Novel triazabenzo[e]azulene derivatives of the formula, (I) in which R1, R2 and R3 have the meanings indicated in Claim 1, are inhibitors of TGF-beta receptor kinase and can be employed, inter alia, for the treatment of tumors.

The invention had the object of finding novel compounds having valuable properties, in particular those which can be used for the preparation of medicaments.
The present invention relates to compounds and to the use of compounds in which the inhibition, regulation and/or modulation of signal transduction by kinases, in particular TGF-beta receptor kinases, plays a role, furthermore to pharmaceutical compositions which comprise these compounds, and to the use of the compounds for the treatment of kinase-induced diseases.
Transforming growth factor beta is the prototype of the TGF-beta superfamily, a family of highly preserved, pleiotropic growth factors, which carry out important functions both during embryo development and also in the adult organism. In mammals, three isoforms of TGF-beta (TGF-beta 1, 2 and 3) have been identified, TGF-beta 1 being the commonest isoform (Kingsley (1994) Genes Dev 8:133-146). TGF-beta 3 is expressed, for example, only in mesenchymal cells, whereas TGF-beta 1 is found in mesenchymal and epithelial cells. TGF-beta is synthesised as pre-proprotein and is released in inactive form into the extracellular matrix (Derynck (1985) Nature 316: 701-705; Bottinger (1996) PNAS 93: 5877-5882). Besides the proregion cleaved off, which is also known as latency associated peptide (LAP) and remains associated with the mature region, one of the 4 isoforms of the latent TGF-beta binding proteins (LTBP 1-4) may also be bonded to TGF-beta (Gentry (1988) Mol Cell Biol 8: 4162-4168, Munger (1997) Kindey Int 51: 1376-1382). The activation of the inactive complex that is necessary for the development of the biological action of TGF-beta has not yet been clarified in full. However, proteolytic processing, for example by plasmin, plasma transglutaminase or thrombospondin, is certainly necessary (Munger (1997) Kindey Int 51: 1376-1382). The activated ligand TGF-beta mediates its biological action via three TGF-beta receptors on the membrane, the ubiquitously expressed type I and type II receptors and the type III receptors betaglycan and endoglin, the latter only being expressed in endothelial cells (Gougos (1990) J Biol Chem 264: 8361-8364, Loeps-Casillas (1994) J Cell Biol 124:557-568). Both type III TGF-beta receptors lack an intracellular kinase domain which facilitates signal transmission into the cell. Since the type III TGF-beta receptors bind all three TGF-beta isoforms with high affinity and type II TGF-beta receptor also has higher affinity for ligands bonded to type III receptor, the biological function is thought to consist in regulation of the availability of the ligands for type I and type II TGF-beta receptors (Lastres (1996) J Cell Biol 133:1109-1121; Lopes-Casillas (1993) Cell 73: 1435-1344). The structurally closely related type I and type II receptors have a serine/threonine kinase domain, which is responsible for signal transmission, in the cytoplasmatic region. Type II TGF-beta receptor binds TGF-beta, after which the type I TGF-beta receptor is recruited to this signal-transmitting complex. The serine/threonine kinase domain of the type II receptor is constitutively active and is able to phosphorylate seryl radicals in this complex in the so-called GS domain of the type I receptor. This phosphorylation activates the kinase of the type I receptor, which is now itself able to phosphorylate intracellular signal mediators, the SMAD proteins, and thus initiates intracellular signal transmission (summarised in Derynck (1997) Biochim Biophys Acta 1333: F105-F150).
The proteins of the SMAD family serve as substrates for all TGF-beta family receptor kinases. To date, 8 SMAD proteins have been identified, which are divided into 3 groups: (1) receptor-associated SMADs (R-SMADs) are direct substrates of the TGF-β receptor kinases (SMAD1, 2, 3, 5, 8); (2) co-SMADs, which associate with the R-Smads during the signal cascade (SMAD4); and (3) inhibitory SMADs (SMAD6, 7), which inhibit the activity of the above-mentioned SMAD proteins. Of the various R-SMADs, SMAD2 and SMAD3 are the TGF-beta-specific signal mediators. In the TGF-beta signal cascade, SMAD2/SMAD3 are thus phosphorylated by the type I TGF-beta receptor, enabling them to associate with SMAD4. The resultant complex of SMAD2/SMAD3 and SMAD4 can now be translocated into the cell nucleus, where it can initiate the transcription of the TGF-beta-regulated genes directly or via other proteins (summarised in Itoh (2000) Eur J Biochem 267: 6954-6967; Shi (2003) Cell 113: 685-700).
The spectrum of the functions of TGF-beta is wide-ranging and dependent on cell type and differentiation status (Roberts (1990) Handbook of Experimental Pharmacology: 419-472). The cellular functions which are influenced by TGF-beta include: apoptosis, proliferation, differentiation, mobility and cell adhesion. Accordingly, TGF-beta plays an important role in a very wide variety of biological processes. During embryo development, it is expressed at sites of morphogenesis and in particular in areas with epithelial-mesenchymal interaction, where it induces important differentiation processes (Pelton (1991) J Cell Biol 115:1091-1105). TGF-beta also carries out a key function in the self-renewal and maintenance of an undifferentiated state of stem cells (Mishra (2005) Science 310: 68-71). In addition, TGF-beta also fulfils important functions in the regulation of the immune system. It generally has an immunosuppressive action, since it inhibits, inter alia, the proliferation of lymphocytes and restricts the activity of tissue macrophages. TGF-beta thus allows inflammatory reactions to subside again and thus helps to prevent excessive immune reactions (Bogdan (1993) Ann NY Acad Sci 685: 713-739, summarised in Letterio (1998) Annu Rev Immunol 16: 137-161). Another function of TGF-beta is regulation of cell proliferation. TGF-beta inhibits the growth of cells of endothelial, epithelial and haematopoietic origin, but promotes the growth of cells of mesenchymal origin (Tucker (1984) Science 226:705-707, Shipley (1986) Cancer Res 46:2068-2071, Shipley (1985) PNAS 82: 4147-4151). A further important function of TGF-beta is regulation of cellular adhesion and cell-cell interactions. TGF-beta promotes the build-up of the extracellular matrix by induction of proteins of the extracellular matrix, such as, for example, fibronectin and collagen. In addition, TGF-beta reduces the expression of matrix-degrading metalloproteases and inhibitors of metalloproteases (Roberts (1990) Ann NY Acad Sci 580: 225-232; Ignotz (1986) J Biol Chem 261: 4337-4345; Overall (1989) J Biol Chem 264: 1860-1869); Edwards (1987) EMBO J 6: 1899-1904).
The broad spectrum of action of TGF-beta implies that TGF-beta plays an important role in many physiological situations, such as wound healing, and in pathological processes, such as cancer and fibrosis.
TGF-beta is one of the key growth factors in wound healing (summarised in O'Kane (1997) Int J Biochem Cell Biol 29: 79-89). During the granulation phase, TGF-beta is released from blood platelets at the site of injury. TGF-beta then regulates its own production in macrophages and induces the secretion of other growth factors, for example by monocytes. The most important functions during wound healing include stimulation of chemotaxis of inflammatory cells, the synthesis of extracellular matrix and regulation of the proliferation, differentiation and gene expression of all important cell types involved in the wound-healing process.
Under pathological conditions, these TGF-beta-mediated effects, in particular the regulation of the production of extracellular matrix (ECM), can result in fibrosis or scars in the skin (Border (1994) N Engl J Med 331:1286-1292).
For the fibrotic diseases, diabetic nephropathy and glomeronephritis, it has been shown that TGF-beta promotes renal cell hypertrophy and pathogenic accumulation of the extracellular matrix. Interruption of the TGF-beta signalling pathway by treatment with anti-TGF-beta antibodies prevents expansion of the mesangial matrix, progressive reduction in kidney function and reduces established lesions of diabetic glomerulopathy in diabetic animals (Border (1990) 346: 371-374, Yu (2004) Kindney Int 66: 1774-1784, Fukasawah (2004) Kindney Int 65: 63-74, Sharma (1996) Diabetes 45: 522-530).
TGF-beta also plays an important role in liver fibrosis. The activation, essential for the development of liver fibrosis, of the hepatic stellate cells to give myofibroblasts, the main producer of the extracellular matrix in the course of the development of liver cirrhosis, is stimulated by TGF-beta. It has likewise been shown here that interruption of the TGF-beta signalling pathway reduces fibrosis in experimental models (Yata (2002) Hepatology 35:1022-1030; Arias (2003) BMC Gastroenterol 3:29)
TGF-beta also takes on a key function in the formation of cancer (summarised in Derynck (2001) Nature Genetics: 29: 117-129; Elliott (2005) J Clin Onc 23: 2078-2093). In early stages of the development of cancer, TGF-beta counters the formation of cancer. This tumour-suppressive action is based principally on the ability of TGF-beta to inhibit the division of epithelial cells. By contrast, TGF-beta promotes cancer growth and the formation of metastases in late tumour stages. This can be attributed to the fact that most epithelial tumours develop a resistance to the growth-inhibiting action of TGF-beta, and TGF-beta simultaneously supports the growth of the cancer cells via other mechanisms. These mechanisms include promotion of angiogenesis, the immunosuppressive action, which supports tumour cells in avoiding the control function of the immune system (immunosurveillance), and promotion of invasiveness and the formation of metastases. The formation of an invasive phenotype of the tumour cells is a principal prerequisite for the formation of metastases. TGF-beta promotes this process through its ability to regulate cellular adhesion, motility and the formation of the extracellular matrix. Furthermore, TGF-beta induces the transition from an epithelial phenotype of the cell to the invasive mesenchymal pheno-type (epithelial mesenchymal transition=EMT). The important role played by TGF-beta in the promotion of cancer growth is also demonstrated by investigations which show a correlation between strong TGF-beta expression and a poor prognosis. Increased TGF-beta level have been found, inter alia, in patients with prostate, breast, intestinal and lung cancer (Wikström (1998) Prostate 37:19-29; Hasegawa (2001) Cancer 91: 964-971; Friedman (1995), Cancer Epidemiol Biomarkers Prey. 4:549-54).
Owing to the cancer-promoting actions of TGF-beta described above, inhibition of the TGF-beta signalling pathway, for example via inhibition of the TGF-beta type I receptor, is a possible therapeutic concept. It has been shown in numerous preclinical trials that interruption of the TGF-beta signalling pathway does indeed inhibit cancer growth. Thus, treatment with soluble TGF-beta type II receptor reduces the formation of metastases in transgenic mice, which develop invasive breast cancer in the course of time (Muraoka (2002) J Clin Invest 109: 1551-1559, Yang (2002) J Clin Invest 109: 1607-1615).
Tumour cell lines which express a defective TGF-beta type II receptor exhibit reduced tumour and metastatic growth (Oft (1998) Curr Biol 8: 1243-1252, McEachern (2001) Int J Cancer 91:76-82, Yin (1999) Jclin Invest 103: 197-206).
Conditions "characterised by increased TGF-β activity" include those in which TGF-β synthesis is stimulated so that TGF-β is present at increased levels or in which latent TGF-β protein is undesirably activated or converted to active TGF-β protein or in which TGF-β receptors are upregulated or in which the TGF-β protein shows enhanced binding to cells or the extracellular matrix in the location of the disease. Thus, in each case "increased activity" refers to any condition in which the biological activity of TGF-β is undesirably high, regardless of the cause.
A number of diseases have been associated with TGF-β1 overproduction. Inhibitors of the intracellular TGF-β signalling pathway are suitable treatments for fibroproliferative diseases. Specifically, fibroproliferative diseases include kidney disorders associated with unregulated TGF-β activity and excessive fibrosis including glomerulonephritis (GN), such as mesangial proliferative GN, immune GN and crescentic GN. Other renal conditions include diabetic nephropathy, renal interstitial fibrosis, renal fibrosis in transplant patients receiving cyclosporin, and HIV-associated nephropathy. Collagen vascular disorders include progressive systemic sclerosis, polymyositis, sclerodermatitis, dermatomyositis, eosinophilic fasciitis, morphea, or those associated with the occurrence of Raynaud's syndrome. Lung fibroses resulting from excessive TGF-β activity include adult respiratory distress syndrome, idiopathic pulmonary fibrosis, and interstitial pulmonary fibrosis often associated with autoimmune disorders, such as systemic lupus erythematosus and sclerodermatitis, chemical contact or allergies. Another autoimmune disorder associated with fibroproliferative characteristics is rheumatoid arthritis.
Eye diseases associated with a fibroproliferative condition include retinal reattachment surgery accompanying proliferative vitreoretinopathy, cataract extraction with intraocular lens implantation, and post-glaucoma drainage surgery and are associated with TGF-β1 overproduction.
Fibrotic diseases associated with TGF-β1 overproduction can be divided into chronic conditions, such as fibrosis of the kidney, lung and liver, and more acute conditions, such as dermal scarring and restenosis (Chamberlain, J. Cardiovascular Drug Reviews, 19(4): 329-344). Synthesis and secretion of TGF-β1 by tumour cells can also lead to immune suppression, as seen in patients with aggressive brain or breast tumours (Arteaga, et al. (1993) J. Clin. Invest. 92: 2569-2576). The course of leishmanial infection in mice is drastically altered by TGF-β1 (Barral-Netto, et al. (1992) Science 257: 545-547). TGF-β1 exacerbated the disease, whereas TGF-β1 antibodies halted the progression of the disease in genetically susceptible mice. Genetically resistant mice became susceptible to leishmanial infection upon administration of TGF-β1.
The profound effects on extracellular matrix deposition have been reviewed (Rocco and Ziyadeh (1991) in Contemporary Issues in Nephrology v.23, Hormones, autocoids and the kidney. ed. Jay Stein, Churchill Livingston, New York pp. 391-410; Roberts, et al. (1988) Rec. Prog. Hormone Res. 44: 157-197) and include stimulation of the synthesis and inhibition of the degradation of extracellular matrix components. Since the structural and filtration properties of the glomerulus are largely determined by the extracellular matrix composition of the mesangium and glomerular membrane, it is not surprising that TGF-β1 has profound effects on the kidney. The accumulation of mesangial matrix in proliferative glomerulonephritis (Border, et al., (1990) Kidney Int. 37: 689-695) and diabetic nephropathy (Mauer, et al. (1984) J. Clin. Invest. 74: 1143-1155) are clear and dominant pathological features of the diseases. TGF-β1 levels are elevated in human diabetic glomerulosclerosis (advanced neuropathy) (Yamamoto, et al. (1993) Proc. Natl. Acad. Sci. 90: 1814-1818). TGF-β1 is an important mediator in the genesis of renal fibrosis in a number of animal models (Phan, et al. (1990) Kidney Int. 37: 426; Okuda, et al. (1990) J. Clin. Invest. 86: 453). Suppression of experimentally induced glomerulonephritis in rats has been demonstrated by antiserum against TGF-β1 (Border, et al. (1990) Nature 346: 371) and by an extracellular matrix protein, decorin, which can bind TGF-β1 (Border, et al. (1992) Nature 360: 361-363).
Excessive TGF-β1 leads to dermal scar-tissue formation. Neutralising TGF-β1 antibodies injected into the margins of healing wounds in rats has been shown to inhibit scarring without interfering with the rate of wound healing or the tensile strength of the wound (Shah, et al. (1992) Lancet 339: 213-214). At the same time there was reduced angiogenesis, a reduced number of macrophages and monocytes in the wound, and a reduced amount of disorganised collagen fibre deposition in the scar tissue.
TGF-β1 may be a factor in the progressive thickening of the arterial wall which results from the proliferation of smooth muscle cells and deposition of extracellular matrix in the artery after balloon angioplasty. The diameter of the restenosed artery may be reduced by 90% by this thickening, and since most of the reduction in diameter is due to extracellular matrix rather than smooth muscle cell bodies, it may be possible to reopen these vessels to 50% simply by reducing excessive extracellular matrix deposition. In undamaged pig arteries transfected in vivo with a TGF-β1 gene, TGF-β1 gene expression was associated with both extracellular matrix synthesis and hyperplasia (Nebel, et al. (1993) Proc. Natl. Acad. Sci USA 90: 10759-10763). The TGF-β1-induced hyperplasia was not as extensive as that induced with PDGF-BB, but the extracellular matrix was more extensive with TGF-β1 transfectants. No extracellular matrix deposition was associated with hyperplasia induced by FGF-1 (a secreted form of FGF) in this gene transfer pig model (Nabel (1993) Nature 362: 844-846).
There are various types of cancer where TGF-β1 produced by the tumour may be deleterious. MATLyLu rat prostate cancer cells (Steiner and Barrack (1992) Mol. Endocrinol 6: 15-25) and MCF-7 human breast cancer cells (Arteaga, et al. (1993) Cell Growth and Differ. 4: 193-201) became more tumorigenic and metastatic after transfection with a vector expressing the mouse TGF-β1. TGF-β1 has been associated with angiogenesis, metastasis and poor prognosis in human prostate and advanced intestinal cancer (Wikstrom, P., et al. (1988) Prostate 37; 19-29; Saito, H., et al. (1999) Cancer 86: 1455-1462). In breast cancer, a poor prognosis is associated with elevated TGF-β (Dickson, et al. (1987) Proc. Natl. Acad. Sci. USA 84: 837-841; Kasid, et al. (1987) Cancer Res. 47: 5733-5738; Daly, et al. (1990) J. Cell Biochem. 43: 199-211; Barrett-Lee, et al. (1990) Br. J. Cancer 61: 612-617; King, et al (1989) J. Steroid Biochem. 34: 133-138; Welch, et al (1990) Proc. Natl. Acad. Sci USA 87: 7678-7682; Walker et al. (1992) Eur. J. Cancer 238: 641-644), and induction of TGF-β1 by tamoxifen treatment (Butta, et al. (1992) Cancer Res. 52: 4261-4264) has been associated with failure of tamoxifen treatment for breast cancer (Thompson, et al. (1991) Br. J. Cancer 63: 609-614). Anti-TGF-β1 antibodies inhibit the growth of MDA-231 human breast cancer cells in athymic mice (Arteaga, et al. (1993) J. Clin. Invest. 92: 2569-2576), a treatment which is correlated with an increase in natural killer cell activity in the spleen. CHO cells transfected with latent TGF-β1 also showed decreased NK activity and increased tumour growth in nude mice (Wallick, et al. (1990) J. Exp. Med. 172: 177-1784). Thus, TGF-β secreted by breast tumours may cause endocrine immune suppression. High plasma concentrations of TGF-β1 show a poor prognosis for advanced breast cancer patients (Anscher, et al. (1993) N. Engl. J. Med. 328: 1592-1598). Patients with high circulating TGF-β before high dose chemotherapy and autologous bone marrow transplantation are at high risk of a hepatic veno-occlusive disease (15-50% of all patients with a mortality rate up to 50%) and idiopathic interstitial pneumonitis (40 to 60% of all patients). The implication of these findings is 1) that elevated plasma levels of TGF-β1 can be used to identify at-risk patients and 2) that reduction of TGF-β1 can decrease the morbidity and mortality of these common treatments for breast cancer patients.
Many malignant cells secrete transforming growth factor β (TGF-β), a potent immunosuppressant, suggesting that TGF-β production may represent a significant tumour escape mechanism from host immunosurveillance. Establishment of a leukocyte sub-population with a disrupted TGF-β signalling pathway in the tumour-bearing host offers a powerful measure for immunotherapy of cancer. A transgenic animal model with a disrupted TGF-β signalling pathway in T cells is capable of eradicating a normally lethal TGF-β-overexpressing lymphoma tumour, EL4 (Gorelik and Flavell, (2001) Nature Medicine 7 (10): 1118-1122). Downregulation of TGF-β secretion in tumour cells results in restoration of immunogenicity in the host, while T-cell insensitivity to TGF-β results in accelerated differentiation and autoimmunity, elements of which may be required in order to combat self-antigen-expressing tumours in a tolerised host. The immunosuppressive effects of TGF-β have also been implicated in a sub-population of HIV patients with lower than predicted immune response based on their CD4/CD8 T cell counts (Garba, et al., J. Immunology (2002) 168: 2247-2254). A TGF-β-neutralising antibody was capable of reversing the effect in culture, indicating that TGF-β signalling pathway inhibitors may be suitable in reversing the immune suppression present in this subset of HIV patients.
During the earliest stages of carcinogenesis, TGF-β1 can act as a potent tumour suppressor and may mediate the actions of some chemopreventive agents. At a certain point during the development and progression of malignant neoplasms, tumour cells appear to escape from TGF-β-dependent growth inhibition in parallel with the appearance of biologically active TGF-β in the microenvironment. The dual tumour suppression/tumour promotion roles of TGF-β have been most clearly elucidated in a transgenic system overexpressing TGF-β in keratinocytes. While the transgenics were more resistant to formation of benign skin lesions, the rate of metastatic conversion in the transgenics was dramatically increased (Cui, et al, (1996) Cell 86(4): 531-42). The production of TGF-β1 by malignant cells in primary tumours appears to increase with advancing stages of tumour progression. Studies in many of the major epithelial cancers suggest that the increased production of TGF-β by human cancers occurs as a relatively late event during tumour progression. Furthermore, this tumour-associated TGF-β provides the tumour cells with a selective advantage and promotes tumour progression. The effects of TGF-β on cell-cell and cell-stroma interactions results in a greater propensity for invasion and metastasis. Tumour-associated TGF-β may allow tumour cells to escape from immunosurveillance since it is a potent inhibitor of the clonal expansion of activated lymphocytes. TGF-β has also been shown to inhibit the production of angiostatin. Cancer therapeutic modalities, such as radiation therapy and chemotherapy, induce the production of activated TGF-β in the tumour, thereby selecting outgrowth of malignant cells that are resistant to TGF-β growth inhibitory effects. Thus, these anticancer treatments increase the risk and hasten the development of tumours with enhanced growth and invasiveness. In this situation, agents targeting TGF-β-mediated signal transduction might be a very effective therapeutic strategy. The resistance of tumour cells to TGF-β has been shown to negate many of the cytotoxic effects of radiation therapy and chemotherapy, and the treatment-dependent activation of TGF-β in the stroma may even be detrimental as it makes the microenvironment more conducive to tumour progression and contributes to tissue damage leading to fibrosis. The development of TGF-β signal transduction inhibitors is likely to benefit the treatment of advanced cancer alone and in combination with other therapies.
The compounds are suitable for the treatment of cancer and other conditions influenced by TGF-β by inhibiting TGF-β in a patient in need thereof by administration of the compound(s) to the patient. TGF-β is also suitable against atherosclerotic (T. A. McCaffrey: TGF-βs and TGF-β Receptors in Atherosclerosis: Cytokine and Growth Factor Reviews 2000, 11, 103-114) and Alzheimer's diseases (Masliah, E.; Ho, G.; Wyss-Coray, T.: Functional Role of TGF-β in Alzheimer's Disease Microvascular Injury: Lessons from Transgenic Mice: Neurochemistry International 2001, 39, 393-400).
It has been found that the compounds according to the invention and salts thereof have very valuable pharmacological properties while being well tolerated.
In particular, they exhibit TGF receptor I kinase-inhibiting properties.
The compounds according to the invention preferably exhibit an advantageous biological activity, which can easily be demonstrated in enzyme-based assays, for example assays as described herein. In such enzyme-based assays, the compounds according to the invention preferably exhibit and cause an inhibiting effect, which is usually documented by IC50 values in a suitable range, preferably in the micromolar range and more preferably in the nanomolar range.
As discussed herein, these signalling pathways are relevant for various diseases. Accordingly, the compounds according to the invention are useful in the prophylaxis and/or treatment of diseases that are dependent on the said signalling pathways by interaction with one or more of the said signalling pathways.
The present invention therefore relates to compounds according to the invention as promoters or inhibitors, preferably as inhibitors, of the signalling pathways described herein. The invention therefore preferably relates to compounds according to the invention as promoters or inhibitors, preferably as inhibitors, of the TGF signalling pathway.
The present invention furthermore relates to the use of one or more compounds according to the invention in the treatment and/or prophylaxis of diseases, preferably the diseases described herein, that are caused, mediated and/or propagated by an increased TGF activity.
The present invention therefore relates to compounds according to the invention as medicaments and/or medicament active ingredients in the treatment and/or prophylaxis of the said diseases and to the use of compounds according to the invention for the preparation of a pharmaceutical for the treatment and/or prophylaxis of the said diseases as well as to a method for the treatment of the said diseases comprising the administration of one or more compounds according to the invention to a patient in need of such an administration.
The host or patient can belong to any mammalian species, for example a primate species, particularly humans; rodents, including mice, rats and hamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are of interest for experimental investigations, providing a model for treatment of a human disease.
The susceptibility of a particular cell to treatment with the compounds according to the invention can be determined by in-vitro testing. Typically, a culture of the cell is combined with a compound according to the invention at various concentrations for a period of time which is sufficient to allow the active agents to induce cell death or to inhibit migration, usually between about one hour and one week. In-vitro testing can be carried out using cultivated cells from a biopsy sample. The viable cells remaining after the treatment are then counted.
The dose varies depending on the specific compound used, the specific disease, the patient status, etc. A therapeutic dose is typically sufficient considerably to reduce the undesired cell population in the target tissue while the viability of the patient is maintained. The treatment is generally continued until a considerable reduction has occurred, for example an at least about 50% reduction in the cell burden, and may be continued until essentially no more undesired cells are detected in the body.
For identification of a signal transduction pathway and for detection of interactions between various signal transduction pathways, various scientists have developed suitable models or model systems, for example cell culture models (for example Khwaja et al., EMBO, 1997, 16, 2783-93) and models of transgenic animals (for example White et al., Oncogene, 2001, 20, 7064-7072). For the determination of certain stages in the signal transduction cascade, interacting compounds can be utilised in order to modulate the signal (for example Stephens et al., Biochemical J., 2000, 351, 95-105). The compounds according to the invention can also be used as reagents for testing kinase-dependent signal transduction pathways in animals and/or cell culture models or in the clinical diseases mentioned in this application.
Measurement of the kinase activity is a technique which is well known to the person skilled in the art. Generic test systems for the determination of the kinase activity using substrates, for example histone (for example Alessi et al., FEBS Lett. 1996, 399, 3, pages 333-338) or the basic myelin protein, are described in the literature (for example Campos-González, R. and Glenney, Jr., J. R. 1992, J. Biol. Chem. 267, page 14535).
For the identification of kinase inhibitors, various assay systems are available. In the scintillation proximity assay (Sorg et al., J. of. Biomolecular Screening, 2002, 7, 11-19) and the flashplate assay, the radioactive phosphorylation of a protein or peptide as substrate with γATP is measured. In the presence of an inhibitory compound, a decreased radioactive signal, or none at all, is detectable. Furthermore, homogeneous time-resolved fluorescence resonance energy transfer (HTR-FRET) and fluorescence polarisation (FP) technologies are suitable as assay methods (Sills et al., J. of Biomolecular Screening, 2002, 191-214).
Other non-radioactive ELISA assay methods use specific phospho-antibodies (phospho-ABs). The phospho-AB binds only the phosphorylated substrate. This binding can be detected by chemiluminescence using a second peroxidase-conjugated anti-sheep antibody (Ross et al., 2002, Biochem. J., just about to be published, manuscript BJ20020786).

Triazabenzo[E]azulene derivatives for the treatment of tumors

Merck Patent Gesellschaft Mit Beschrankter Haftung


A system and method for analyzing social media data by obtaining social media data from a social media platform, where the social media data includes documents from multiple users of the social media platform; classifying the documents using a sentiment classifier; tokenizing the documents into terms; associating a sentiment with each term; detecting a first event based on a number of occurrences of a first term in the documents; and providing information associated with the event to a user, where the information includes the first term and a sentiment associated with the first term.

Social media platforms are valuable sources of information on public expressions and opinions. For example, social media platform users often post opinions or comments related to particularly good or particularly bad experiences with a good or service they have used. Such information would be beneficial to the providers of the goods and/or services, and can allow the providers to receive real-time feedback from their customers.
The large volume of data produced by social media platforms can offer the providers of goods and/or services the overall opinions of their customers, but it is virtually impossible to manually monitor and analyze such large amounts of data.
Therefore, there is a need for methods and systems for monitoring and analyzing social media data.

Methods and systems for monitoring and analyzing social media data


A wireless diagnostic sensor link for providing wireless communication between a signal source and a monitoring device. The wireless diagnostic sensor link includes a signal input device operable for receiving a signal from the signal source in a first communication protocol in the form of an analog signal, converting the analog signal to a digital signal, and transmitting the digital signal in the form of a wireless communication protocol. The wireless diagnostic sensor link also includes a signal output device, which receives the digital signal. The signal output device is in electrical communication with the monitoring device, and is also operable for communicating with the signal input device. The signal output device converts the digital signal back to an analog signal, and sends the signal to the monitoring device in the form of a second communications protocol.

A transducer is a device that converts one type of energy to another. The conversion can be to/from electrical, electro-mechanical, electromagnetic, photonic, photovoltaic, or any other form of energy. While the term "transducer" commonly implies use as a sensor/detector, any device which converts energy can be considered a transducer. A transducer, or transducer kit (TK), is often categorized by application: sensor, actuator, or combination.
A transducer in the form of a sensor is used to detect a parameter in one form and report it in another form of energy (usually an electrical and/or digital signal). For example, a pressure sensor might detect pressure (a mechanical form of energy) and convert it to electricity for display at a remote gauge.
A transducer in the form of an actuator accepts energy and produces movement (action). The energy supplied to an actuator might be electrical or mechanical (pneumatic, hydraulic, etc.). An electric motor and a loudspeaker are both transducers, converting electrical energy into motion for different purposes.
Combination transducers have both functions—they both detect and create action. For example, a typical ultrasonic transducer switches back and forth many times a second between acting as an actuator to produce ultrasonic waves, and acting as a sensor to detect ultrasonic waves.
Modern TK devices are interfaced with a personal computer through the use of a cable connection, such as a Universal Serial Bus (USB), or the like. The interface allows the computer to record measurements as they are made if the transducer is functioning as a sensor, or send commands to the transducer, if the transducer is functioning as an actuator.
However, using an actual wire connection between a TK and a computer, such as a USB or the like, is limiting because the TK and device under test must be located at a distance in relation to the computer. The distance between the TK and device under test must be substantially equal to or less than the length of the wire because the wire must be connected to both the computer and the transducer. This limits the use of a TK when it is physically impossible to have the device under test in proximity to the computer such that the wire connection can be made between the TK and the computer.
Several attempts have been made to provide a wireless connection between a transducer or other diagnostic sensor, and a device such as a computer or protocol adapter. Many of these attempts have involved converting a first communications protocol in the form of an analog signal to a digital signal, then converting the digital signal to a wireless communications protocol, such as an RF or infrared signal, and transmitting the signal wirelessly from the transducer or other diagnostic sensor to the protocol adapter or computer, then performing another protocol conversion to convert the signal from a wireless signal back to a digital signal suitable for use with the communication protocol used by the protocol adapter or computer. However, this process involves several protocol conversions, such as analog-to-digital and digital-to-analog, and wireless to digital. Additionally, the upper frequency end of messages or sensor signals is restricted, and because there are at least two adapters for performing the analog-to-digital and digital-to-analog conversions, the device or system has an increased number of components.
Accordingly, there exists a need for a device such as a TK which is able to record desired measurements or parameters of a device under test, and communicate wirelessly with a computer, allowing the computer to record the measurements or parameters, without limiting the location of the computer or the device under test, while limiting the amount of conversions of the signal from the TK.


The present invention generally relates to an apparatus and method for stimulating respiration during sleep. In one aspect, a respiration stimulation system is provided. The respiration stimulation system includes a detector configured to measure a respiratory cycle or a user and provide an electrical output signal indicative of the respiratory cycle. The respiration stimulation system further includes a control device configured to receive the electrical output signal from the detector and monitor the respiratory cycle of the user. Additionally, the respiration stimulation system includes a stimulator configured to apply stimuli to at least one point of stimulation upon receipt of a signal from the control device. In another aspect, a method of stimulating respiration in a user is provided. In a further aspect, a respiration stimulation system is provided.

1. Field of the Invention
Embodiments of the present invention generally relate to respiration. More specifically, the present invention relates to an apparatus and method for stimulating respiration during sleep.
2. Description of the Related Art
A clinical pathologic entity called Sleep Apnea syndrome (SAS) affects many individuals around the world. Sleep apnea means "cessation of breath." It is characterized by repetitive stops of respiration, each lasting for more than about 10 seconds, which brings the brain into a hypoxic state (reduced arterial oxygen tension). SAS may cause severe disturbances of sleep itself and may have deleterious effects on mental activities, such as intellectual performance, memory, and behavior. Further, SAS is known as one of the causes of cardiovascular diseases, increased blood pressure (hypertension), stroke, heart arrhythmia, and conduction disturbances which may lead even to fatal cardiac arrest. SAS is especially dangerous in patents having chronic lung and heart diseases.
Many patients are at risk of suffering from SAS. Certain populations of patients are at higher risk than others. For instance, 30% of the middle-aged population, mainly men, suffers from respiratory disturbances during sleep. Additionally, frequent sleep apneas are found in about 50% of cardiovascular patients. Furthermore, there are many more patients with "unrecognized" SAS, since only direct observation of the respiratory cycle of a patient during sleep can reveal this pathology.
There are essentially two main types of apnea. One type relates to stops in respiration during sleep caused by cessation or reduction of nerve stimuli extending from the respiratory center in the brain to respiratory muscles. This type of apnea is commonly referred to as central apnea. The second type of apnea relates to the uncontrolled excessive decrease of muscle tone in the upper airway resulting in obstruction. This type of apnea is commonly referred to as obstructive apnea. The incomplete obstruction of the upper airway usually causes snoring. Frequently, patients have a combination of central and obstructive apneas, which is referred to as mixed apnea.
Obstructive apnea is caused by the abnormal, excessive reduction of muscle tone of the oropharynx, pharynx, and hypopharynx; the retraction of the tongue; and negative pressure in nasal space which independently or collectively can result in the collapse and obstruction of the upper airway. Generally, the oropharyngeal muscles maintain the upper airway passage open in order to allow a normal breathing. As such, the reduction of muscle tone of oropharyngeal muscles is one of the main mechanisms of SAS.
A common means of protection against SAS is usually arousal from the sleep and restoration of normal breathing as a result of temporary normalization of the cortical neural control of respiration. However, as expected, these repetitive arousals result in fragmented disturbed sleep.
Current treatments of SAS have been limited to mechanical stenting of the airway via CPAP (continuous positive airway pressure) devices and oral appliances; and surgical procedures aimed at removing, reducing, repositioning, or stiffening tissue in the upper airway. CPAP and oral devices have a 50%-60% compliance rate because of patients' feelings of claustrophobia, nasal stuffiness, and inconvenience related to these devices' awkward and cumbersome equipment. Surgical treatments are usually very painful, require the use of general anesthesia, and can have severe complications. In the medical literature, surgical interventions are at best 60-70% effective at curing sleep apnea.
The most widely used device is the CPAP, which prevents collapse of the pharynx by blowing air into the upper airway tract. However, the CPAP device has several substantial shortcomings. For instance, the CPAP device tends to be uncomfortable and noisy. Further, the CPAP device requires the use of a mask on the face of the patient, preventing free movement during sleep. Additionally, the inflow of the air pressure during the use of the CPAP device sometimes causes the sensation of suffocation, nasal drying, and even pain in the ears due to barotrauma. Furthermore, the regulation and tuning of the CPAP device requires time and observation. As a result, patient compliance is the greatest hurdle with the CPAP device and the CPAP device rarely gets above a 60% compliance rate.
Therefore, there remains a need for a device to aid in the restoration of normal breathing to SAS patients that is simple to use, comfortable, non-invasive, painless, and does not cause the sensation of suffocation or nasal drying.


In a semiconductor device in which the surface of a semiconductor substrate which was subjected to impurity diffusion process, and includes a multilayer metal interconnection layer which is formed on top of it by alternately laminating a metal wiring layer and an interlayer insulating film, the present semiconductor device is characterized in that in a lower layer metal wiring layer there is provided a dummy wiring stripe which is arranged in parallel to two wiring stripes that are formed away from other wiring stripes at a space according to design rules. The width of the wiring stripe is augmented effectively due to the presence of the dummy stripe, and the holding quantity of the material of the coating film which constitutes a part of the interlayer insulating film is increased. Therefore, the flatness of the interlayer insulating film directly over these wiring stripes can be improved, and it becomes possible to secure the uniformity of the film of the upper layer metal wiring layer that is formed on top of the interlayer insulating film.

1. Field of the Invention
The present invention relates to a semiconductor device, and more particularly to a semiconductor device having a multilayer metal interconnection.
2. Description of the Prior Art
With the enhancement of the level of integration of semiconductor devices the multilayer metal interconnection has become to be employed extensively. A multilayer metal interconnection is formed ordinarily by alternately laminating a metal wiring layer consisting of aluminum (A1) or tungsten (W) and an interlayer insulating film after coating the surface of a semiconductor substrate which was subjected to an impurity diffusion process or the like for the formation of semiconductor devices with an insulating film such as a silicon oxide film. The interlayer insulating film between two metal wiring layers consists of a lower layer silicon oxide film by a chemical vapor deposition (CVD) method, a coating (spin on glass (SOG)) film, and an upper layer silicon oxide film by the CVD method which covers the coating film (see Japanese Patent Application Laid Open No. 57-100748). Since the right-angled parts of the edges of the metal film pattern of the metal wiring layer are substantially dulled by the above-mentioned coating film, and the steep level difference due to the lower layer metal wiring is ameliorated, making the surface of the interlayer insulating film covering the wiring layer more flat. As a result, even in the upper metal wiring layer formed on the surface of the interlayer insulating film over the lower metal wiring layer, corresponding to the region of the lower metal wiring layer where a plurality of extra fine metal film stripes are arranged parallel with each other at the minimum allowable space according to design rules, there will not occur too much deterioration in the step coverage, that is, the ratio of the smallest thickness of the metal wiring at the step part to the thickness of the metal wiring at the flat part.
However, when the lower metal wiring layer includes a part where just two extra fine metal film stripes are formed parallel with each other away from other wiring pattern at the minimum space, the flatness of the interlayer insulating film is deteriorated because it is not possible to thoroughly fill in the space between the two metal film stripes in forming the interlayer insulating film that covers the lower metal wiring layer. Accordingly, if an upper layer metal wiring is formed on an interlayer insulating film with a low degree of flatness as in the above, the step coverage of the wiring film is reduced and the disconnection of the wiring is liable to take place. Even if it does not lead to the disconnection of the wiring, there will be generated, in the wiring film, portions with very small thickness which induce electromigration or stress-migration, deteriorating the reliability and the yield of the semiconductor device.

Semiconductor device having multilayer metal interconnection


A separating device for separating a semiconductor substrate includes: a cutting element for cutting the semiconductor substrate into a plurality of chips along with a cutting line on the semiconductor substrate; an adsorbing element for adsorbing a dust on a surface of the semiconductor substrate by using electrostatic force; and a static electricity generating element for generating static electricity and for controlling the static electricity in order to remove the dust from the adsorbing element.

In recent years, in a dicing process for separating a silicon wafer (hereinafter called a wafer) forming a semiconductor integrated circuit and MEMS (Micro Electro Mechanical Systems) into respective semiconductor chips, consideration and research of a dicing process (laser dicing) using a laser beam are advanced. For example, a processing technique of the wafer using a laser is disclosed in JP-A-2002-192367. FIGS. 9A and 9B are explanatory views showing the dicing process using the laser beam. FIG. 9A is an explanatory view of a reforming area forming process using irradiation of the laser beam. FIG. 9B is an explanatory view of a divisional cutting process.
As shown in FIG. 9A, a laser head H for irradiating the laser beam L has a condenser lens CV for converging the laser beam L, and can converge the laser beam L at a predetermined focal distance. In the reforming area forming process, the laser head H is moved along a divisional cutting schedule line DL (in the direction of this side in FIGS. 9A and 9B) for divisionally cutting the wafer W in a laser beam irradiating condition set such that a convergent point P of the laser beam L is formed in a position of depth d from a substrate face of the wafer W. The laser beam L is irradiated from the substrate face of the wafer W. Thus, a reforming area K using multiphoton absorption is formed in a path of depth d in which the convergent point P of the laser beam L is scanned. When a foreign substance is attached onto the divisional cutting schedule line DL, the irradiation of the laser beam L is obstructed. Therefore, it is necessary to remove the foreign substance.
Here, the multiphoton absorption is that a substance absorbs plural photons of the same kind or different kinds. A phenomenon called optical damage is generated by this multiphoton absorption at the convergent point P of the semiconductor substrate W and its vicinity. Thus, thermal strain is induced, and a crack is generated in its portion. A layer constructed by gathering these cracks, i.e., the reforming area K is formed.
When the laser beam L is a pulse wave, intensity of the laser beam L is determined by peak power density (W/cm2) of the convergent point P. For example, the multiphoton absorption is generated in a condition in which peak power density is 1×108 (W/cm2) or more and pulse width is 1 μs or less. For example, a laser beam using a YAG (Yttrium Aluminum Garnet) laser is used as the laser beam L. For example, the wavelength of this laser beam L is a wavelength of 1064 nm in an infrared light area.
Subsequently, as shown in FIG. 9B, stress is loaded in an in-plane direction (direction shown by arrows F2 and F3 in this figure) of the semiconductor substrate W. Thus, a crack C is developed in the substrate thickness direction with the reforming area K as a starting point, and the semiconductor substrate W is divisionally cut along the divisional cutting schedule line DL. At a divisional cutting time, one portion of the semiconductor substrate W is chipped, and dust is generated. When this dust is attached to the substrate face, there is a fear that this dust has a bad influence on a product. Therefore, it is necessary to remove this dust.
As a method for removing an attachment substance such as dust, a foreign substance, etc. mentioned above, a technique for removing the attachment substance by suction and a technique for blowing-off the attachment substance by air cleaning are disclosed in, for example, JP-A-2003-10986 and JP-A-2003-10992.
However, in the removal using suction, there is a problem of a fear that the attachment substance is moved in a wide range along the semiconductor substrate at a sucking time, and has a bad influence such as damage of a product, etc. There is also a problem that the attachment substance can be removed in only a narrow area near a sucking portion, and removing efficiency is bad. Further, in the air cleaning, there is a problem of a fear that the attachment substance is moved in a wide range along the semiconductor substrate, and has a bad influence such as damage of a product, etc.
Further, a manufacturing device of a semiconductor chip is formerly used in manufacture of the semiconductor chip. In this manufacturing device, with respect to the semiconductor substrate of a state diced on a divisional scheduled line and stuck to a sheet, this sheet is extended and enlarged, and the semiconductor substrate is divided into semiconductor chips by loading stress in a planar direction of the semiconductor substrate. FIGS. 16A and 16B show one example of a former manufacturing device of the semiconductor chip. FIG. 16A is an explanatory view of a state in which the semiconductor substrate is adhered to the sheet and an outer circumferential portion of the sheet is held in a frame. FIG. 16B is an explanatory view of a process for dividing the semiconductor substrate into semiconductor chips by a pressing device.
As shown in FIG. 16A, the substrate face of a rear face of the semiconductor substrate, i.e., the semiconductor wafer W constructed by a semiconductor of silicon, etc. is adhered to the sheet S manufactured by resin and having a drawing property in a state in which laser dicing, etc. are performed. An outer circumferential portion of the sheet S is held by a frame F of an annular shape.
As shown in FIG. 16B, the semiconductor substrate W is pressed so as to be pushed up from the rear side of the sheet S by using a pressing device PD arranged below the semiconductor substrate W and moved in the vertical direction by an unillustrated moving means. Thus, the sheet S is extended in the planar direction (the directions of arrows F11 and F12 in FIG. 16B). Thus, stress is loaded to the semiconductor substrate W adhered to the sheet S in the planar direction. Therefore, the semiconductor substrate W is divided into plural semiconductor chips C. The above device is disclosed in JP-A-2003-334675.
However, in the former manufacturing device of the semiconductor chip, the sheet S is extended in a state in which the outer circumference of the sheet S is held. Therefore, the extension of the sheet S tends to become large toward its outer circumferential portion, and the extension of the sheet S tends to become small in its central portion. Namely, the semiconductor substrate W is properly divided in the vicinity of the outer circumference, but no semiconductor substrate W is easily divided in the vicinity of the center. Therefore, a problem exists in that yield of the semiconductor chip C is reduced.
Further, it is preferable to uniformly extend the sheet S so as to improve yield for obtaining the semiconductor chip C by divisionally cutting the semiconductor substrate W. However, in the former divisional cutting device of the semiconductor substrate, the sheet S is extended in a holding state of the outer circumference of the sheet S. Therefore, the extension of the sheet S tends to become large toward its outer circumferential portion, and tends to become small in its central portion. Namely, the semiconductor substrate W is properly divisionally cut near the outer circumference, but is not easily divisionally cut near the center. Therefore, a problem exists in that yield of the semiconductor chip C is reduced.

Method for separating a semiconductor substrate into a plurality of chips along with a cutting line on the semiconductor substrate


A reverse wedgelock device with multiple draw blocks disposed about a lead screw passing through the draw blocks, wherein the draw blocks may be compressed together and caused to displace about respective wedge surfaces upon tightening of the screw. Compression and displacement of the draw blocks can function to draw anchors associated with the draw blocks inward, which, when engaged with opposing objects, functions to draw the objects together.

Interfacing cold plates with electronics or electronics components for cooling purposes has been a longstanding problem. For example, in computing systems, it is not uncommon for large amount of heat to be generated during operation of the system. In low power systems, sufficient cooling is often achieved through edge cooling of an electronic component and an associated chassis. However, in many cases, as computing systems have become much more sophisticated and powerful, edge cooling has proven to be an inefficient and insufficient solution. As such, many computing systems now employ a base cooling solution in order to improve thermal performance. Base cooling solutions can result in a greater amount of surface area of the electronic component and chassis being in contact with the cooling plate, which functions as a heat dissipating device or heat sink, and can increase the amount and rate at which the heat can be removed or dissipated away from the electronic component. The larger the surface area in contact with the heat sink or cooling plate the higher the heat transfer efficiency becomes.
Wedge block chains, commonly known as wedgelocks, are devices used within a confined space, wherein the wedgelock provides a thermal interface and is configured to expand and apply a force upon the walls of the confined space to thereby spread the space apart. Wedgelocks may be used in electronic or electronics applications typically employing an edge cooled solution in order to provide an external pressure or force on an integral electronic component, forcing it against a cooling plate. Two opposing wedgelocks are commonly employed to press against an outer surface or frame and to pinch the electronic component and cooling plate between them in order to ensure good thermal contact between the electronic component and the cooling plate. Wedgelocks are particularly desirable for electronics because they can be configured to facilitate tightening along the entire length of the wedge block chain by means of a screw that can be accessed about an end, which allows easy access to what would otherwise be a constrictive working space. Also, by arranging wedgelocks in series one can optimize pressure distribution across an entire surface area to ensure contact between the electronic component and the cooling plate. Although wedgelocks may be employed in a large variety of applications they are particularly useful for providing thermal contact between electronic processing chips and chassis and cooling plates, particularly in applications where there may be multiple electronic components located in series within the confined space.


An unmanned aerial vehicle having counterrotating ducted rotors that are driven by electric motors. The vehicle has a low weight and a small profile. The unmanned aerial vehicle is suitable for a number of different tasks, including control, surveillance and reconnaissance, communication, and other tasks without exposing personnel to dangerous situations. The vehicle is particularly suited for entering buildings and other enclosed structures and spaces such as caves. The unmanned aerial vehicle can also be equipped for potential offensive actions.

In many military and law enforcement situations, it is desirable to perform control, surveillance and reconnaissance, communication, and other tasks without exposing personnel to dangerous situations.
For example, it is often necessary for military and law enforcement personnel to enter buildings and other enclosed structures and spaces. Entry into structures is done for various reasons, including searching the interiors of the structures, surveillance and reconnaissance, and apprehending individuals within the structures.
For military and law enforcements personnel, entry into structures can be extremely dangerous. Often, the personnel may not know whether there are potentially dangerous or potentially friendly occupants within a structure, how many occupants there are, or where the occupants are located within the structure. In addition, the personnel may not know the interior configuration of the structure or the location of potentially dangerous obstacles. As a result of these unknowns, the personnel may need to make spur of the moment decisions during and after entry, which can lead to dangerous, and potentially fatal, errors in judgment. Further, to enter a structure, the personnel often leave the safe confines of a location, for example an armored vehicle, thereby exposing themselves to potential danger prior to entry.
The use of unmanned vehicles for performing control, surveillance, reconnaissance, communications, and other tasks is known. These include ground based remote-controlled wheeled or tracked vehicles, and aerial vehicles including the Honeywell Micro Air Vehicle, the Honeywell Kestrel, and the Allied Aerospace iSTAR.
Many prior unmanned vehicles are powered by combustion engines, making the vehicles noisy even with sounds mufflers in place. In addition, the use of an engine(s) and the need to carry the requisite fuel supply increases the weight of the vehicle, thereby decreasing the portability of the vehicle, especially by humans.

Unmanned aerial vehicle with electrically powered, counterrotating ducted rotors


A shoe including a sole 1 for absorbing an impact of landing, an upper 2 for wrapping around an instep, and shoelace means 3 for fitting the upper 2 to the instep, the upper 2 including: a main portion 2M covering a medial side surface, a lateral side surface, a toe, the instep and a back surface of a foot; a side edge portion having a plurality of first eyelets H1; a first side panel 51 covering the medial side surface of the foot; and a second side panel 52 covering the lateral side surface of the foot, wherein each side panel includes: a tip portion 53 having a second eyelet H2 which is provided at a tip of the side panel and which the shoelace means passes through and engages with; a bottom portion 54 attached to the main portion and/or the sole; and a middle portion 55 arranged between the tip portion and the bottom portion so as to allow the tip portion to move in the front-back direction of the foot with respect to the bottom portion, wherein with at least one of the side panels, the middle portion 55 can stretch and shrink to increase a length from the tip portion to the bottom portion.

A shoelace fits an upper to the foot. The upper fitting the foot supports the foot.
However, during dorsal flexion of the MP joint, the foot shape changes, and therefore the foot circumference also changes. When shoes are worn over a long period of time, the foot circumference increases in many cases. In such a case, the foot inside a shoe will be compressed by the upper. Moreover, the shoe and the foot are likely to slip against each other during action.    [First Patent Document] Japanese Laid-Open Patent Publication No. 2006-258 (abstract)    [Second Patent Document] Japanese Laid-Open Patent Publication No. 11-18803 (abstract)    [Third Patent Document] Japanese Utility Model Publication for Opposition No. 33-5240 (FIG. 1)    [Fourth Patent Document] Japanese Utility Model Publication for Opposition No. 5-9843 (FIG. 3)    [Fifth Patent Document] EPO 329,392 A2 (abstract)    [Sixth Patent Document] Japanese Laid-Open Patent Publication No. 4-44701 (page 2, upper right col.)    [Seventh Patent Document] WO 2004/93587 A1, US 2006/0162190 A1 (abstract)
With a shoe of the first document, non-stretchable belts are fixed to the inner side of a stretchable upper, and the non-stretchable belts prevent the upper from stretching. In the shoe of the first document, an eyelet (loop) is provided at the tip of each non-stretchable belt, and therefore the eyelet will not move in the foot circumference direction in the shoe (while the shoe is worn).
The belts are continuous with each other in the front-back direction, with the tips of the belts attached to the stretchable member of the upper, and therefore the belts are prevented from being displaced freely.
A shoe of the second document has a size that is variable in the foot length direction. In order for the size to be variable in the foot length direction, this shoe includes, provided in the middle foot portion, a flexible fabric portion that is stretchable in the front-back direction of the upper. The flexible fabric portion does not stretch in the circumference direction. Therefore, since the eyelets provided in the flexible fabric portion do not move in the circumference direction, the foot will be compressed while the shoe is worn.
A shoe of the third document includes a wide stretchable piece on each side surface of the front foot portion. The wide stretchable piece may feel less compressive to the foot. However, the wide stretchable piece will not be able to support the side surface of the foot.
Since the ornamental eyelets are continuous with each other in the front-back direction, the eyelets will not move in the front-back direction. Therefore, the eyelets are prevented from moving freely.
The eyelet members of the fourth document are formed by a resin whose Shore hardness is 90 to 100. A resin whose Shore hardness is 90 to 100 will hardly stretch.
With a shoe of the fifth document, the rear foot portion is supported by a non-stretching supporting stirrup.
A shoe of the sixth document includes a pair of side panels (fastening bands) sandwiched between the inner skin and the outer skin of the upper. The side panels may be formed by a rubber sheet or a stretchable fabric, and each includes three eyelets. The aim of the shoe of the sixth document is that the side panel stretches and shrinks in the circumference direction depending on the magnitude of the foot circumference (circumferential length) of the person.
However, with the invention of the sixth document, the object is that the side panels connected together with shoelaces do not move on the upper skin in the front-back direction and reliably fasten a predetermined position of the instep of the foot, as stated on (page 1, right col. or) page 2, lower right col. of the publication, and the side panels are wide. Therefore, eyelets formed in the side panels are not at all intended to move in the front-back direction of the foot, and it is believed that they do not substantially move so.
With the invention of the sixth document, the side panels formed by a rubber sheet or a stretchable fabric cover large areas of the side surfaces of the foot, and even cover areas posterior to the metatarsal bones. This will detract from the upper's function of holding or supporting the foot of the wearer.
With a shoe of the seventh document, eyelets formed by loops are provided in the vicinity of stretchable portions. Although it may appear from FIG. 5 of the seventh document that the loops are connected to the stretchable portions, the loops are provided on hard portions of the upper as can be seen from FIGS. 3 to 6 of the publication.
Therefore, the eyelets formed by loops shown in the publication cannot move in the circumference direction.

This patent is subject to a terminal disclaimer.


Methods and Devices for performing a device-to-device, D2D, operation are disclosed. A first reference timing for each of two or more non-terrestrial synchronization sources is obtained. Further a second reference timing of a terrestrial synchronization source is obtained. One of the non-terrestrial synchronization sources is determined based on a comparison between the first reference timings and the second reference timing, and the D2D operation is performed using the first reference timing of the determined non-terrestrial synchronization source.

During Release 12 of the 3rd Generation Partnership Project (3GPP), the Long Term Evolution (LTE) standard has been extended with support of a device-to-device (D2D) operation for a so-called sidelink (SL) targeting both commercial and Public Safety applications. The D2D operation according to 3GPP LTE Release 12 includes device discovery, which enables D2D devices to sense the proximity of another D2D device, and associated application by broadcasting and detecting discovery messages that carry device and application identities. The D2D operation further includes direct communication based on physical channels terminated directly between the D2D devices.
The D2D communication enables D2D devices in the proximity of each other to communicate in a peer-to-peer (i.e., direct) fashion, rather than communicating through a wireless access point or base station of the LTE radio access network. For example, D2D devices in an LTE system utilize the cellular uplink spectrum. That is, the D2D devices transmit D2D signals in the uplink part of the LTE spectrum.
A legacy D2D operation may support a half-duplex mode, i.e. the D2D device can either transmit D2D signals or receive D2D signals. A more advanced D2D operation may uses a further D2D device to relay D2D signals to one or more receiving D2D devices.
Based on the 3GPP contribution document R4-164751, "WF on RRM core requirement for V2V", LG Electronics, the Radio Resource Management (RRM) core requirements for vehicle-to-vehicle (V2V) operation are under study. The V2V operation typically uses a global navigation satellite system (GNSS) for acquiring timing information for the V2V operation on the sidelink.
Conventional D2D devices may be capable of supporting multiple GNSSs, e.g. Global Positioning System (GPS), Galileo, BeiDou, etc. While multiple GNSSs exist and may be supported by the D2D device, conventional D2D devices use a pre-defined GNSS.
However, using the pre-defined GNSS may be not optimal.

Technique for performing device-to-device operation


A mist of liquid coolant is introduced into the path of atomized, molten, solder droplets. The mist and other conditions within the chamber are engineered to enable the liquid coolant droplets in the mist to contract the surfaces of molten solder droplets and be flash vaporized upon contact, thereby rapidly extracting heat from the molten solder droplets and accelerating cooling and solidification to produce an enhanced solder ball as a product of this process.

Surface mounting technology (SMT) is a desirable method of mounting electronic components, such as resisters, capacitors, inductors, transistors, integrated circuits, chip carriers and the like, to circuit boards and other electronics substrates, and is particularly desirable for fabricating small circuit structures. In addition, surface mounting technology lends itself well to process automation and high-density electronic manufacturing, wherein surface-mountable microelectronic devices are bonded to circuit boards and electronic substrates by solder reflowing processes.
For example, a common surface-mountable microelectronic device, referred to as a "flip chip," includes an integrated circuit device with numerous connecting leads attached to pads mounted on its underside. Either a circuit board, to which the flip will be mounted, or the flip chip itself is provided with small bumps or balls of solder (hereinafter referred to as "solder balls" or "solder spheres") that are positioned at locations on the board or the chip that correspond to the chip pads. The flip chip is mounted to the circuit board by (a) placing it in contact with the board such that the solder spheres become sandwiched between the board and the corresponding pads on the chip underside, forming an assembly; (b) heating the assembly to a point at which the solder reflows; and (c) cooling the assembly. Upon cooling, the solder hardens, thereby mounting the flip chip to the surface of the circuit board.
Tolerances in assemblies using flip chip technology are critical, as the spacing between individual microelectronic devices as well as the spacing between the chip and the circuit board is typically very small. For example, the spacing of chips from the surface of the board may be in a range of about 0.5 to about 3.0 mil (about 12.7 to about 76.2 μm), and is expected to approach micron spacing in the near future.
Electrical connections are also achieved with ball grid array (BGA) packages that are made by placing solder spheres of precisely controlled diameter and unblemished surface condition between circuit pads. Solder spheres are then heated above the liquidus temperature of the solder alloy, thereby melting the solder spheres, which wet and flow onto contact pads, creating a mechanical joint and an electrical interconnection between the circuit board and mounted component.
Solder alloys that are commonly used to manufacture solder and solder spheres for reflowing and BGA soldering applications include relatively soft base metals, such as lead, tin, silver, aluminum or copper, that can be easily damaged during manufacture of solder spheres as well as during transport and storage of solder spheres. In particular, during stream-jet fabrication of solder alloy spheres, cooling and solidification of spheres are important to the formation of smooth, unblemished and homogeneous sphere surface finishes. The cooling and solidification phases of solder sphere production are typically conducted in controlled atmospheres, such as an inert atmosphere created by nitrogen gas. However, the ability of nitrogen gas to cool solder spheres rapidly enough to form the desired surface finishes is limited by the heat transfer coefficient of nitrogen and the absolute difference between the temperatures of nitrogen gas and molten solder droplets. This limited heat transfer causes metallurgical phases to segregate on surfaces of cooling solder droplets, forming blemished surface finishes on the solidified solder spheres. In addition, the relatively slow rate of cooling facilitates the growth of large or coarse metal grains that impair surface finishes of solidified spheres.
Damage to surfaces of solder spheres can have a number of consequences. For example, automated vision systems may not be able to distinguish a solder sphere from the background if the surface reflectivity of the solder sphere has been diminished due to surface damage. Physical surface damage will also hinder the ability of most automated BGA assembly hardware to pick and place individual solder spheres. In addition, the presence of extraneous particles or grains on solder sphere surfaces may impair the mechanical function of the BGA assembly hardware. Extraneous particles and grains may also cause low resistivity or electrical shorts between contact pads on the microelectronic devices and circuit boards or other electronic substrates, as well as compromise the electrical performance of BGA joints once formed. Finally, surface damage exacerbates the oxidation of base metals of solder sphere surfaces. Surface oxidation impairs proper wetting and flow of solder spheres onto contact pads, as required with BGA packages to form reliable mechanical joints and electrical interconnections. Existing methods of manufacturing metal spheres and fine metal powders include atomizing and centrifuging techniques, wherein a metal melt is finely divided to form molten metal droplets. Molten metal droplets are often contacted downstream of an atomizing or centrifuging location with a coolant medium to cool and solidify droplet metal into particles and spheres. Typically, the coolant medium is a gas. In some cases, others have introduced a mist in the vicinity of the atomizer to extract heat from the coolant gas.

Rapid surface cooling of solder droplets by flash evaporation


A system for environmentally acceptably disposing of BTEX and/or VOC containing off gases, including entrained vapors and liquids that originate from gas processing equipment including a flare stack communicating at an upper end with the atmosphere, a steam cup supported within the flare stack, a gas inlet extending into the flare stack and into the steam cup and serving to convey off gasses into the flare stack and collect any entrained liquid carried by the off gasses and a burner positioned within the flare stack below the steam cup and connected to receive and burn a combustion gas/air mixture, heat produced by the burner serving to vaporize any entrained liquid collected in the steam cup and to combust any BTEX and/or VOC components of the off gasses and vaporized liquid into inert oxidized states that pass out the flare stack upper end.

This application is not referenced in any microfiche appendix.
Previously issued United States Patents that provide background information concerning the technology to which this invention is directed include the following:
Hodgson, U.S. Pat. No. 4,280,867, discloses a reboiler used to heat wet glycol and water vapor is discharged. The dehydrated glycol then flows through a stripping column where glycol comes into contact with dry flue gas generated by a catalytic burner.
Anwar et al., U.S. Pat. No. 4,182,659, provides a system where wet glycol is initially drawn off into an expansion chamber where part of the hydrocarbon gases separate out, are drawn off and may be re-used as heating gas. The glycol is then heated to remove the majority of the water which is vented to the atmosphere. Finally, then glycol is heated at sub-atmospheric pressure (vacuum) to further purify it.
Holter, U.S. Pat. No. 4,003,722, discloses a system where gas may be purified by cleansing fluid. The cleansing fluid may be admitted from a flow circuit into an evaporator causing the impurities to be evaporated by heating. The impurities liberated in the evaporator are conveyed to a burner or combustion chamber and combusted.
The other previously issued patents provide information as to the state of the art of glycol dehydration of natural gas.
Accordingly, it is a principal object and purpose of the present invention to provide a system for control and disposal on contaminants released by natural gas dehydration processes.
It is further an object and a purpose of the present invention to provide a system for control and disposal of contaminants released in the glycol regeneration process wherein the contaminants are incinerated to reduce them to non-pollutant states.
It is further an object and a purpose of the present invention to provide a system for control and disposal of contaminants released in the glycol regeneration process which will not add undo back pressure to the reboiler.
The present invention relates to a system for use to incinerate contaminants released in the regeneration or reconcentration of glycol, or similar liquid desiccant, employed in the process of dehydration of natural gas.
Natural gas processing usually includes removal of contaminants in order to produce a transportable natural gas product. One of the major contaminants removed from natural gas is water, either in the gaseous state or in condensed form. Other contaminants present in smaller quantities are BTEX and VOCs and other pollutants.
Most large volume dehydration units are of the glycol type. Glycol is a preferred liquid desiccant because it has a relatively high boiling point, is thermally stable and does not oxidize in normal use. The glycol used is normally of one of three kinds: ethylene, diethylene, or triethylene, with triethylene being the most frequently used at the present time. Water, including other pollutants in natural gas, is absorbed by contact with the glycol.
A typical dehydration facility includes an inlet gas scrubber and a separator where liquid accumulations that are easily separated are removed. The natural gas is then directed to a gas contractor where the glycol comes into contact with the gas, a majority of any entrained water and the water vapor being absorbed by the glycol producing what is known as xe2x80x9cwet glycolxe2x80x9d. The dehydrated natural gas leaves the contractor tower where it is directed to be transported for use as fuel or raw material for the chemical industry. The wet glycol is directed from the contractor tower to a reconcentrator or reboiler column.
In the reboiler column the wet saturated glycol is heated to a temperature of between 380xc2x0 to 400xc2x0 Fahrenheit to boil off the water. The reboiler is usually maintained at the lowest possible pressure so that the water solubility of glycol is not increased. The vaporized water, along with the contaminants not removed with the skimming and filtration process, have, in the past, been vented to the atmosphere. Venting the contaminants to the atmosphere is becoming an increasing environmental problem. These odorous vapors emitted from the reboiler create uncomfortable living conditions and health concerns for local residents and workers.
New environmental laws have mandated a great reduction in the amount of pollutants that can be emitted from natural gas dehydrators. These pollutants consist primarily of BTEX and VOCs, and are absorbed from the gas stream by the glycol. Also, some natural gas becomes dissolved in the glycol, and since the function of a dehydrator is to remove water vapor from the gas stream, the glycol will also contain water. The glycol regeneration process utilizes a reboiler to heat the glycol and drive off the water, but the process also liberates the pollutants that are dissolved in the glycol. Current technology to control emissions consists of two methods: 1) The stream from the still column""s outlet is condensed. The waste gas is flared and the liquid is trucked to disposal. Or, 2) The stream from the still column""s outlet is condensed and the waste gas is compressed and injected into a gas sales line, the liquid, once again, being trucked to disposal. Obviously, the problem with both systems is dealing with the disposal of the BTEX and/or VOCs laden water. It is to this problem that the present invention is directed.

Process Equipment and Service Company, Inc.


A computer (10, 11, 12) is provided with a physically-removable resource in the form of a smartcard (20) including user logon information (for local and/or remote resources). Upon at least the removal of the smartcard (20), different behaviours are produced depending on whether a predetermined keyboard key, such as the ALT key, is depressed. Thus, assuming that the smartcard (20) has been used for logging on, then upon removal of the smartcard if the ALT key is not depressed, a logoff procedure is effected whereas if the ALT key is depressed at the time the smartcard (20) is removed, an alternative behavior is effected such as the display of a user option menu. This approach of causing the behavior of the computer to vary upon resource removal in dependence on whether there is a current sustained operation of an input device, can also be applied to other types of removable resources and input devices.

Smartcards have a variety of uses amongst the most important of which is as a secure data-storage unit for storing critical information such as passwords and electronic funds information. Smartcards may also be used to provide specific functionality (such as encryption/decryption) under password control.
It is known to provide computers with smartcard interface units (often called smartcard readers though, in fact, data is frequently both read from, and passed to, the card). Such smartcard interface units have traditionally been provided as separate peripherals, interfacing with the computer through a dedicated port (for example, an RS232 serial port or more recently with the advent of the Universal Serial Bus for low speed peripheral connection, through a USB port). For user convenience, rather than providing the smartcard interface unit as a separate peripheral, it is also known to incorporate a smartcard interface into the keyboard unit of the computer.
In a typical computer-related smartcard application, encryption keys for electronic commerce transactions are stored in the smartcard and these keys must be read and used by the computer to enable a transaction with a remote third party via a computer network. The storage of passwords for accessing network resources is another common application (controlled remote logon) and, indeed, use of the computer itself may require the presense of a smartcard with the right passwords (controlled local logon).
The insertion of a smartcard into an active smartcard interface unit will generally be detected but whether or not the current operation of the associated computer is affected will depend on how the computer has been set up by a system manager or the user his/herself. For example, the computer may be set up by a system manager to respond to insertion of a smartcard by initiating a remote logon procedure using information held on the smartcard; however, this automatic behaviour may not always be appropriate as a user may be inserting the card for another reason entirely. Thus, whilst it is generally useful to have an automatically-triggered default behaviour on smartcard insertion, this automatic execution of the default behaviour needs to be overrideable.
A similar situation is known with respect to CD-ROM drives provided in computers both for reading CD-ROMs holding computer programs and data, and for playing back audio CD's. It is common practice for such CDs to be run automatically upon insertion (the "autorun" feature). However, immediate running may not always be required. To deal with this situation, in Microsoft's Windows 95 operating system, for example, it is possible to override the autorun feature by holding down the SHIFT key during CD insertion. This arrangement simply overrides autorun--it does not give the user any other choice.
Removal of a CD is always interpreted as meaning that the user no longer wishes to use the CD or any dependent program (on the basis that removal was not accidental which may be checked via a user dialogue window).
It is an object of the present invention to provide increased flexibility of control in the use of a smartcard (or, indeed, any other physically removable resource).

Behavior control of apparatus having a physically-removable resource


A liquid crystal display device includes a liquid crystal display panel and a backlight. The backlight includes a light guide plate arranged so as to overlap the liquid crystal display panel, an optical sheet arranged between the liquid crystal display panel and the light guide plate, a frame accommodating the light guide plate therein and facing a circumferential edge portion of the liquid crystal display panel, and an adhesive fixing the circumferential edge portion of the liquid crystal display panel to the frame. The frame includes a recess penetrating an outer side surface and an upper surface facing the circumferential edge portion of the liquid crystal display panel. The adhesive is arranged in the recess.

1. Field of the Invention
The present invention relates to a liquid crystal display device.
2. Description of the Related Art
A backlight of a liquid crystal display device includes a light guide plate for converting a point light source to a surface light source. A plurality of light-emitting components are arranged in a line so as to face an edge surface of the light guide plate (JP 2010-62016 A). Light emitted from the light-emitting component as a point light source is incident on the edge surface of the light guide plate, and emitted by reflection from a surface of the light guide plate to a liquid crystal display panel. The light-emitting components and the light guide plate are accommodated in a frame. Such a backlight is fixed by means of a double-faced tape in an area called a picture-frame that is located around an image display area of the liquid crystal display panel (JP 2007-78912 A).
Since the double-faced tape is formed by punching, there is a limit to a reduction in width and a predetermined width or more is necessary also for performing attaching work. In the market, a liquid crystal display panel whose picture-frame is narrow (a liquid crystal display panel having a narrow picture-frame) is strongly required. However, when the picture-frame of the liquid crystal display panel is narrowed, an area for attaching the double-faced tape is not secured in the liquid crystal display panel, leading to a problem that the backlight and the liquid crystal display panel cannot be fixed to and integrated with each other.


There is provided a substrate inspection apparatus capable of inspecting the electrical characteristics of a packaged semiconductor device in a mounting environment. A prober includes a test box, a probe card and a package inspection card. A packaged device is attached to the package inspection card. A test board of the test box and a card board of the package inspection card reproduce the mounting environment in which a wafer-level system-level test is performed.

A prober is known as a substrate inspection apparatus for inspecting electrical characteristics of semiconductor devices, such as power devices and memories, formed on a semiconductor wafer (hereinafter simply referred to as a "wafer") as a substrate.
The prober includes a probe card having a number of pin-like probes, a stage which freely moves a wafer placed on the stage vertically and horizontally, and an IC tester. Each probe of the probe card is brought into contact with an electrode pad or a solder bump formed on the semiconductor device, and a signal obtained from the semiconductor device is transmitted to the IC tester to inspect the electrical characteristics of the semiconductor device (see, e.g., Patent Document 1).
The IC tester determines the acceptability of the electrical characteristics and functions of the semiconductor device based on the transmitted signal. The IC tester has a circuit configuration different from a circuit configuration in which a packaged semiconductor device (hereinafter referred to as a "packaged device") is mounted, for example, the circuit configuration of a motherboard or a function expansion card. Because of this, the IC tester fails to determine the acceptability of the electrical characteristics in the mounted state. As a result, there is a problem that defects of the semiconductor device which have not been detected by the IC tester are found when the packaged device is mounted on the motherboard or the like. Particularly, in recent years, with the complication and speeding up of semiconductor devices, a test pattern in the IC tester becomes larger in size, and a fine control of the test timing is required. This makes the above-mentioned problem conspicuous.
Therefore, in order to guarantee the quality of a semiconductor device, there has been proposed a technique for installing, in place of the IC tester, an inspection circuit for reproducing a circuit configuration in which a packaged device is mounted on a probe card, for example, a circuit configuration of a motherboard, and using the probe card to measure the electrical characteristics of the semiconductor device without detaching the semiconductor device from a wafer in an environment in which the packaged device is mounted on the mother board (hereinafter referred to as a "mounting environment") is reproduced (see, e.g., Patent Document 2). The semiconductor device inspection performed in such a mounting environment is referred to as a wafer-level system-level test.
Meanwhile, after packaging and shipping semiconductor devices that passed the wafer-level system-level test, the packaged devices may malfunction on the market. In this case, in order to pursue a cause of the malfunction, it is necessary to inspect the electrical characteristics of the packaged devices in a mounting environment where the wafer-level system-level test is performed.
[Prior Art Documents]
Patent Documents
Patent Document 1: Japanese laid-open publication No. Hei 7-297242
Patent Document 2: Japanese laid-open publication No. 2015-84398
The probe card of the prober which performs the wafer-level system-level test is brought into electrical contact with the electrode pad or the solder bump of the semiconductor device by using each probe. However, the packaged device does not include an electrode pad and a solder bump. Therefore, there is a problem that the use of the probe card fails to inspect the electrical characteristics of the packaged device in the mounting environment.


An internal combustion engine that replaces the throw journal of a crankshaft with a set of contours that are dynamic rather than static. The contour is such that three cycles of engine operation are not affected, i.e., exhaust, intake, and compression. The contour deviates only during the power stroke where an increased incidence to the circular is incorporated. This defers from previous attempts by eliminating complex geometries such as epitrochoidal or sinusoidal that by their nature negatively affect the exhaust, intake, and compression strokes of the Otto cycle when compared to the traditional crankshaft. Additionally, the deviation from the circular orbit during the power cycle optimizes to a larger extent the leverage available for peak thermodynamic pressures in the cylinder in the brief optimum time afforded by that pressure.

1. Field of the Invention
The invention is relative to internal combustion engines which are in present use for transportation, manufacturing, electrical power production, agriculture, forestry, lawn maintenance, and compressors in common use for applications including heating and air conditioning, refrigeration, and inflation.
Internal combustion engines currently used are of two basic designs: Otto cycle or Brayton cycle. Piston engines incorporate a sequential division of a 360 or 720 degree circle roughly segmented in four cycles or strokes. Brayton (turbine) engines perform the same cycles but are continuous in those cycles because of a constant pressure design.
The operation of reciprocating internal combustion engines follows this sequence: the intake stroke, comprising roughly one fourth of the rotation, permits the introduction of combustibles, i.e., fuel and air. The compression stroke, covering again roughly one fourth of the rotation, compresses the air, further atomizing the fuel and heating both to the point of ignition in the case of the diesel concept, or to the point readily ignitable by a device for ignition in the gas engine. The power cycle, covering once again roughly one fourth of the total rotation, is the point in time and revolution where mechanical parts are subjected to the thermodynamic force induced by the rapidly expanding gases. The fourth and last stroke, exhaust, is the sequence of the rotation that allows for the escape of burnt fuel vacating the cylinders thereby providing space and time for the intake cycle and subsequent repetition of the other cycles. Finally, in difference to whether the strokes described be of the two or four stroke design, they occur in either a 360 or 720 degree rotation respectively.
The relative efficiency comparison between the two and four stroke is dependant on not only the physical advantages of one compared to the other, but also some subjective concerns that could loosely be tied to efficiency. The four stroke's increased complexity and increased size and weight compared to its power output is detrimental and the requirement of operating on a relatively horizontal plane are somewhat offset by its comparative fuel efficiency, less pollution, and intended use of the engine. Obviously an engine that has a power impulse once every 360 degrees instead of 720 degrees will produce more power. However, due to a number of physical dictums, what would seem to be an apparent potential of doubling the power output is mitigated by several factors. Some of these are: a decrease in the available volume of the cylinder due to intake, exhaust, and transfer ports, an increase of frictional loses due to higher operating temperatures and the loss of some fuel to the exhaust port during the intake cycle. Subjectively, the efficiency of a two stroke is its relative lightness and its ability to operate in positions other than the horizontal.
2. Description of the Related Art
Engines using a crankshaft suffer first and foremost during the power stroke. At the point whereby the burning and rapidly expanding gases deliver their peak pressure the cyclic progression of the piston, articulated rod, and crank journal assembly is such that leverage imparted to the output shaft is relatively small. This is unavoidable due to the extreme rapidity of the detonation (on the order of 3/1000th of a second). By the time leverage increases the design dictates that the piston is pulled down the cylinder thus increasing the volume and subsequently reducing available thermodynamic pressure. Man or animal powered devices using the crankshaft principle are extremely efficient largely due to a constant pressure availability. Attempts to mitigate this dictate have thus far been at the cost of a considerable increase in complexity. Ref. classification 123/197.4 documents U.S. Pat. No. -2001/0017122A1 and U.S. Pat. No. -1,349,660. In the case of the first classification myriad rollers and guide pins are fixed to a rod that has to be forked and offset to accommodate the same and still maintain centering on the piston. These rollers and pins follow the contour of a very difficult to manufacture epitrochoidal drum that likely would encounter severe wear problems, sidereal movement, and flexing. In the second classification an elliptical contour to which a thrust pin is drivingly connected to an output shaft would suffer from severe wear as its function necessitates a 180 degree reversal between cycles. It is in fact, relatively simple, but would suffer from severe vibration resulting in a shorter operational life than the journals of a conventional crank shaft. Additionally, a second piston connected to this elliptical contour would require a cylinder or sleeve to reciprocate and a commensurate increase in complexity and lubrication requirements.


The present invention, for example, forms a test pattern image on the surface of a photosensitive member at predetermined periodicity and detects the density of said test pattern image. If the detected density value of the test pattern image is other than said target value, the charging voltage is preferentially adjusted to maintain a stable toner density. When the adjusted charging voltage attains either an upper limit or a lower limit, the toner density is adjusted.

1. Field of the Invention
The present invention relates to an image density adjustment method for image forming apparatus of the electrophotographic type.
2. Description of the Related Art
In conventional copiers and printers of the electrophotographic type, a test pattern image of constant area is formed on the surface of a photosensitive drum and the density of this test pattern image is optically detected, and the charge voltage of the photosensitive member, developing bias voltage, and amount of optical exposure is changed in accordance with said detected density value so as to maintain an optimum image density. This control is based on changing the optimum image forming conditions to maintain a constant image density by changing the environmental conditions which to compensate for fatigue of the photosensitive member and developer (carrier) over time. Developer is particularly susceptible to fluctuation of environmental conditions and developing capability is markedly reduced under conditions of high temperature and high humidity. Since image density is naturally reduced if developing capability is reduced, the charge voltage or toner density must be increased.
When adjustment of the charge voltage of the photosensitive member and adjustment of the toner density are compared, it can be understood that adjustment of the charging voltage is advantageous inasmuch as it provides excellent responsiveness to image density, but is disadvantageous insofar as optical exposure becomes inadequate due to the decrease in potential of the background area of the photosensitive member in conjunction with the increase in charging voltage. Optical exposure cannot be set too high from the perspectives of additional power consumption of the lamp, temperature elevation, and service life of the lamp and photosensitive member. On the other hand, whereas adjustment of toner density does not produce the aforesaid disadvantage of inadequate optical exposure, it is nevertheless disadvantageous in that responsiveness to image density is delayed because the toner density changes only gradually, and when toner density is increased beyond necessity, toner adheres to non-image regions and causes image noise.

Image density adjustment method for image forming apparatus