The present invention provides pharmaceutical compositions and methods for liver proliferation and protection. Specifically useful are VEGFR modulating agents capable of promoting liver growth. Disclosed compositions and methods may be useful for promoting proliferation or treating pathological conditions in other organs of significant biological functions.

Liver
The liver is the major metabolic control organ of the human body that comprises thousands of minute lobules (lobuli hepatis), the functional units of the organ. Liver tissue contains two major differentiated cell types: parenchymal cells (i.e., hepatocytes) and non-parenchymal cells. The complex functions of liver are exerted to a large extent by hepatocytes, whereas non-parenchymal cells such as Kupffer cells, Ito cells and liver sinusoidal endothelial cells (LSEC) play important roles in supporting and providing supplies to hepatocytes. Mochida et al. (1996) Biochem. Biophy. Res. Comm. 226:176-179.
The liver acts as a guardian interposed between the digestive tract and the rest of the body. A major hepatic function involves effective uptake, storage, metabolism and distribution to blood and bile large amounts of substances such as carbohydrates, lipids, amino acids, vitamins and trace elements. Another function of the liver is the detoxification of xenobiotic pollutants, drugs and endogenous metabolites, through both phase I (oxidation/reduction) and phase II (conjugation) mechanisms.
Because of its essential role to life, liver dysfunction and diseases are often debilitating and life threatening. A number of acute or chronic pathological conditions are associated with structural and/or functional abnormalities of the liver. These include, but are not limited to, liver failure, hepatitis (acute, chronic or alcohol), liver cirrhosis, toxic liver damage, medicamentary liver damage, hepatic encephalopathy, hepatic coma or hepatic necrosis.
Many chemical and biological agents, either therapeutic or purely harmful, can induce liver damages and thus are hepatotoxic. The susceptibility of the liver to damage by hepatotoxic agents may be related to its primary role in metabolism or is a consequence of hypersensitivity reactions. Up to 25% of cases of fulminant hepatic failure may be the result of adverse reactions to medical agents. Hepatotoxic compounds are also an important cause of chronic liver disease including fatty liver, hepatitis, cirrhosis and vascular and neoplastic lesions of the liver. (Sinclair et al., Textbook of Internal Medicine, 569-575 (1992) (editor, Kelley; Publisher, J. B. Lippincott Co.).
Hepatotoxic agents may induce liver damage by cytotoxicity to the liver directly or through the production of toxic metabolites (this category includes the hypersensitivity reaction which mimics a drug allergy); cholestasis, an arrest in the flow of bile due to obstruction of the bile ducts; and vascular lesions, such as in veno occlusive disease (VOD), where injury to the vascular endothelium results in hepatic vein thrombosis. Individual susceptibility to liver damage induced by hepatotoxic agents is influenced by genetic factors, age, sex, nutritional status, exposure to other drugs, and systemic diseases (Sinclair et al., Textbook of Internal Medicine, Supra).
In addition to normal growth during early development, liver tissue has a unique ability to regenerate at adult stage. Liver regeneration after the loss of hepatic tissue is a fundamental component of the recovery process in response to various forms of liver injury such as hepatotoxicity, viral infection, vascular injury and partial hepatectomy. Following partial hepatectomy, for example, the liver size is usually restored to its original mass within about six days. Liver growth and regeneration involves proliferation of both hepatocytes and non-parenchymal cells such as sinusoidal endothelial cells. Typically, hepatocytes are the first to proliferate, and other cells of the liver enter into DNA synthesis about 24 hours after the hepatocytes. Michalopoulos and DeFrances (1997) Science 276:60-65.
Factors for Liver Proliferation
Several growth factors and cytokines have been implicated as being able to induce liver regeneration, most notably hepatocyte growth factor (HGF), epidermal growth factor (EGF), transforming growth factor-α (TGF-α), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), basic and acidic fibroblast growth factors, CTGF, HB-EGF, and norepinephrine. Fujiwara et al. (1993) Hepatol. 18:1443-9; Baruch et al. (1995) J. Hepatol. 23:328-32; Ito et al. (1994) Biochem. Biophys. Res. Commun. 198:25-31; Suzuma et al. (2000) J. Biol. Chem. 275:40725-31; Michalopoulos and DeFrances (1997) supra. As one of the most potent liver mitogens, HGF was first identified as a factor capable of stimulating DNA synthesis in cultured hepatocytes but is now known to have multiple distinct functions on a variety of epithelial cells. Nakamura et al. (1984) Biochem. Biophys. Res. Comm. 122:1450; Russell et al. (1984) J. Cell. Physiol. 119:183-192. Scatter factor (SF), which enhances motility and invasiveness of certain cell types, was found to have identical amino acid sequence as HGF, leading to the designation HGF/SF. Stoker and Perryman (1985) J. Cell Sci. 77:209-223; Gherardi and Stoker (1990) Nature 346:228. HGF/SF is synthesized as an inactive, single-chain zymogen that is subsequently cleaved to produce an active, dimeric glycoprotein composed of a 69-kDa α-subunit and a 34-kDa β-subunit held together by a single disulfide bond. Nakamura et al. (1989) Nature 342:440-443; Roos et al. (1995) Am. J. Physiol. 268:G380-6.
All known biological effects of HGF are transduced via a single tyrosine kinase receptor, Met, the product of the Met protooncogene. HGF/SF acts predominantly on Met-expressing epithelial cells in an endocrine and/or paracrine fashion, to mediate such diverse biological activities as proliferation, branching, cell migration, morphogenesis and lumen formation. van der Voort et al. Adv. Cancer Res. 79:39-90 (2000). In the liver, HGF is expressed in non-hepatocyte cells such as Ito cells and LSECs, whereas met transcripts are strongly expressed in hepatocytes. Hu et al. Am. J. Pathol. 142:1823-1830 (1993). After chemical or mechanical liver injury, HGF levels sharply increase, leading to a strong hepatocyte proliferation. Horimoto et al. J. Hepatol. 23:174-183 (1995). Livers from transgenic mice with liver-specific overexpression of HGF are twice the size of livers of control animals and they regenerate much faster after partial hepatectomy. Sakata et al. (1996) Cell Growth Differ. 7:1513-1523; Shiota et al. (1994) Hepatol. 19:962-972. Furthermore, HGF null mutant mouse embryos fail to develop a fully functional liver, demonstrating the essential role of HGF during liver development. Schmidt et al. (1995) Nature 373:699-702. The continuous infusion of large doses (5 mg/kg/day) of HGF directly into the portal vein has been shown to result in a significant increase of relative liver mass in mice. Patijn et al. (1998) Hepatol. 28:707-16. While HGF was found to be a potent inducer of hepatocyte mitosis, however, it failed to induce proliferation of nonparenchymal cells including sinusoidal endothelial cells. Patijn et al., supra. In other biological contexts, conversely, HGF has been shown as a potent endothelial cell mitogen. Rosen and Goldberg (1997) In: Regulation of Angiogenesis. Rosen, E, Goldberg, ID, Eds. Springer Verlag. pp 193-208.
It has been suggested that substantially high HGF plasma concentrations may be required in order to promote liver growth in vivo (Roos et al. (1995) Am. J. Physiol. 268:G380-6). HGF, by virtue of its strong heparin-binding properties, is largely sequestered in extrahepatic tissues following intravenous administration (Zioncheck et al. (1994) Endocrinology 134:1879-87) and the co-administration of dextran sulfate is required for an effective liver-promoting action (Roos et al., 1995).
Angiogenesis and Liver
Angiogenesis is an important cellular event in which vascular endothelial cells proliferate, prune and reorganize to form new vessels from preexisting vascular network. There are compelling evidences that the development of a vascular supply is essential for normal and pathological proliferative processes (Folkman and Klagsbrun (1987) Science 235:442-447). Delivery of oxygen and nutrients, as well as the removal of catabolic products, represent rate-limiting steps in the majority of growth processes occurring in multicellular organisms. Thus, it has been generally assumed that the vascular compartment is necessary, albeit but not sufficient, not only for organ development and differentiation during embryogenesis, but also for wound healing and reproductive functions in the adult. However, recent evidence suggests that, at least in the mouse embryo, the vascular endothelium may have an inductive effect on liver (Matsumoto et al. (2001) Science 294:559-563) and pancreas organogenesis (Lammert et al. (2001) Science 294:564-567), even prior to the establishment of a blood flow. The mechanism of such induction is unknown.
Angiogenesis is also implicated in the pathogenesis of a variety of disorders, including but not limited to, proliferative retinopathies, age-related macular degeneration, tumors, rheumatoid arthritis (RA), and psoriasis. Folkman (1995) Nat Med 1:27-31. Regenerating liver, in analogy to rapidly growing tumors, must synthesize new stroma and blood vessels. Not surprisingly, therefore, many studies have focused on angiogenesis in liver development and regeneration, as well as the roles of many known angiogenic factors therein. Michalopoulos and DeFrances (1997) supra; Mochida et al. (1996).
Vascular endothelial cell growth factor (VEGF), a potent mitogen for vascular endothelial cells, has been reported as a key regulator of angiogenesis and vasculogenesis. Ferrara and Davis-Smyth (1997)Endocrine Rev. 18:4-25; Ferrara (1999) J. Mol. Med. 77:527-543. Compared to other growth factors that contribute to the processes of vascular formation, VEGF is unique in its high specificity for endothelial cells within the vascular system. Recent evidence indicates that VEGF is essential for embryonic vasculogenesis and angiogenesis. Carmeliet et al. (1996) Nature 380:435-439; Ferrara et al. (1996) Nature 380:439-442. Furthermore, VEGF is required for the cyclical blood vessel proliferation in the female reproductive tract and for bone growth and cartilage formation. Ferrara et al. (1998) Nature Med. 4:336-340; Gerber et al. (1999) Nature Med. 5:623-628.
In addition to being an angiogenic factor in angiogenesis and vasculogenesis, VEGF, as a pleiotropic growth factor, exhibits multiple biological effects in other physiological processes, such as endothelial cell survival, vessel permeability and vasodilation, monocyte chemotaxis and calcium influx. Ferrara and Davis-Smyth (1997), supra. Moreover, recent studies have reported mitogenic effects of VEGF on a few non-endothelial cell types, such as retinal pigment epithelial cells, pancreatic duct cells and Schwann cells. Guerrin et al. (1995) J. Cell Physiol. 164:385-394; Oberg-Welsh et al. (1997) Mol. Cell. Endocrinol. 126:125-132; Sondell et al. (1999) J. Neurosci. 19:5731-5740.
Substantial evidence also implicates VEGF's critical role in the development of conditions or diseases that involve pathological angiogenesis. The VEGF mRNA is overexpressed by the majority of human tumors examined (Berkman et al. J Clin Invest 91:153-159 (1993); Brown et al. Human Pathol. 26:86-91 (1995); Brown et al. Cancer Res. 53:4727-4735 (1993); Mattern et al. Brit. J. Cancer. 73:931-934 (1996); and Dvorak et al. Am J. Pathol. 146:1029-1039 (1995)). Also, the concentration of VEGF in eye fluids are highly correlated to the presence of active proliferation of blood vessels in patients with diabetic and other ischemia-related retinopathies (Aiello et al. N. Engl. J. Med. 331:1480-1487 (1994)). Furthermore, recent studies have demonstrated the localization of VEGF in choroidal neovascular membranes in patients affected by AMD (Lopez et al. Invest. Ophtalmo. Vis. Sci. 37:855-868 (1996)). Anti-VEGF neutralizing antibodies suppress the growth of a variety of human tumor cell lines in nude mice (Kim et al. Nature 362:841-844 (1993); Warren et al. J. Clin. Invest. 95:1789-1797 (1995); Borgström et al. Cancer Res. 56:4032-4039 (1996); and Melnyk et al. Cancer Res. 56:921-924 (1996)) and also inhibit intraocular angiogenesis in models of ischemic retinal disorders (Adamis et al. Arch. Ophthalmol. 114:66-71 (1996)). Therefore, anti-VEGF monoclonal antibodies or other inhibitors of VEGF action are promising candidates for the treatment of solid tumors and various intraocular neovascular disorders.
Human VEGF was obtained by first screening a cDNA library prepared from human cells, using bovine VEGF cDNA as a hybridization probe. Leung et al. (1989) Science, 246:1306. One cDNA identified thereby encodes a 165-amino acid protein having greater than 95% homology to bovine VEGF; this 165-amino acid protein is typically referred to as human VEGF (hVEGF) or VEGF165. The mitogenic activity of human VEGF was confirmed by expressing the human VEGF cDNA in mammalian host cells. Media conditioned by cells transfected with the human VEGF cDNA promoted the proliferation of capillary endothelial cells, whereas control cells did not. Leung et al. (1989) Science, supra.
Although a vascular endothelial cell growth factor could be isolated and purified from natural sources for subsequent therapeutic use, the relatively low concentrations of the protein in follicular cells and the high cost, both in terms of effort and expense, of recovering VEGF proved commercially unavailing. Accordingly, further efforts were undertaken to clone and express VEGF via recombinant DNA techniques. (See, e.g., Ferrara (1995) Laboratory Investigation 72:615-618 (1995), and the references cited therein).
VEGF is expressed in a variety of tissues as multiple homodimeric forms (121, 145, 165, 189, and 206 amino acids per monomer) resulting from alternative RNA splicing. VEGF121 is a soluble mitogen that does not bind heparin; the longer forms of VEGF bind heparin with progressively higher affinity. The heparin-binding forms of VEGF can be cleaved in the carboxy terminus by plasmin to release a diffusible form(s) of VEGF. Amino acid sequencing of the carboxy terminal peptide identified after plasmin cleavage is Arg110-Ala111. Amino terminal "core" protein, VEGF (1-110) isolated as a homodimer, binds neutralizing monoclonal antibodies (such as the antibodies referred to as 4.6.1 and 3.2E3.1.1) and soluble forms of VEGF receptors with similar affinity compared to the intact VEGF165 homodimer.
Several molecules structurally related to VEGF have also been identified recently, including placenta growth factor (PIGF), VEGF-B, VEGF-C, VEGF-D and VEGF-E. Ferrara and Davis-Smyth (1987) Endocr. Rev., supra; Ogawa et al. (1998) J. Biological Chem. 273:31273-31281; Meyer et al. (1999) EMBO J., 18:363-374. A receptor tyrosine kinase, Flt-4 (VEGFR-3), has been identified as the receptor for VEGF-C and VEGF-D. Joukov et al. (1996) EMBO. J. 15:1751; Lee et al. (1996) Proc. Natl. Acad. Sci. USA 93:1988-1992; Achen et al. (1998) Proc. Natl. Acad. Sci. USA 95:548-553. VEGF-C has recently been shown to be involved in the regulation of lymphatic angiogenesis. Jeltsch et al. (1997) Science 276:1423-1425.
Two VEGF receptors have been identified, Flt-1 (also called VEGFR-1) and KDR (also called VEGFR-2). Shibuya et al. (1990) Oncogene 8:519-527; de Vries et al. (1992) Science 255:989-991; Terman et al. (1992) Biochem. Biophys. Res. Commun. 187:1579-1586. Neuropilin-1 has been shown to be a selective VEGF receptor, able to bind the heparin-binding VEGF isoforms (Soker et al. (1998) Cell 92:735-45). Both Flt-I and KDR belong to the family of receptor tyrosine kinases (RTKs). The RTKs comprise a large family of transmembrane receptors with diverse biological activities. At present, at least nineteen (19) distinct RTK subfamilies have been identified. The receptor tyrosine kinase (RTK) family includes receptors that are crucial for the growth and differentiation of a variety of cell types (Yarden and Ullrich, Ann. Rev. Biochem. 57:433-478, 1988; Ullrich and Schlessinger, Cell 61:243-254, 1990). The intrinsic function of RTKs is activated upon ligand binding, which results in phosphorylation of the receptor and multiple cellular substrates, and subsequently in a variety of cellular responses (Ullrich & Schlessinger, 1990, Cell 61:203-212). Thus, receptor tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), typically followed by receptor dimerization, stimulation of the intrinsic protein tyrosine kinase activity and receptor trans-phosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response. (e.g., cell division, differentiation, metabolic effects, changes in the extracellular microenvironment) see, Schlessinger and Ullrich, 1992, Neuron 9:1-20. Structurally, both Flt-1 and KDR have seven immunoglobulin-like domains in the extracellular domain, a single transmembrane region, and a consensus tyrosine kinase sequence which is interrupted by a kinase-insert domain. Matthews et al. (1991) Proc. Natl. Acad. Sci. USA 88:9026-9030; Terman et al. (1991) Oncogene 6:1677-1683.
There are compelling evidences suggesting that Flt-1 and KDR have different signal transduction properties and possibly mediate different functions. Moreover, the signals mediated through Flt-1 and KDR appear to be cell type specific. Recent studies have provided considerable experimental data indicating that KDR is the major mediator of the mitogenic, angiogenic and permeability-enhancing effects of VEGF (Ferrara (1999) Kidney Int. 56:794-814). VEGF stimulation leads to a robust auto-phosphorylation of KDR and activation of the MAPK cascade, which may directly contribute to endothelial cell proliferation (Kroll and Waltenberger (1997) J. Biol. Chem. 272:32521-7). In contrast, the function of VEGFR-1 has been less clear, and many apparently conflicting reports on its function exist in the literature. This molecule displays a very weak or undetectable tyrosine autophosphorylation in endothelial cells in response to VEGF (Gille et al. (2000) EMBO J. 19:4064-4073). Flt-1 has been shown to have inhibitory effects on endothelial mitogenesis in several biological contexts, including early embryonic development, either by acting as a "decoy" receptor that prevents VEGF binding to VEGFR-2 or by directly inhibiting VEGFR-2 activities. Park et al. (1994) J. Biol. Chem. 269:25646-54; U.S. Pat. No. 6,107,046 (Alitalo et al.); Fong et al. (1999) Development 126:3015-25; Zeng et al. (2001). J. Biol. Chem. 276:26969-79). Other studies suggest that VEGFR-1 may mediate recruitment of monocytes and endothelial cell progenitors to the tumor vasculature (Barleon et al. (1996) Blood 87:3336-43) (Lyden et al. (2001) Nat. Med. 7:1194-201). Thus, the importance of VEGFR-1 signaling in the vascular endothelium is largely unclear.
Recent studies have attempted to elucidate the molecular mechanisms of various physiological and pathological processes in the liver, particularly liver regeneration. There have been proposed two reciprocal paracrine communication systems existing in hepatic tissues between hepatocytes and non-parenchymal cells such as sinusoidal endothelial cells. In one direction, growth factors such as HGF/SF are released from non-parenchymal cells such as sinusoidal endothelial cells and Kupfer cells, bind to their receptors (such as the c-Met receptor) on hepatocytes, and in turn induce and promote hepatocyte proliferation. In the opposite direction, it is suggested that VEGF expressed in and secreted from hepatocytes acts as a stimulatory factor that binds to its receptors (KDR and Flt-1) on sinusoidal endothelial cells, thereby stimulating the proliferation and maintenance of the sinusoidal endothelial cells in the liver. Yamane et al. (1994) Oncogene 9:2683-2690 observed that the endogenous expression of VEGF and VEGF receptors (Flt and KDR) as well as HGF and c-Met are strictly regulated in a cell-type specific manner in liver: using a flt-1 cDNA as a probe, flt-1 mRNA was found to be expressed at very high levels in sinusoidal endothelial cells in normal rat liver, but was hardly detectable in hepatocytes. Similar expression pattern was found for KDR, although the expression level was much lower. Yamane et al. further observed that, in an in vitro cell culture system, VEGF demonstrated a remarkably specific growth-stimulatory activity as well as maintenance activity on the sinusoidal endothelial cells.
Mochida et al. (1996) Biochem. Biophy. Res. Comm. 226:176-179 conducted in vitro experiments to monitor the expression levels of VEGF and VEGFRs in isolated hepatic cells from normal livers or partially resected livers. They found that in 70% resected rat liver, expression of VEGF, Flt-1 and KDR were all significantly increased. And the timing of the expression peaks for Flt-1 and KDR suggested that the upregulation of VEGFRs may be involved in proliferation of sinusoidal endothelial cells during liver regeneration.
More recently, Ajioka et al. (1999) Hepatology 29:396-402 examined the fate of transplanted hepatic tissues in the presence of exogenous VEGF. Isolated hepatocytes of adult mice were transfected with VEGF gene in vitro then transplanted intraperitoneally (i.p.) in mice, into an area adjacent to the pancreas. The transplanted hepatocytes formed a large number of tissue aggregates in vivo. In vitro staining showed that these VEGF-transfected tissues underwent substantial proliferation and developed a significant vascular network therein. Thus, the results suggested that the expression of VEGF conferred the formation of a vascular network, which in turn may promoted tissue formation. The results, however, showed absence of any nonparenchymal cells or growth factors derived from them in the VEGF-transfected, transplanted hepatic tissues.
Assy et al. (1999) J. Hepatol. 30:911-915 studied the effect of VEGF as an angiogenic factor in liver regeneration following partial hepatectomy in rat. Rats undergoing 30% partial hepatectomy were administered intravenously (i.v.) VEGF and sacrificed at 24, 36 and 48 hour postoperatively. Whilst the study showed increased DNA synthesis activities of hepatocytes in the VEGF-treated rats at 36 and 48 h after PHx, and suggested that stimulation of neovascularization by VEGF is important during liver regeneration, no statistically significant changes in restituted liver mass were observed in VEGF-treated rats as compared to control rats without VEGF treatment.

Compositions and methods for liver growth and liver protection


The invention discloses methods and apparatus for detecting vibrations from machines which indicate an impending malfunction for the purpose of preventing additional damage and allowing for an orderly shutdown or a change in mode of operation. The method and apparatus are especially suited for reliable operation in providing thruster control data concerning unstable vibration in an electrical environment which is typically noisy and in which unrecognized ground loops may exist.

Vibration analysis has been used for years to provide a determination of the proper functioning of different types of machinery, including rotating machinery and rocket engines. A determination of a malfunction, if detected at a relatively early stage in its development, will allow changes in operating mode or a sequenced of the machinery prior to a total failure. Such preventative measures result in less extensive and/or less expensive repairs, and can also prevent a sometimes catastrophic failure of equipment. In a rocket thruster, for instance, certain frequencies can be calculated as a function of the geometry of the thruster dimensions and, if detected, indicate thruster instability. If thruster vibration is monitored with respect to these critical frequencies or is detected in bands of frequencies around the critical frequencies, then it is possible to either change operating modes or provide an orderly shutdown of the thruster prior to failure. A change of operating mode for a thruster may include changing control signals to the thruster from a pulsed mode to a continuous mode signal. If such a change in operating mode is not successful to eliminate vibrations at a critical frequency, then it becomes necessary to shut down the thruster.
Accelerometers which are commercially available are contained within a package that houses only the transducer itself and may include wiring to a connector. In application, this packaging presents a number of problems. The signal wire from the accelerometer will typically go through a connector and then make its way through an electrically noisy environment before reaching a second connector, which will take the signal to a detector circuit. Noise may be picked up on this signal wire and cause false machine instability signals. Also, because the detector circuitry and accelerometer transducer may be located some distance apart and may be powered by different power supplies, ground loop errors may occur. Ground loops or ground shifts are differences between circuit grounds which may occur when circuits are powered by different power supplies, or are powered by the same power supply when the circuits are located a considerable distance apart. Relatively higher currents carried by one part of a grounding system can also result in voltage differences between other parts of a grounding system. These voltage differences between grounds, which are often called ground shifts or ground loops, are typically variable, unknown, and insidiously cause false signals. When adding vibration monitoring and detecting circuitry it may be difficult or impossible to determine whether ground loops exist in other circuitry which may cause errors or false signals in the vibration monitoring apparatus. Similarly, noise and ground loop problems may occur when connecting an instability or fault signal wire from the detection circuitry of a vibration monitoring apparatus to a distant control circuit or computer which utilizes the fault signal to supervise a machine shut down. Typically, vibrating machinery will produce a noisy electrical environment. As well, the vibration may produce occasional changes in electrical resistance in contacts, connectors, etc. which may produce spurious machinery fault signals.
R. J. Bozeman U.S. Pat. No. 4,977,395 discloses an adjustable delay circuit which can be used to delay the output of an instability signal until the particular type of vibration signal which denotes instability has occurred consistently enough over a period of time (e.g. 40 msec for a rocket thruster) to indicate an instability signal which is more likely to be valid. However, adding this delay circuit increases overall circuit complexity which increases the possibility of a circuit failure, and requires additional room. Also, the output of the delay circuit is itself subject to the noise and ground loop problems so that its purpose may still be defeated even if it is effective to distinguish spurious signals up to the input of the delay circuit.
Consequently, a need exists for improvements in accelerometer circuitry to provide a highly reliable means for preventing false signals from the accelerometer transducers and related circuitry operating in a vibrating, electrically harsh environment. Those skilled in the art have long sought and will appreciate the novel features of the present invention which solves these problems.

The United States of America as represented by the Administrator of the National Aeronautics and Space Administration


The present invention relates to methods for determining whether a subject having prostate cancer is at an increased risk for relapse or rapid relapse. It is based, at least in part, on the results of a comprehensive genome analysis of 273 prostate cancer samples, which indicate that the percentage of large size CNVs predicts prostate cancer relapse. In certain embodiments, a method for determining whether a prostate cancer patient has an increased risk of suffering a relapse or a rapid relapse comprises determining the number and size of CNVs in a sample and determining a large size ratio, where if the large size ratio exceeds a particular threshold, the patient is deemed to be at an increased risk for relapse or rapid relapse.

Prostate cancer is one of the leading causes of death for men in the United States, and about 30,000 patients die of prostate cancer annually (4). Since the implementation of serum prostate specific antigen (PSA) screening, the clinical detection rate of prostate cancer has increased substantially due primarily to the identification of small, low grade cancers that would likely not progress (1). Several treatment options are available for prostate cancer patients including watchful waiting, radiation, hormonal/chemo-therapy and radical prostatectomy. Gleason grading, alone or in combination with other clinical indicators such as serum PSA levels, and pathological or clinical staging, has been the guiding tool in selecting these treatment options. However, prostate cancer has considerable heterogeneity in biological aggressiveness and clinical prognosis (1-3) and accurate prediction of the aggressive behavior of prostate cancer remains difficult. In addition, a significant number of prostate cancer patients experience recurrence after surgical resection of the prostate gland. Therefore, there is a need in the art for methods for more accurately determining the prognosis of prostate cancer.

Methods for predicting prostate cancer relapse

UNIVERSITY OF PITTSBURGH—OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION


An exhaust system can comprise a NOx adsorber, a reformer disposed upstream of a NOx adsorber and in fluid communication with a fuel source, a first valve for controlling the introduction of the fluid to an exhaust conduit; and a particulate filter disposed upstream and in fluid communication with the NOx adsorber and downstream an in fluid communication with the reformer such that the first valve controls introduction of fluid to the exhaust conduit upstream of the particulate filter. The reformer can be designed to generate a fluid comprising sufficient thermal energy, hydrogen, and carbon monoxide. Optionally, the particulate filter can be designed to be regenerated by the thermal energy and to adsorb a sufficient amount of the thermal energy to reduce the temperature of a gas stream comprising the fluid from a first temperature of about 600° C. to about 1,000° C. to a second temperature of less than or equal to about 500° C.

This disclosure relates to an exhaust system and to thermal energy management and more particularly relates to management of thermal energy flowing into and out of engine exhaust components.
The elimination of hydrocarbons, carbon monoxide, soluble organic fraction, nitric oxide, nitrogen dioxide, nitrous oxide, sulfur oxides, sulfurous oxides, hydrogen sulfide, ammonia and particulates in exhaust gas is a widely addressed problem as a result of environmental concerns and mandated government emissions regulations.
Diesel particulate filters collect particulates from exhaust gas streams. A problem with diesel particulate filters is that they gradually become clogged with particulate matter impeding exhaust flow. The impeded exhaust flow increases pressure back through the exhaust valves into the engine cylinders. This excessive backpressure results in poor engine performance and poor fuel economy. Particulate matter typically consists of carbon, heavy organics, sulfur compounds, nitrogen compounds and phosphorous compounds.
Regeneration of diesel particulate filters occurs when diesel engines emit an exhaust gas stream at a high enough temperature to burn out particulate matter. High temperature exhaust is generated at high engine speeds. However, many passenger diesel vehicles are operated for protracted periods of time at, or close to, idling speed. At idle speed the exhaust gas stream is below the combustion temperature of particulate matter.
Passive diesel particulate filters are used in heavy duty applications that generate enough exhaust temperature for effective regeneration. However passive diesel systems regenerate particulate traps, but do little for NOx reduction. Further, while passive diesel particulate traps effectively remove coarse particulates, the nano-phase particulates are greatly increased when a passive regeneration is used. An effective active regeneration method is greatly desired. Especially for acceptance of lean bum passenger vehicles.
The doping of diesel fuels with diesel combustion aids is an effective active regeneration method for small passenger vehicles. The combustion additive lowers engine out particulates then collects as an oxide on the particulate trap. Further, the collected oxide aids in the combustion of trapped particulates at lower temperatures. However, particulate oxides cannot pass through the particulate trap. And the particulate oxides are rapidly poisoned by engine oil deposits and become "vitrified". Eventually, at relatively low hours of engine use, the particulate trap has to be physically removed and vitrified particulate oxides removed. Stricter emission standards make particulate trap cleaning during the useful life of a vehicle undesirable if not unacceptable.
The most common particulate trap and catalyst deactivation occurs because vaporized engine oils decompose and form diffusion limiting glass coatings. For example, most engine oil contains zinc dialkyl phosphate and calcium phosphate. The materials form the glass zinc calcium phosphate over particulate traps, catalysts and sensors. Eventually particulate traps cannot be regenerated because the glass layer cannot be vaporized.
What is needed in the art is a system and method for the regeneration of particulate traps that does not adversely affect a NOx adsorber disposed downstream of the particulate trap.

This patent is subject to a terminal disclaimer.

Exhaust system and method of thermal management


A method of controlling drivability of a vehicle detects an overall load acting on the vehicle. A mass of the vehicle or an estimate thereof is obtained. A controller determines whether the vehicle is negotiating a curve during a driving situation. If the vehicle is negotiating a curve during the driving situation, the controller determines whether the vehicle has a tendency to oversteer or to understeer. The load acting on the vehicle is dynamically changed or a suspension stiffness of the vehicle is dynamically adjusted to reduce the tendency of the vehicle to oversteer or to understeer.

Modern motor vehicles are often equipped with a vehicle dynamics control system, such as the known ESC (Electronic Stability Control) system that stabilizes the vehicle in critical driving situations. For this purpose, the braking force is usually increased in a targeted manner at individual wheels of the vehicle in order to generate a yaw moment which stabilizes the vehicle. However, the brake intervention, which is carried out particularly by the ESC system, can be sensed clearly by the driver as a vehicle deceleration, and therefore, can be unexpected and uncomfortable. The ESC system also typically reacts after the instability has occurred.
Thus, there is a need to provide a system and method that dynamically changes the load on the vehicle or suspension stiffness to reduce oversteer or understeer tendencies based on vehicle load information along with other vehicle information prior to the instability.

System and method utilizing detected load for vehicle handling


A ski assembly for a stroller for allowing more proficient movement through snow includes a ski attachment for a stroller assembly having a chair portion, a back portion, a plurality of wheels is attached to the chair portion. The attachment includes a leg having an upper end and a lower end. A ski has an upper surface, a lower surface, a back end and a front end. The lower end of the leg is attached to the upper surface of the ski. The leg is rotatably coupled to the chair portion such that the ski may be positioned in a substantially horizontal lowered position or in a substantially vertical lifted position adjacent to the chair portion.

1. Field of the Invention
The present invention relates to ski attachment devices and more particularly pertains to a new ski attachment device for providing improvement through the snow for a stroller.
2. Description of the Prior Art
The use of ski attachment devices is known in the prior art. U.S. Pat. No. 2,539,686 describes a runner attachment for a baby carriage which includes runners to be attached to the wheels of the carriage. Another type of ski attachment device is U.S. Pat. No. 5,407,217 which includes a detachable ski assembly for a stroller so that both of the front and rear wheels of the stroller are positioned on a ski. Yet another such device is U.S. Pat. No. 5,427,390 which includes skis that may each be attached to one of the wheels of a stroller or carriage.
While these devices fulfill their respective, particular objectives and requirements, the need remains for a device that attaches a ski to a stroller in such a manner that the ski is easily moved from a engaged to a disengaged position without having to physically remove the entire ski device from the stroller. This will allow more proficient moving through snow but will then also provide a means for returning to the wheels of the stroller for areas of little or no snow.


A method is provided for preparing preceramic polymers and and silicious ceramic materials which derive therefrom. The preceramic polymers are polysiloxanes which are synthesized by catalytically activating Si--H bonds in a hydridosiloxane starting material and replacing the activated hydrogen atoms with non-hydrogen substituents. These preceramic polysiloxanes are pyrolyzed in a selected atmosphere to give the desired ceramic product. Ceramic products which may be prepared by this technique include silica, silicon oxynitride, silicon carbide, and metal silicates.

The invention relates primarily to: (1) the preparation of polymers that are useful as precursors to ceramic materials (i.e., which serve as "preceramic" polymers); and (2) catalytic activation of Si--H bonds. The invention also concerns, in one embodiment, the use of sol-gel processing techniques.
The sol-gel process is an important route for advanced metal-oxide glasses and ceramics. The method is currently used or of potential for protective, optical and electronic coatings, optical fiber preforms, nonlinear optical devices, dielectrics or superconductors, display materials, and structures. The sol-gel technique provides a relatively low temperature, controlled method of producing a large variety of shapes such as monodispersed particles, uniform coatings, fibers, dense or porous articles, and mixed metal oxides having controlled stoichiometry and purity at the molecular level.
The sol-gel process has been based mostly on the same group of starting materials, the metal alkoxides, carboxylates and diketonates. These precursors are hydrolyzed, then condensed in the presence of an alcohol/water solution to form a gel which is dried and fired to give the final product. Chemical control of product formation is manipulated by temperature, type of catalyst and pH as well as by the type and ratio of reactants in solution. See, e.g., C. J. Brinker et al., in "Ultrastructure Processing of Ceramics, Glasses and Composites I" (1984), at pp. 43 et seq.
Thus, the reaction procedure controls to a large extent the morphology of the final gel, and, therefore, the final ceramic microstructure as well. Low water content and/or acidic conditions will give spinnable gels because the precursor polymer will, as noted above, be substantially linear. Higher water content will give slightly crosslinked, coatable gels, while a very high water content and/or basic conditions will give highly crosslinked gel products that are useful in casting processes and for powder formation. See B. J. J. Zelinski et al., J. Phys. Chem. Solids 45:1069 (1984), and L. C. Klien et al., Ann. Rev. Mat. Sci. 15:227 (1985).
It has recently been suggested that alkoxide-siloxane oligomers may serve as molecular building blocks for unique ceramic silica structures (V. W. Day et al., J. Am. Chem. Soc. 107:8264 (1985)). A rigid cubic alkoxysesquisiloxane, [Si.sub.8 O.sub.12 ](OCH.sub.3).sub.8, offers the possibility of generating porous materials, yet rigid due to the molecular block structure.
As noted above, the invention also relates to preparation of preceramic polymers, i.e., polymers which may be converted upon pyrolysis to ceramic products. The present invention provides preceramic siloxane polymers which are useful for preparing a wide variety of siliceous ceramic materials and articles, e.g., articles such as fibers, films, shaped products, and the like, comprising materials such as silica, silicon oxynitride, silicon carbide, or metal silicate.
The preceramic polymers, or "ceramic precursors", of the invention are prepared by catalytic activation of Si--H bonds. To date, catalytic activation of Si--H bonds has mainly been used for hydrosilylation reactions of unsaturated compounds, as illustrated by reactions (1) and (2): ##STR1## Over the past 25 years, numerous homogeneous and heterogeneous catalysts have been found which promote these reactions. See, e.g., J. L. Speier et al., J. Am. Chem. Soc., 79:974 (1957). Typical applications of these reactions have been in organic synthesis or in the crosslinking of silicon rubbers (J. P. Collman et al., in "Principles and Applications of Organotransition Metal Chemistry", pp. 384-392, University Science Books, 1980). Only recently have such reactions been found useful in another application, crosslinking of preceramic polymers, as described in co-pending, commonly assigned application Ser. No. 012,874, the disclosure of which is hereby incorporated by reference in its entirety.
Related reactions involving substitution at an Si--H bond have been used to form compounds containing Si-Y groups wherein Y is, for example, halogen, alkoxy, or substituted or unsubstituted amino: ##STR2## L. H. Sommer et al., J. Org. Chem. 32 :4270 (1967). Only mono- and di-substituted aminosilanes, halosilanes and alkoxysilanes have been synthesized by this method. Surprisingly, there have been virtually no attempts to enlarge the potential capability of reaction (3). For example, the inventors herein are unaware of any work involving reaction of compounds containing multiple Si--H bonds with water to form oligomeric or polymeric siloxane products.
Investigators at SRI, the assignee of the present application, have recently discovered that catalytic activation of Si--H bonds is extremely useful in the synthesis of polysilazane ceramic precursors, according to reaction (4): ##STR3## To date, however, efforts have not been focused on enlarging the scope of the analogous reaction in the presence of water, i.e., instead of using ammonia or monoalkylamines. Preliminary research indicates that similar reactions (as illustrated by reactions (5) and (6)) will occur in the presence of water, to produce monomeric, oligomeric or polymeric siloxanes, at room temperature, or lower: ##STR4##
The present invention is directed to a new approach to polymer processing, and involves combining the fields of research summarized hereinabove: (a) preparation of preceramic polymers useful in making ceramic materials; and (b) reaction of hydridosiloxane compounds by catalytic activation of the Si--H bonds contained therein. In a preferred embodiment, the invention also involves the use of (c) sol-gel processing techniques. Gels or preceramic polymers produced using the present method are highly "processable" and, upon pyrolysis, give the desired ceramic material in relatively high yield.

Hydridosiloxanes as precursors to ceramic products


A method for growing planar, semi-polar nitride film on a miscut spinel substrate, in which a large area of the planar, semi-polar nitride film is parallel to the substrate's surface. The planar films and substrates are: (1) {10 11} gallium nitride (GaN) grown on a {100} spinel substrate miscut in specific directions, (2) {10 13} gallium nitride (GaN) grown on a {110} spinel substrate, (3) {11 22} gallium nitride (GaN) grown on a {1 100} sapphire substrate, and (4) {10 13} gallium nitride (GaN) grown on a {1 100} sapphire substrate.

1. Field of the Invention.
The present invention relates to a technique for the growth of planar semi-polar gallium nitride. 2. Description of the Related Art.
The usefulness of gallium nitride (GaN), and its ternary and quaternary compounds incorporating aluminum and indium (AlGaN, InGaN, AlInGaN), has been well established for fabrication of visible and ultraviolet optoelectronic devices and high-power electronic devices. These devices are typically grown epitaxially using growth techniques including molecular beam epitaxy (MBE), metalorganic chemical vapor deposition (MOCVD), and hydride vapor phase epitaxy (HVPE).
GaN and its alloys are most stable in the hexagonal würtzite crystal structure, in which the structure is described by two (or three) equivalent basal plane axes that are rotated 120° with respect to each other (the a-axes), all of which are perpendicular to a unique c-axis. Group III and nitrogen atoms occupy alternating c-planes along the crystal's c-axis. The symmetry elements included in the würtzite structure dictate that III-nitrides possess a bulk spontaneous polarization along this c-axis, and the würtzite structure exhibits piezoelectric polarization.
Current nitride technology for electronic and optoelectronic devices employs nitride films grown along the polar c-direction. However, conventional c-plane quantum well structures in III-nitride based optoelectronic and electronic devices suffer from the undesirable quantum-confined Stark effect (QCSE), due to the existence of strong piezoelectric and spontaneous polarizations. The strong built-in electric fields along the c-direction cause spatial separation of electrons and holes that in turn give rise to restricted carrier recombination efficiency, reduced oscillator strength, and red-shifted emission.
One approach to eliminating the spontaneous and piezoelectric polarization effects in GaN optoelectronic devices is to grow the devices on non-polar planes of the crystal. Such planes contain equal numbers of Ga and N atoms and are charge-neutral. Furthermore, subsequent non-polar layers are equivalent to one another so the bulk crystal will not be polarized along the growth direction. Two such families of symmetry-equivalent non-polar planes in GaN are the {11 20} family, known collectively as a-planes, and the {1 100} family, known collectively as m-planes. Unfortunately, despite advances made by researchers at the University of California, for example, as described in the applications cross-referenced above, growth of non-polar GaN remains challenging and has not yet been widely adopted in the III-nitride industry.
Another approach to reducing or possibly eliminating the polarization effects in GaN optoelectronic devices is to grow the devices on semi-polar planes of the crystal. The term "semi-polar planes" can be used to refer to a wide variety of planes that possess both two nonzero h, i, or k Miller indices and a nonzero 1 Miller index. Some commonly observed examples of semi-polar planes in c-plane GaN heteroepitaxy include the {11 22}, {10 11}, and {10 13} planes, which are found in the facets of pits. These planes also happen to be the same planes that the inventors have grown in the form of planar films. Other examples of semi-polar planes in the würtzite crystal structure include, but are not limited to, {10 12}, {20 21}, and {10 14}. The nitride crystal's polarization vector lies neither within such planes or normal to such planes, but rather lies at some angle inclined relative to the plane's surface normal. For example, the {10 11} and {10 13} planes are at 62.98° and 32.06° to the c-plane, respectively.
The other cause of polarization is piezoelectric polarization. This occurs when the material experiences a compressive or tensile strain, as can occur when (Al, In, Ga, B)N layers of dissimilar composition (and therefore different lattice constants) are grown in a nitride heterostructure. For example, a thin AlGaN layer on a GaN template will have in-plane tensile strain, and a thin InGaN layer on a GaN template will have in-plane compressive strain, both due to lattice matching to the GaN. Therefore, for an InGaN quantum well on GaN, the piezoelectric polarization will point in the opposite direction than that of the spontaneous polarization of the InGaN and GaN. For an AlGaN layer latticed matched to GaN, the piezoelectric polarization will point in the same direction as that of the spontaneous polarization of the AlGaN and GaN.
The advantage of using semi-polar planes over c-plane nitrides is that the total polarization will be reduced. There may even be zero polarization for specific alloy compositions on specific planes. Such scenarios will be discussed in detail in future scientific papers. The important point is that the polarization will be reduced compared to that of c-plane nitride structures.
Bulk crystals of GaN are not available, so it is not possible to simply cut a crystal to present a surface for subsequent device regrowth. Commonly, GaN films are initially grown heteroepitaxially, i.e. on foreign substrates that provide a reasonable lattice match to GaN.
Semi-polar GaN planes have been demonstrated on the sidewalls of patterned c-plane oriented stripes. Nishizuka et al. have grown {11 22} InGaN quantum wells by this technique. (See Nishizuka, K., Applied Physics Letters, Vol. 85, No. 15, 11 Oct. 2004.) They have also demonstrated that the internal quantum efficiency of the semi-polar plane {11 22} is higher than that of the c-plane, which results from the reduced polarization.
However, this method of producing semi-polar planes is drastically different than that of the present invention; it is an artifact from epitaxial lateral overgrowth (ELO). ELO is used to reduce defects in GaN and other semiconductors. It involves patterning stripes of a mask material, often SiO2 for GaN. The GaN is grown from open windows between the mask and then grown over the mask. To form a continuous film, the GaN is then coalesced by lateral growth. The facets of these stripes can be controlled by the growth parameters. If the growth is stopped before the stripes coalesce, then a small area of semi-polar plane can be exposed. The surface area may be 10 μm wide at best. Moreover, the semi-polar plane will be not parallel to the substrate surface. In addition, the surface area is too small to process into a semi-polar LED. Furthermore, forming device structures on inclined facets is significantly more difficult than forming those structures on normal planes.
The present invention describes a technique for the growth of planar films of semi-polar nitrides, in which a large area of (Al, In, Ga)N is parallel to the substrate surface. For example, samples are often grown on 10 mm×10 mm or 2 inch diameter substrates compared to the few micrometer wide areas previously demonstrated for the growth of semi-polar nitrides.

Technique for the growth of planar semi-polar gallium nitride

The Regents of the University of California


A method for operating a content addressable memory that includes receiving a first data value for evaluation at a first memory block during a first time interval, receiving a second data value for evaluation at a second memory block during a second time interval and evaluating said both the first and second data values during a third time interval. According to one embodiment of the invention the first and second time intervals are separate so that the first and second data blocks receive unique data out of phase with one another from a single address bus. Evaluation of both data values takes place substantially simultaneously in the respective memory blocks. Also included is a device architecture and a device adapted to control data transfer to two CAM memory blocks in response to alternate phase transitions of a control signal.

A content addressable memory (CAM) is a memory device that permits rapid parallel searching of stored data to find a particular data value. In contrast to most other memory formats (such as ROM and RAM memory), which are based on address-driven storage architectures, the typical CAM memory device offers both address-driven and content-driven data access.
Address-driven memory device architectures are well-known. According to an address-driven architecture, during a memory access, a user supplies an address and stores data, or retrieves data previously stored, at that specific address. For example, in an address-driven architecture, data values may be stored at a particular logical address by specifying the address on an address bus, and supplying data on a data bus to be stored at the specified address. In the same fashion, data may be retrieved on the data bus in response to a memory address supplied on the address bus.
As noted, the typical CAM memory device can be accessed in both address-driven and content-driven fashion. Storage of data in a CAM may be performed in an address-driven mode, as described above. Additionally, some CAM memory devices allow storage of data in a "first available storage location." For example a logical flag may be provided for each storage location of the CAM device, indicating whether a storage location contains stored data, or is available to receive new data. When a new data item is presented to the CAM device, each logical flag of the logical flag set is tested simultaneously and an unused storage location is identified. The new data item is then stored in the unused storage location, and the logical flag associated with that location is reconfigured to indicate that the location is in use.
As with data storage, data retrieval in a CAM memory may be performed on an address-driven basis. More importantly, however, CAM memory provides content-driven data retrieval. In a content-driven data retrieval, a data pattern is presented to the CAM memory device. If the CAM memory device contains a previously stored data item of the same data pattern, that presence is indicated and the location in the CAM where the searched data is stored is identified and an address connected with the matched data is returned. The CAM memory device is structured to perform the search on a highly parallel basis, conducting the search on all the data in the CAM substantially simultaneously. Consequently, a CAM can provide search results much more rapidly than an address-driven memory device, in which searches are typically performed serially, one address at a time.
The content-driven data retrieval facility of a CAM memory is typically implemented by providing an array of storage cells connected in an extensive wired-or configuration. This architecture allows a multi-bit data word applied to an input of the CAM device to be compared, substantially simultaneously, with the data words stored in every location of the CAM.
FIG. 1 shows a simplified schematic representation of a CAM memory device 10, as known in the art. The CAM device includes a search register 12 and a plurality of storage words 14. Each storage word 14 includes multiple CAM memory cells 16. The search register 12 includes a corresponding plurality of search register bits 18. The search register 12 is coupled to each of the storage words 14 by a parallel bus 20, so that each cell 16 (for example cell 22) of a storage word 14 is coupled to a corresponding bit (for example 24) of the search register 12. Each storage word is coupled to a corresponding match line 26. The match line 26 exhibits electrical capacitance (represented as lumped capacitance 28) and can be pre-charged to a particular electrical potential by a precharge circuit 30.
As shown at 22 each CAM memory cell 16 of each storage word 14 includes a circuit 34 adapted to switchingly couple a particular match line 27 to ground 32. The circuit includes an input 36 coupled to the data bus 20. The input 36 is coupled to a gate of a transistor 38. Transistor 38 is coupled in series with another transistor 40 between the particular match line 27 and ground 32. Input 36 is also coupled, through an inverter 42, to a gate of another transistor 44. Transistor 44 is coupled in series with another transistor 46 between the particular match line 27 and ground 32. A gate of transistor 46 is coupled to a memory element 50. The memory element 50 controls the gate of transistor 46 according to a binary value D stored within memory element 50. A gate of transistor 40 is coupled to a memory element 48. The memory element 48 controls the gate of transistor 40 according to a binary value equal to the complement of D stored within memory element 48.
If the binary data received at input 36 is not equal to D, then the particular match line 27 is switchingly coupled to ground 32 through either transistor 38 and transistor 40 or transistor 44 and transistor 46. If the binary data received at input 36 is equal to D, then the particular circuit 34 does not ground the particular match line 27. If the data values received at the other respective inputs of the particular storage word 29 all match the corresponding "D" values of the respective memory cells 16 of storage word 29, then the particular match line 27 is not grounded at all. Accordingly, match line 27 remains at a detectably high potential, and a data match between the data values held in the search register 12 and the particular storage word 29 is indicated.
In operation, each match line is charged to a precharge voltage by the action of the precharge circuit 30. A binary value is stored in the search register 12. Corresponding binary values are applied to the storage words 14 over the parallel bus 20. If a bit value in the search register differs from a corresponding bit value in a search word 14, that search word switches to provide an electrical path between the respective match line 26 and ground 32. The capacitance 28 of the match line 26 is thus discharged, indicating, by a resulting low match line voltage, that the value in the storage word 14 does not match the value in the search register 12. If a match line remains high (ungrounded), this indicates that the storage word 14 coupled to that match line 26 contains the same value as that present in the search register 12.
In at least some prior art CAM devices, memory cells are arranged in a plurality of memory blocks on a substrate. Each memory block is connected to a respective dedicated data bus that supplies data to the memory block. Different data can be provided on each dedicated data bus. As a result different data may be searched in different memory blocks at the same time. A device 100 constructed according to this architecture is shown in FIG. 2.
FIG. 2 shows a substrate 201 on which are formed first 202 and second 204 memory blocks. Each memory block includes a plurality of CAM memory cells 16 formed on the substrate. The first memory block 202 has a first data input port 206 coupled to a first search register 208. The second memory block 204 has a second data input port 210 coupled to a second search register 212. The first 208 and second 212 search registers are each coupled to a respective search data bus 215, 217. A first control line 219 is coupled to a first control input 218 of the first memory block 202 and a second control input 222 of the first search register 208. A second control line 221 is coupled to a third control input 220 of the second memory block 204 and to a fourth control input 224 of the second search register 212.
A control circuit 226 is coupled to the control lines 219, 221. The control circuit 226 is adapted to apply respective control signals to the control lines 219, 221, thereby initiating comparisons between the values in the search registers 208, 212 and storage words made up of memory cells 16 within the corresponding memory blocks 202, 204. Because each memory block has its own data bus 219, 221, this arrangement is costly in terms of device complexity and associated manufacturing yields, device real estate, and device energy and thermal budgets.
This costliness is a factor in the economics of CAM applications. Accordingly it is desirable to produce a CAM a memory integrated circuit having an improved data bus architecture.

CAM memory architecture and a method of forming and operating a device according to a CAM memory architecture


A preprocessing device used in a video coding apparatus, comprising a motion compensation prediction estimating unit for detecting a change of an video from a current picture and a past picture to generate change data, and a filter for deforming the current picture in accordance with the change data generated by the motion compensation prediction estimating circuit such that a deformed current picture is sent to a motion compensation prediction coding section of the video coding apparatus to be coded.

1. Field of the Invention
The present invention relates to a video coding/decoding apparatus used in a video communication system such as a videophone, a video conference system, a system of a storage apparatus such as a digital VTR, a video disk, a broadcast system such as a terrestrial, a satellite, a CATV system.
2. Description of the Related Art
In each field of the broadcast system, the storage apparatus, and the video communication system, importance of a video coding for compression-coding a video signal with high efficiency has been considerably increased. In the filed of the broadcast system, there have been advanced the study and development in which the CATV broadcast, the satellite broadcast, and the terrestrial broadcast are digitized so as to realize the multi-channel broadcast, and diversity of service. In the field of the system of the storage apparatus, there have been advance the study and development of the digital VTR and digital video disk, which are applied to the present TV and a HDTV in the future. In the field of the video communication system, there have been advanced the study and development for realizing a multi-media communication through a broadband communication network. Moreover, in the field of the video communication system, a multi-media communication using a mobile radio communication network has been also studied. The former communication system is used in a relatively wide band. In contrast, the latter communication system is used in a finite radio band. Due to this, it is required that an amount of data be largely compressed in the transmission of the video signal.
In recent years, in the field of the video coding, there has been a trend in improving quality of prediction of a motion compensation prediction coding, which is currently performed by the parallel shift of blocks, in order to improve a compression ratio, that is, coding efficiency. One of these new techniques of motion compensation is called a patch motion compensation or a motion interpolation. More specifically, in this new the motion compensation, a motion vector corresponding to each pixel is calculated from motion vectors obtained for sample points by a linear interpolation (see "Basic Study on Motion Compensation with Triangles" by Nakaya, Harashima, Technical Report of IEICE, IE90-106, G. Sullivan, R. Baker, "Motion Compensation for Video Compensation Using Control Grid Interpolation" ICASSP '91, M9.1). According to these methods, since the motion can be set by a pixel unit even if the motion vector having the same amount of data as the conventional motion compensation coding system is sent, a predictive precision can be improved, and this can contribute to the compression ratio of video data. Moreover, since the basis of the conventional motion compensation coding system lies in the preparation of a predictive video signal by a block unit, there is a tendency to generate blocking artifacts in a decoded video signal. According to these methods, the predictive video signal is continuously generated, and no inter block gap in the video content is generated.
On the other hand, as a general technique in the video coding, it is needed that a coding output amount of an coding apparatus be smoothed, that is, a rate control for adjusting the coding output amount to a target coding output amount is required. According to the conventional video coding apparatus, a quantization step size is changed as viewing a storage amount (amount of occupation) of an output buffer so as to control the coding output amount. However, if there is used an orthogonal transform coding such as H. 261, which is an international standard system of video coding, and DCT used in MPEG, there is a problem in that the blocking artifacts are generated to largely deteriorate a subjective quality of video.
In order to solve the above problem, there is known a rate control using a low-pass filter, for example, "Review of Variable Pre-filter Control System in Video Coding" by Takishima, Wada, PCSJ'92 6.6). This technique explains that not only the quantization step size but also resolution of an input video signal before being coded is reduced so as to control the coding output amount. As compared with the rate control in which the coding output amount is controlled by only the quantization step size, resolution of the large motion video drops, but the blocking artifacts can be reduced, so that the subjective quality can be improved.
Among the above-mentioned prior art, regarding the patch motion compensation and the motion interpolation, the prediction quality in the small motion of the video can be improved, and the coding efficiency can be also improved. However, regarding the large motion of the video in which motion compensation cannot be performed, influence of its deformation is exerted on the large area. As a result, there may be a case that a prediction error is increased, and the coding efficiency is reduced. Particularly, in the case of a change of a scene in which the motion compensation does not originally work, no improvement is made.
The motion vector is normally detected by comparing the input video signal and the decoded video signal. Due to this, in a case where the coding is performed at a low bit rate, a suitable motion vector cannot be easily detected by deterioration of the decoded video signal due to influence of coding noise, unfavorable influence is exerted on the predictive video. Moreover, for obtaining the motion vector suitable for the patch motion compensation and the motion interpolation, the motion vector, which is obtained by the block matching, which is the conventional vector detection system, is set as an initial value, and the motion vector is optimized by an iterative operation. Due to this, the amount of calculations are largely increased.
On the other hand, in the rate control using the low-pass filter, since the filter is passed over the entire screen, there is a problem in that deterioration is prominent when resolution largely drops. Particularly, in a case where the large motion and deformation are formed in only a part of the area of the same video, resolution of the small motion area where the coding output amount does not become large is dropped. Due to this, the subjective quality is caused to be reduced as visual deterioration.

Video preprocessing device with motion compensation prediction processing similar to that of a main prediction processing device


A system and method for operating an imaging device is shown. The method includes detecting the malfunction when the imaging device is in a normal mode of operation; causing the imaging device to enter a reduced function mode following the detecting; enabling only one or more functions of the imaging device when in the reduced function mode, the one or more functions being less than all of the functions available when the imaging device is in the normal mode of operation. The one or more functions have operating points when the imaging device is in the reduced function mode that are different than the operating points of the one or more functions when the imaging device is in the normal mode of operation.

1. Field of the Disclosure
The present disclosure relates generally to controlling a malfunctioning device, and particularly to a device having a reduced function mode in which a reduced set of functions remains available despite an occurrence of a malfunctioning subsystems of the device.
2. Description of the Related Art
In an effort to better and more timely manage equipment, corporations often consolidate equipment and employ a managed environment for overseeing same. However, the ability to keep devices online is not progressing at the same rate, and any delay in bringing the devices online following a device malfunction can impact company workflow and productivity. In an imaging device, when a sensor or feed roll of the imaging device, for example, causes repetitive media jams or other repetitive malfunctions, the imaging device is typically brought offline and not usable until it is serviced and/or the malfunctioning part is replaced. Repetitive malfunctions are also seen to occur more frequently in the imaging device as the components of the device wear over time, resulting in increased downtime over the life of the imaging device.

Imaging system with reduced function mode, and methods therefor


In order to detect via an external circuit whether male and female connector housings 1 and 2 have been correctly fitted together, a short-circuiting terminal 19 which bends when a locking arm 10 bends either short circuits or fails to short circuit a pair of detecting terminals 7 located on the male housing 1. The area surrounding the short-circuiting terminal 19 is surrounded by an interior protecting wall which is covered by a flexible sealing cover 27. The sealing cover covers only the short-circuiting terminal and the locking arm remains exposed. The upper face of the interior protecting wall has an opening 25A. When the locking arm 19 is bent while the housings are being fitted, the short-circuiting terminal 19 is moved via the sealing cover 27 and the short-circuiting terminal and the detecting terminals 7 separate.

Conventionally, connectors are provided with fitting detecting terminals which detect electrically whether male and female connectors have been fitted together correctly. For example, a pair of fitting detecting terminals is provided on one connector housing, and the other is provided with a short-circuiting terminal and a locking arm. When the two connector housings are correctly fitted together, the short-circuiting terminal short-circuits the two detecting terminals by making contact with them. The locking arm locks the connector housings in a fitted state. Typically, while the connector housings are being fitted, the locking arm is used to bend the short-circuiting terminal away from the detecting terminal as the locking arm bends; when the connectors are in a correctly fitted state, the return of the locking arm is used to return the short-circuiting terminal to its original position, thereby short-circuiting the detecting terminal. By this means, the fitting detecting function is realised.
However, in this type of connector, in which the fitting detection is carried out through the bending of the locking arm, the locking arm must be operated from the exterior. As a result, an open configuration tends to be employed. This kind of configuration is unsuitable for locations which require waterproofing. Currently, the waterproofing requirement cannot be met with this type of fitting detecting configuration.
The present invention has been developed after taking the above problem into consideration, and aims to present a fitting detecting connector which is provided with a waterproofing function.


An automatic programming method includes a first processing including detecting a turning surface having a largest diameter in the product model, and determining a central axis of rotation on the turning surface detected as a turning axis of the product model; a second processing including shifting or rotating the product model so that the turning axis of the product model determined matches a turning axis of the work model; and a third processing including shifting the product model so that an end face of the product model shifted at the second processing matches a program origin preset in the work model, for automatically arranging the product model so as to be overlapped on the work model.

In a machine tool on which an NC unit (numerical control unit) is mounted, a work is machined into a desired product shape by executing the NC program. To create the NC creation program for creating the NC machining program, recently, an automatic programming technique using a microcomputer referred to as an automatic programming device has been frequently used.
The early automatic programming devices were not connected to the CAD data, and hence, it was necessary to perform programming, while watching the machining shape in a drawing or the like. However, recently, some techniques relating to the automatic programming device that creates the NC machining program by the CAD data have been proposed.
For example, in (Japanese Patent Application Laid-Open No. 2002-189510), feature data of a machined product is extracted from the CAD data to set a machining process and a machining area for each machining process, material data and a machining model for each machining process are created, the created machining process data and machining model data are stored, tool path data is created based on the machining process data, material data, machining model data, tool data, and cutting condition data, to create virtual work shape data after completing the respective processes, as well as creating fabrication information based on the created process data, material data, tool path data, and virtual work shape data.
In (Japanese Patent Application Laid-Open No. 2002-268718), when a machining path for machining a workpiece based on a three-dimensional CAD data of a part is created, machining information for all portions to be machined in a shape indicated by the three-dimensional CAD data is extracted, the extracted machining information is edited to determine a machining process, and the machining path is created based on the determined machining process.
In such type of automatic programming device, a product model is arranged in a work model, and machining data has to be created as a difference between the product model and the work model. At this time, it is desired that the product model can be automatically arranged easily in the work model.
In (Japanese Patent Application Laid-Open No. 2001-117616), it is disclosed that an object solid model (product model) and a workpiece solid model (work model) are overlapped on each other and combined, to obtain a synthesis model indicating a capacity portion of a workpiece, which has to be removed in order to form the object. Specifically, a human user selects at least one of topological feature types, selects a surface of the synthesis model, associates a related one portion of the model having the selected surface with the selected topological feature type, defines the portion having the selected surface as a machining feature topologically equivalent to the selected topological feature type, and divides the capacity portion to be removed into many machining features.
In the conventional art described in Japanese Patent Application Laid-Open No. 2001-117616, however, how to overlap the object solid model (product model) and the workpiece solid model (work model) is not particularly described.
The present invention has been achieved in order to solve the above problems, and it is therefore an object of the invention to provide an automatic programming method and device that can position the product model on the work model with quite simple operation, and can achieve efficient programming operations.


The present invention is related to a circuit for converting the sample rate of a digital signal, comprising                an input for applying the digital signal,        a conversion filter having either a symmetrical or anti-symmetrical impulse response and implemented as a plurality of subfilters in parallel, each subfilter having a symmetrical or anti-symmetrical response derived from components of a polyphase decomposition of said impulse response,        combining means for deriving from said applied digital signal input signals of said plurality of subfilters or for combining output signals of said plurality of subfilters into a digital signal with converted sample rate,        an output for outputting said digital signal with converted sample rate.

Digital sample rate conversion (SRC) is a technique to replace a system that includes a variety of master clock rates with a fixed clock rate system. Applications are abundant, e.g. acquisition (signal generator) systems with an oversampled ADC (DAC), followed (preceded) by a digital decimator (interpolator) to relieve the analog anti-aliasing (reconstruction) filter specifications. Integer factor SRC also appears in analysis (i.e. decimation) and synthesis (i.e. interpolation) filter banks.
To explain the problem tackled in the present invention a linear phase digital filter is assumed of order N, implying a finite impulse response h(k) of length N+1 (Eq. 1) with symmetric (Eq. 2) or anti-symmetric (Eq. 3) impulse response.
                              y                                [            n            ]                          =                              ∑                          k              =              0                        N                                                                                h                                            [                k                ]                                                                x                                            [                                  n                  -                  k                                ]                                                                        (                  Eq          .                                                    1                )                                          h                                [            k            ]                          =                                            h                                            [                                  N                  -                  k                                ]                                                                                with                                                                          k                    ∈                      0                                                                          …                                                                          N                                              (                  Eq          .                                                    2                )                                          h                                [            k            ]                          =                                            -                              h                                                  [                                      N                    -                    k                                    ]                                                                                with                                                                          k                    ∈                      0                                                                          …                                                                          N                                              (                  Eq          .                                                    3                )            Tƒis defined as the sample period of the output signal (for an interpolator) or the input signal (for a decimator). Thus, Tƒis the sample period of the signal with the fastest sample rate. For a single-rate filter Tƒis equal to the sample period of both input and output signals.#M is defined as the number of multiplications per output sample and per sample period Tƒ. A single rate realisation of Eq. 1 results in #M as given in Eq. 4. Also naive realisations of Eq. 1 in integer factor interpolators and decimators have that same #M as shown in Eq. 4.#M=N+1  (Eq. 4)In a single-rate system a linear phase FIR realisation can take advantage of its impulse response symmetry (Eq. 5) or anti-symmetry (Eq. 6); whereby └ ┘ denotes a truncation to the lower integer.
                                          y                                      [              n              ]                                =                                    ∑                              k                =                0                                            ⌊                                  N                  2                                ⌋                                                                                h                                                  [                  k                  ]                                                                          (                                                      x                                                              [                                              n                        -                        k                                            ]                                                        +                                      x                                                              [                                              n                        +                        k                        -                        N                                            ]                                                                      )                                                                                for                                                                                N                                                                                odd                                                                                y                                      [              n              ]                                =                                                    h                                                  [                                      ⌊                                          N                      2                                        ⌋                                    ]                                                                          x                                                  [                                      ⌊                                          N                      2                                        ⌋                                    ]                                                      +                                          ∑                                  k                  =                  0                                                                      ⌊                                          N                      2                                        ⌋                                    -                  1                                                                                h                                                        [                    k                    ]                                                                                (                                                            x                                                                    [                                                  n                          -                          k                                                ]                                                              +                                          x                                                                    [                                                  n                          +                          k                          -                          N                                                ]                                                                              )                                                                                for                                                                                N                                                                                even                                                                        (                  Eq          .                                                    5                )                                                      y                                      [              n              ]                                =                                    ∑                              k                =                0                                            ⌊                                  N                  2                                ⌋                                                                                h                                                  [                  k                  ]                                                                          (                                                      x                                                              [                                              n                        -                        k                                            ]                                                        -                                      x                                                              [                                              n                        +                        k                        -                        N                                            ]                                                                      )                                                                                for                                                                                N                                                                                odd                                                                                y                                      [              n              ]                                =                                                    h                                                  [                                      ⌊                                          N                      2                                        ⌋                                    ]                                                                          x                                                  [                                      ⌊                                          N                      2                                        ⌋                                    ]                                                      +                                          ∑                                  k                  =                  0                                                                      ⌊                                          N                      2                                        ⌋                                    -                  1                                                                                h                                                        [                    k                    ]                                                                                (                                                            x                                                                    [                                                  n                          -                          k                                                ]                                                              -                                          x                                                                    [                                                  n                          +                          k                          -                          N                                                ]                                                                              )                                                                                for                                                                                N                                                                                even                                                                        (                  Eq          .                                                    6                )            By means of Eq. 5 and Eq. 6 the number of multiplications per output sample #M is reduced from N+1 to
                              #                                                              M                =                              ⌊                          N              2                        ⌋                    +          1                                    (                  Eq          .                                                    7                )
Another generally known principle is multi-phase decomposition for sample rate conversion. Equation 8 defines the polyphase components hλ(n·LTƒ) for an L-fold decomposition of impulse response h(k·Tƒ).h′λ(n·LTƒ)=h((nL+λ)Tƒ)  (Eq. 8)                with λ=0 . . . L−1The filter h(k·Tƒ) has a frequency response to select the desired signal image (for an interpolator) or anti-aliasing band (for a decimator).The corresponding Z-transforms are combined in vector H(z) (Eq. 9).Hλ(z)=Z{(hλ(n·LTƒ)} H(z)=[H0(z) . . . H1(z) . . . HL−1(z)]T  (Eq. 9)The polyphase equation for an L-factor interpolator is shown in Eq. 10: Y(z)= H(z)·X(z)  (Eq. 10)whereby X(z) denotes the Z-transform of the input signal x(n·LT) and Y(z) the decomposition of the output signal y(k·Tƒ) as defined in Eq. 11.yλ(n·LTƒ)=y((nL+λ)Tƒ)Yλ(z)=Z{yλ(n·LTƒ)} Y(z)=[Y0(z) . . . Y1(z) . . . YL−1(z)]T  (Eq. 11)        with λ=0 . . . L−1For an L-factor decimator the polyphase equation is shown in equation 12.Y(z)= HT(z)· X(z)  (Eq. 12)y(n·LTƒ) hereby represents the output signal. The decomposition of the input signal x(k·Tƒ) is as defined in equation 13.xλ(n·LTƒ)=x((nL+λ)Tƒ)Xλ(z)=Z{xλ(n·LTƒ)} X(z)=[X0(z) . . . X1(z) . . . XL−1(z)]T  Eq. 13        with A=0 . . . L−1The efficiency of the polyphase realisations (as in Eqs. 10 and 12) lies in the fact that all filter operations are performed at the lowest rate, i.e. at 1/(LTƒ) instead of at 1/Tƒ. The average number of multiplications per output sample and per Tƒfor a polyphase interpolator (or decimator) is given in Eq. 14.
                              #                                                              M                =                              N            +            1                    L                                    (                  Eq          .                                                    14                )
However, the h(kTƒ) (anti-)symmetry generally does not yield intra-phase (anti)-symmetry in most hλ(nLT) phases. The 2-fold decomposition for an even (N=8) order impulse response h(kTƒ) as shown in Eq. 15 is one example of an exception. Since h8=i=hi, both phases H0(z) and Hf(z) are symmetric.H0(z)=h0+h2z−1+h4z−2+h6z−3+h8z−4 H1(z)=h1+h3z−1+h5z−2+h7z−3  (Eq. 15)In Eq. 16 (where L=3 and N=11), H1(z) is symmetric for a symmetric H(z), but the other phases H0(z) and H2(z) are not symmetric.H0(z)=h0+h3z−1+h6z−2+h9z−3 H1(z)=h1+h4z−1+h7z−2+h10z−3 H2(z)=h2+h5z−1+h8z−2+h11z−3  (Eq. 16)However, in general, the multiplication reduction offered by filter response (anti-)symmetry, as in (Eq. 4) and (Eq. 5), is partially or completely lost with a polyphase realisation.