mature TFT-LCD industrial technology without additional large capital investments. Also, the photosensitive display may be used to sense the photo images of the objects that come into contact with the display and may operate as a scanner with real-time display.
U.S. Pat. No. 4,345,248 discloses a liquid crystal display device with write-in capability, wherein display data lines and readout lines of the photosensitive elements share the column lines, and the photosensitive element is a two-terminal rectifier. The display signal and the photosensitive signal are transmitted with a time sharing manner. However, a photocurrent may be leaked into a display data input due to shared column lines.
U.S. Pat. No. 7,053,967 discloses a light sensitive display, wherein photosensitive elements and a readout circuit are disposed between LCD pixels. That is, photo-sensors are disposed between column lines and row lines. For example, there may be 30 lines sharing a sensor. The current is generated by the sensor according to ambient light charges or discharges the capacitor Cst. However, the column lines connected with the sensors may appear as dim lines, causing a non-uniform display of the image.
Thus, a display circuit and a display device for low signal leakage and high display uniformity is provided.

Photosensitive circuit and system for photosensitive display

Industrial Technology Research Institute


A motor vehicle is provided incorporating an integrated bike rack. That bike rack includes a support arm, a first sill segment that is received in a slot and aligned with a closure sill of the motor vehicle when the bike rack is in a stowed position and a second sill segment that is received in a slot and aligned with the closure sill when the bike rack is in a deployed position. A related method is also disclosed.

The concept of providing a bike rack that may be installed on a motor vehicle to carry one or more bicycles is well known in the art. Unfortunately, prior art bike racks are generally after-market devices that are inconvenient to use. When one wishes to carry a bicycle, the bike rack must be installed on the motor vehicle. Bike rack installation is typically time consuming and at times frustrating. It is also very easy to mar the finished surfaces of the motor vehicle during bike rack installation.
Such bike racks are also somewhat cumbersome and, when installed, may hinder or interfere with proper operation of a trunk lid, tailgate or other closure of the motor vehicle. Accordingly, it is often desirable to remove the bike rack from the motor vehicle when not in use. Removal can be another time consuming, and frustrating task and provides another opportunity to inadvertently scratch, mar or otherwise damage the finished surfaces of the motor vehicle. Further, after the bike rack has been removed, it must be stored and is often in the way in a garage or other storage area.
This document relates to a new and improved bike rack that is integrated into the design of the motor vehicle as well as to a motor vehicle incorporating an integrated bike rack. Thus, the integrated bike rack is stowed on the motor vehicle in an aesthetically pleasing manner and is available at all times to be conveniently deployed and used as needed by the motor vehicle operator.


The present invention involves a gaming device with a bonus scheme which includes at least one input value; a plurality of selections and at least one modifier associated with a selection. The gaming device enables a player to apply input values to desired selections and depending upon which modifiers are associated with the selections, the player can gain a relatively high or low output value. This type of bonus scheme adds excitement to bonus rounds and increases player entertainment.

A portion of the disclosure of this patent document contains or may contain material which is subject to copyright protection. The copyright owner has no objection to the photocopy reproduction by anyone of the patent document or the patent disclosure in exactly the form it appears in the Patent and Trademark Office patent file or records, but otherwise reserves all copyright rights whatsoever.
The present invention relates in general to a gaming device, and more particularly to a gaming device which has a bonus scheme which involves applying one or more input values to one or more selections and receiving one or more output values in return.
Many existing gaming machines, such as traditional slot machines, include bonus rounds. Typically, a bonus round begins when the player reaches a bonus triggering event in the primary game of the gaming device. In slot machines with reels, the triggering event usually occurs when the player reaches a predetermined combination of symbols on the reels. The bonus scheme generally provides the player with an opportunity to gain a bonus value before the bonus round terminates.
Some bonus schemes enable a player to choose from a plurality of selections. Each selection is associated with a value. Depending upon which choice a player makes, the player will receive a relatively high, low or no value at all.
To increase player enjoyment and excitement, it is desirable to provide players with new bonus schemes for gaming devices which enable players to apply certain input values to desired selections, resulting in output values.
The present invention provides a gaming device which includes a plurality of selections and one or more input values. An input value, at times referred to herein as a xe2x80x9cstarting valuexe2x80x9d includes any input or starting bonus value which a player can relate to or apply to a selection or symbol. When a player is described herein in terms of xe2x80x9crelatingxe2x80x9d a value to a location, this includes the player associating a value with a location. One or more, and preferably all, of the selections are associated with a modifier. A selection, which is preferably a symbol, can be a representation of any person, place or thing. The term modifier, as used herein, includes one or more numerical multiplication factors, addition factors or subtraction factors (including zero, the number one and all other numbers in fractional, whole or decimal form) and any game, award opportunity or event. When a modifier is applied to an input value, the result is an output value. An output value, at times referred to herein as an xe2x80x9cending value,xe2x80x9d is the mathematical result of a modifier being applied to an input value. In other words, the gaming device processor uses the numerical modifier to mathematically change the starting value or starting bonus value to an ending value or ending bonus value. For example, the gaming device may provide the player with an input value or starting value of ten. If the modifier of this input value or starting value is an addition factor of five, the output value or ending value would be fifteen. Generally, in operation the player applies one or more input values or starting values to one or more selections or symbols. The numerical modifiers associated with certain selections or symbols determine the output values or ending values for each selection or symbol. As an award, the player receives the total output value or ending value, which is the sum of the output values or ending values for each selection or symbol.
In one embodiment, the gaming device displays the selections to the player while masking or not revealing the associated modifiers. The gaming device enables the player to apply various input values to the selections on a one-by-one basis. Here, it is preferable that the player can only choose one selection one time for any one input value. When the player applies an input value to a particular selection, the gaming device reveals the modifier associated with that selection. Preferably, the gaming device also reveals the output value associated with that selection. When the player completes applying all of the input values, the gaming device awards the player with the sum of the output values for all of the selections.
In an alternative embodiment, the gaming device enables the player to apply more than one input value to a single selection. When a player does so, the gaming device preferably displays on the selection itself a current listing of the input values applied to that particular selection. In this embodiment, the gaming device does not display the modifiers associated with the selections until the player has applied all of the input values to the selections.
In another embodiment, the gaming device provides the player with one input value and a plurality of selections and associated modifiers. The gaming device enables the player to apply incremental portions of the input value to desired selections. The player continues to make selections until the input value is depleted. For example, the gaming device may provide the player with a starting bonus amount of one hundred and enable the player to apply this one hundred value or amount in increments or portions of ten. The player thus applies or relates starting bonus amount portions to symbols on multiple occasions. After the player completes applying the entire starting bonus amount, the gaming device preferably displays the ending bonus amount portions associated with each symbol. The gaming device can display the total ending bonus amount instead of or in addition to the separate ending bonus amount portions.
In one embodiment, the bonus scheme of the present invention is used to imitate the workings of financial investment, risk and return. The gaming device displays the input values as bills and the selections as investment opportunities such as real estate. The total output value mimics the player""s return on investments.
The bonus scheme of the present invention thus enables the player to apply one or more input bonus values to a plurality of selections. Each selection is associated with a modifier, such as a multiplication factor of two or one-half. Depending upon which selections the player makes, the player can obtain a relatively high or relatively low total bonus output. This type of bonus scheme provides players with increased entertainment and enjoyment.
It is therefore an advantage of the present invention to provide a gaming device having a bonus scheme with an input-output value bonus scheme.
Other objects, features and advantages of the invention will be apparent from the following detailed disclosure, taken in conjunction with the accompanying sheets of drawings, wherein like numerals refer to like parts, elements, components, steps and processes.

Gaming device having an input-output value bonus scheme