A method for manufacturing a silicon carbide semiconductor device includes steps below. A silicon carbide substrate having a first main surface and a second main surface opposite to the first main surface, the first main surface having a maximal diameter greater than 100 mm, is prepared. An impurity region is formed on a side of the first main surface of the silicon carbide substrate. In a plan view, a cover member is arranged on the side of the first main surface so as to cover at least the entire impurity region. The silicon carbide substrate is annealed at a temperature lower than a melting point of the cover member while the cover member is arranged on the side of the first main surface of the silicon carbide substrate.

In order to allow a semiconductor device such as a metal oxide semiconductor field effect transistor (MOSFET) to be high in breakdown voltage and low in loss and to be used in a high-temperature environment, silicon carbide has recently increasingly been adopted as a material forming a semiconductor device. Silicon carbide is a wide band gap semiconductor greater in band gap than silicon which has conventionally widely been used as a material forming a semiconductor device. Therefore, by adopting silicon carbide as a material forming a semiconductor device, a higher breakdown voltage and a lower on-resistance of a semiconductor device can be achieved. A semiconductor device in which silicon carbide has been adopted as a material is also advantageous in that lowering in characteristics during use in a high-temperature environment is less than in a semiconductor device in which silicon has been adopted as a material.
For example, Japanese Utility Model Laying-Open No. 4-34732 (PTD 1) describes an apparatus for annealing a wafer. With the apparatus for manufacturing by annealing of a wafer, a GaAs wafer is annealed, with a ring-shaped cover over the GaAs wafer being provided to cover only an outer circumferential portion of the GaAs wafer having a diameter of 76 mm.
S. J. Pearton and R. Caruso, "Rapid thermal annealing of GaAs in a graphite susceptor-comparison with proximity annealing," J. Appl. Phys. 66 (2), 15 Jul. 1989, page 663-665 (NPD 1) describes a method of rapid thermal annealing, with a GaAs substrate being arranged in a susceptor made of graphite. According to the rapid thermal annealing method, a GaAs substrate is annealed, with a graphite cap being arranged above the GaAs substrate having a diameter of 2 inches (approximately 50 mm).

Method for manufacturing silicon carbide semiconductor device


2-Aminopyridine compounds of Formula I are provided, and various substituents including stereoisomers, tautomers, and pharmaceutically acceptable salts thereof, useful for modulating USP7, and for treating cancer and immune disorders such as inflammation mediated by USP7. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, and treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

Ubiquitin, a small protein that acts as a post-translational mark on other proteins, has a surprising amount of conformational heterogeneity (Lange, O. F. et al. (2008) Science 320, 1471-1475). Protein ubiquitination mediates numerous cellular processes, such as cell cycle control, apoptosis, epigenetics and transcriptional regulation (Clague, M. J. et al (2010) Cell 143:682-685). The C terminus of ubiquitin is covalently attached to a lysine or the N terminus of a substrate protein through the coordinated action of three classes of enzymes: an E1 activator, an E2 conjugator and ubiquitin ligase (ubiquitin E3) (Pickart, C. M. (2001) Annu. Rev. Biochem. 70:503-533). Each of the seven lysines or the N terminus of ubiquitin can also serve as a substrate for further ubiquitination, allowing the polymerization of ubiquitin chains with linkages that convey a wealth of information (Pickart, C. M. et al (2004) Curr. Opin. Chem. Biol. 8:610-616). Motions within the β1-β2 loop of ubiquitin have been implicated in its recognition by partner proteins, though it is currently unknown how the conformational state of apo ubiquitin is 'read' by each partner. The multiple conformations of apo ubiquitin could represent a compromise that allows its single protein surface to bind a wide variety of unrelated partners with moderate affinity (Humphris, E. L. et al (2007) PLoS Comput. Biol. 3, e164 (2007); Friedland, G. D., et al (2009) PLoS Comput. Biol. 5, e1000393).
Deubiquitinases (DUBs) are a class of specialized proteases that regulate ubiquitin-mediated signaling by disassembling ubiquitin chains or removing monoubiquitination from substrates (Heideker, J. and Wertz, I. E. (2015) Biochem. J. 465:1-26; Lill, J. R. and Wertz, I. E. (2014) Trends in Pharm. Sci. 35(4):187-207; Komander, D., et al (2009) Nat. Rev. Mol. Cell Biol. 10:550-563). There are approximately 100 identified human DUBs, the majority of which await extensive investigation. One exception is USP7 (also known as HAUSP), a ubiquitin-specific protease (USP) which has an established role in tumorigenesis via its action on Mdm2, p53, FOXO4 and PTEN (Nicholson, B. et al (2011) Cell Biochem. Biophys. 60:61-68); Hussain, S., et al (2009) Cell Cycle 8:1688-1697). Although the determination of USP7's precise function in certain pathways has been complicated by conflicting reports (Li, M., et al (2004) Mol. Cell 13:879-886); Li, M. et al. (2002) Nature 416:648-653), this enzyme's participation in many cancer related processes has made it an attractive therapeutic target.
Despite its cellular importance, the catalytic core of USP7 is unexpectedly inactive, with a catalytic efficiency (kcat/Km) around 103 M-1 s-1 and an affinity (KD) for ubiquitin of several hundred micromolar (Faesen, A. C. et al. (2011) Mol. Cell 44:147-159); Fernández-Montalván, A. et al. (2007) FEBS J. 274, 4256-4270). The conformationally heterogeneous β1-β2 loop is directly contacted by all DUBs, including USP7. Hence, it is sought to determine whether stabilizing a USP7-binding conformation of ubiquitin's β1-β2 region could yield variants with a high affinity for the target DUB. Given USP7's role in cell division and technical difficulties surrounding USP7 knockdown, a conformationally optimized, ubiquitin-based inhibitor with high affinity and specificity for USP7 could prove a potent tool for understanding USP7's cellular functions. In a related approach, surface engineering of ubiquitin was used to generate potent binders of ubiquitin-signaling enzymes (Ernst et al, Science doi:10.1126/science. 1230161 (3 Jan. 2013); Zhang, Y., et al (2013) Nature Chemical Biology 9(1):51-58).
USP7 or HAUSP (herpesvirus-associated USP) is a ubiquitin specific protease or a deubiquitylating enzyme that cleaves ubiquitin from its substrates (Holowaty M N, et al (2003) J. Biol. Chem. 278 (48):47753-47756). Since ubiquitylation (polyubiquitination) is most commonly associated with the stability and degradation of cellular proteins, HAUSP activity generally stabilizes its substrate proteins. HAUSP is most popularly known as a direct antagonist of Mdm2, the E3 ubiquitin ligase for the tumor suppressor protein, p53 (Li M, et al (2002) Nature 416 (6881): 648-53). Normally, p53 levels are kept low in part due to Mdm2-mediated ubiquitylation and degradation of p53. In response to oncogenic insults, HAUSP can deubiquitinate p53 and protect p53 from Mdm2-mediated degradation, indicating that it may possess a tumor suppressor function for the immediate stabilization of p53 in response to stress. Another important role of HAUSP function involves the oncogenic stabilization of p53. Oncogenes such as Myc and E1A are thought to activate p53 through a p19 alternative reading frame (p19ARF, also called ARF)-dependent pathway, although some evidence suggests ARF is not essential in this process. A possibility is that HAUSP provides an alternative pathway for safeguarding the cell against oncogenic insults.
USP7 is a DUB that controls cell proliferation by altering the stability of Mdm2, p53, PTEN and FOXO4. Despite USP7's importance in tumor-related pathways, relatively little is known about its cellular and biochemical regulation, and there has been some confusion about its precise role in the Mdm2-p53 axis, in part because of a lack of inhibitory tools. The catalytic domain of USP7 is relatively inefficient in vitro, with a nearly undetectable affinity for its ubiquitin substrate and relatively poor catalytic efficiency. The C terminus and the fourth and fifth Ubl domains of USP7 greatly increase its activity via a combination of increased kcat and decreased Km, though the mechanism by which these effects are achieved is currently unknown. Engineering of ubiquitin conformation can greatly increase its interaction with deubiquitinases such as USP7 (Zhang, Y., et al (2013) Nature Chemical Biology 9(1):51-58).
Deregulation of the ubiquitin/proteasome system (UPS) has been implicated in the pathogenesis of many human diseases, including cancer (Vucic, D., et al (2011) Nature Reviews Molecular Cell Biology 12:439-452). Ubiquitin-specific proteases (USP) are cysteine proteases involved in the deubiquitination of protein substrates. Functional connections between USP7 and essential viral proteins and oncogenic pathways, such as the p53/Mdm2 and phosphatidylinositol 3-kinase/protein kinase B networks, strongly suggest that the targeting of USP7 with small-molecule inhibitors may be useful for the treatment of cancers and viral diseases.
Therapeutic agents that target apoptotic regulatory proteins that are part of the ubiquitin-proteasome system, might afford clinical benefits (Vucic, D., et al (2011) Nature Reviews Molecular Cell Biology 12:439-452). Deubiquitinase inhibitors and antagonists have been reported (Lill, J. R. and Wertz, I. E. (2014) Trends in Pharm. Sci. 35(4):187-207, see Table 2, page 195, Ndubaku, C. and Tsui, V. (2015) J. Med. Chem. DOI:10.1021/jm501061a). The rationale for targeting the ubiquitin-proteasome system for the treatment of cancer is validated by FDA approval, and the clinical efficacy, of bortezomib (VELCADE®; Millennium Pharmaceuticals) for the treatment of multiple myeloma and mantle cell lymphoma. Phenotypes associated with USP7 silencing strongly suggest that small molecule inhibitors of USP7 may have the potential for antiviral and anticancer therapies (Li, M. et al. (2002) Nature 416:648-653; Daviet, L. and Colland, F. (2008) Biochimie 90:270-283).

USP7 inhibitor compounds and methods of use


Voice based biometric authentication method, apparatus (system), and computer program product. Provided is voice verification solution with a high accuracy rate that can prevent cheating via recording. The method includes: transmitting to the user a question prompt requiring the user to speak out a voice segment and an answer to a dynamic question, the voice segment having a corresponding text dependent speaker verification model enrolled before the authentication; segmenting, in response to receiving the voice answer, the voice segment part and the dynamic question answer part out from the voice answer; and verifying boundary smoothness between the voice segment and the answer to the dynamic question within the voice answer. With this method, whether a voice answer relates to cheating via recording is determined according to the degree of smoothness at a detected boundary. The apparatus and computer program product carry out the steps of the above-mentioned method.

The present invention relates to user authentication. More specifically, the present invention relates to a voice based biometric authentication method and apparatus.
With the development of technology, users need to conduct a large amount of communication and internet based activities during work and everyday living. These internet based activities generally require user authentication in order to ensure security of the user's activities.
Password, as a traditional authentication approach, has the defect of being easily cracked, lost, and/or forgotten. To improve security in password authentication, UKey can also be used in a desktop or notebook to ensure security. However, this approach is difficult to apply to a hand-held mobile terminal or call center. More importantly, the foregoing approach has low personal relevance and a person who illegally acquires the above information can easily be regarded as the user himself/herself. Currently, there are many scenarios where it is required to confirm that an operation is made by the user himself/herself. Therefore, in order to enhance personal relevance in user authentication, authentication approaches utilizing biometric features such as fingerprint recognition, iris detection, face recognition, and sound recognition have been widely used and developed.
Speaker verification is a mainstream approach among current biometric information authentication approaches and generally includes two types of voiceprint recognition approaches: text dependent and text independent. Furthermore, voiceprint recognition also generally includes two steps: enrollment and verification. In text dependent voiceprint recognition, the same voice segment that is spoken in enrollment must also be spoken in verification. This approach has a high accuracy rate (i.e. above 99%) and the length of the voice segment employed in enrollment only needs to be several seconds. Text dependent voiceprint recognition can be easily applied and, thus, is a widely used voice authentication approach. However, since what is spoken is always the couple of sentences in the enrollment set and the voice is available to public, the voice is prone to be stolen via recording, which is then used to cheat the authentication system by a manner of playing back.
In text independent voiceprint recognition, what is spoken in verification can be different from that in enrollment. This approach can solve the problem of cheating via recording by providing a dynamic question during authentication. However, its accuracy rate is low (i.e. generally is about 70%). Thus, this approach cannot be fully put into practical use, especially in the user authentication field that requires a high accuracy rate (such as in banking, etc). Furthermore, in enrollment the user is required to speak out content that is at least several tens of seconds in length, which is not very convenient. Thus, in practical use, text independent voiceprint verification is hard to be taken as a standalone detection approach and is generally combined with other biometric feature authentication approaches. Thus, the application scope is limited.
In summary, there are still deficiencies in the prior art. What is urgently needed is a voice verification solution with a high accuracy rate that can prevent cheating via recording.

Voice based biometric authentication method and apparatus


A method to quantify the vascular irregularity of aortoiliac arteries is provided. Inner wall and/or outer wall outlines of a vessel of interest are determined. The cross sectional area is determined for the area outlined by each outline. Using this cross sectional area a shape is selected that has substantially the same area as the outline. Subsequently, the shape is fitted to the outline. In one aspect, the irregularity index is calculated as the ratio of the outline and the outline of the fitted shape. In another aspect, the irregularity index is calculated as the ratio of at least a part of the outline and the outline of the fitted shape that corresponds to the same part of the outline. The irregularity index is visualized using a color scheme, a range of numbers, or a set of labels.

Treatment of abdominal aortic aneurysms (AAAs) with minimally invasive endovascular stent-grafts is gaining wide acceptance (See e.g. Zarins et al. (2001) in a paper entitled "The AneuRx stent graft: four-year results and worldwide experience" and published in J Vasc Surg 33:S135-145). However complications related to the breakdown of stent-graft fixation still occur (See e.g. Holzenbein et al. (2001) in a paper entitled "Midterm durability of abdominal aortic aneurysm endograft repair: a word of caution" and published in J Vasc Surg 33:S46-54). The characteristics of the intended proximal and distal landing zones (also referred to as attachment sites) of the stent-graft have a significant impact on its long-term stability (See e.g. Makaroun et al. (2001) in a paper entitled "Is proximal aortic neck dilatation after endovascular aneurysm exclusion a cause for concern?" and published in J Vasc Surg 33:S39-45). After endovascular repair, aneurysm regression leads to a progressive change in aortoiliac morphology that subjects the attachment sites of the stent-graft prosthesis to angular and torsional stress. Expansion of the proximal neck and distal migration of the device can also occur, promoting the loss of the seal between the stent-graft and the vessel wall. A breakdown of fixation can cause re-perfusion and re-pressurization of the aneurysm sac, thereby increasing the likelihood of aneurysm enlargement or rupture (See e.g. Makaroun et al. (2001) in a paper entitled "Is proximal aortic neck dilatation after endovascular aneurysm exclusion a cause for concern?" and published in J Vasc Surg 33:S39-45). Consequently, preoperative assessment of the intended stent-graft attachment sites is routinely performed as a part of the preoperative workup, usually by employing Computed Tomography Angiography (CTA) to quantify the size, length and angulation of the proximal and distal necks of the aneurysm and of the common iliac arteries (See e.g. White et al. (2001) in a paper entitled "Computed tomography assessment of abdominal aortic aneurysm morphology after endograft exclusion" and published in J Vasc Surg 33:S1-10).
However, stent-graft attachment would be compromised by excessive irregularity at the attachment sites, for instance due to an incomplete seal possibly causing an endoleak. The present invention advances the art by providing new methods of quantifying vascular irregularity to aid in the assessment of stent-graft surgery.

The Board of Trustees of the Leland Stanford Junior University


This invention relates to methods for screening compounds for antitubulin activity, evaluation of cells for sensitivity to antitubulin drugs, resistance monitoring and quantifying tubulin using certain amides that inhibit the growth of eukaryotic cells as probes in binding assays, said amides having the structural formula

Microtubules are intracellular filamentous structures present in all eukaryotic cells. As components of different organelles such as mitotic spindles, centrioles, basal bodies, cilia, flagella, axopodia and the cytoskeleton, microtubules are involved in many cellular functions including chromosome movement during mitosis, cell motility, organelle transport, cytokinesis, cell plate formation, maintenance of cell shape and orientation of cell microfibril deposition in developing plant cell walls. The major component of microtubules is tubulin, a protein composed of two subunits called alpha and beta. An important property of tubulin in cells is the ability to undergo polymerization to form microtubules or to depolymerize under appropriate conditions. This process can also occur in vitro using isolated tubulin.
Microtubules play a critical role in cell division as components of the mitotic spindle, an organelle which is involved in distributing chromosomes within the dividing cell precisely between the two daughter nuclei. Various drugs and pesticides prevent cell division by binding to tubulin or to microtubules. Anticancer drugs acting by this mechanism include the alkaloids vincristine and vinblastine, and the taxane-based compounds paclitaxel and docetaxel {see, for example, E. K. Rowinsky and R. C. Donehower, Pharmacology and Therapeutics, 52, 35-84 (1991)}. Other antitubulin compounds active against mammalian cells include benzimidazoles such as nocodazole and natural products such as colchicine, podophyllotoxin and the combretastatins. Benzimidazole compounds which bind to tubulin are also widely used anthelmintics {McKellar, Q. A. and Scott, E. W., J. Vet. Pharmacol. Ther., 13, 223-247 (1990)}. Anti-tubulin herbicides are described in xe2x80x9cThe Biochemical Mode of Action of Pesticidesxe2x80x9d, by J. R. Corbett, K. Wright and A. C. Baillie, pp. 202-223, and include dinitroanilines such as trifluralin, N-phenylcarbamates such as chlorpropham, amiprophos-methyl, and pronamide. Fungicides believed to act by binding to tubulin include zarilamide {Young, D. H. and Reitz, E. M., Proceedings of the 10th International Symposium on Systemic Fungicides and Antifungal Compounds, Reinhardsbrunn, ed by H. Lyr and C. Polter, 381-385, (1993)}, the benzimidazoles benomyl and carbendazim, and the N-phenylcarbamate diethofencarb {Davidse, L. C and Ishi, H. in xe2x80x9cModern Selective Fungicidesxe2x80x9d, ed. by H. Lyr, 305-322 (1995)}.
Due to the success of tubulin as a biochemical target for drugs and pesticides, there is considerable interest in discovering new compounds which bind to tubulin. Various cell-free methods are available for detecting such compounds. A common method involves measuring the ability of test compounds to inhibit the polymerization of isolated tubulin into microtubules in vitro {see for example, E. Hamel, Medicinal Research Reviews, 16, 207-231 (1996)}. In a second method, interactions of test compounds with isolated tubulin can be detected in binding assays by measuring the ability of the test compound to influence binding of a second tubulin-binding ligand, used as a probe. (The term xe2x80x9ctest compoundxe2x80x9d means a compound which one wishes to evaluate, i.e. to test, for its ability to affect tubulin). Typically, the probe is radiolabeled to enable binding to be measured. A test compound which binds to tubulin may influence binding of the probe by binding to the same site on the tubulin protein as the probe, and thus reduce the amount of probe which binds. Alternatively, binding may be influenced by means of an xe2x80x9callostericxe2x80x9d interaction in which the test compound binds to a different site from that of the probe and induces a conformational change in the tubulin protein which affects the binding site of the probe. Such an allosteric interaction may either increase or decrease binding of the probe. A third approach involves measuring the effect of test compounds on tubulin-associated guanosine triphosphatase activity {Duanmu, C., Shahrik, L. K., Ho, H. H. and Hamel, E., Cancer Research, 49, 1344-1348 (1989)}.
To screen large numbers of compounds by any of these methods is feasible at present only using tubulin from mammalian brain tissue, since it has not been possible to isolate sufficiently large amounts of purified tubulin from other sources. This limits the usefulness of these methods since many anti-tubulin compounds show great specificity with respect to their effects on microtubules from different sources. For example, the herbicides oryzalin and amiprophosmethyl inhibit the polymerization of plant tubulin but not brain tubulin, whereas colchicine is more than 100-fold more effective as an inhibitor of brain tubulin polymerization than of plant tubulin polymerization {Morejohn, L. C. and Fosket, D. E., xe2x80x98Tubulin from Plants, Fungi, and Protistsxe2x80x99, in xe2x80x9cCell and Molecular Biology of the Cytoskeletonxe2x80x9d, ed. by J. W. Shay, 257-329 (1986)}.
The present invention relates to the use of certain amide derivatives, known to inhibit the growth of eukaryotic cells, including fungal and plant cells {see, for example, U.S. Pat. Nos. 3,661,991, 4,863,940 and 5,254,584}. Said amides have now been found useful as probes in binding assays to screen compounds for antitubulin activity, a use which U.S. Pat. Nos. 3,661,991, 4,863,940 and 5,254,584 neither disclose nor suggest. While radiolabeled probes such as colchicine {see for example, M. H. Zweig and C. F. Chignell, Biochemical Pharmacology, 22, 2141-2150 (1973)} and vinblastine (see for example, R. Bai et al., Journal of Biological Chemistry, 265, 17141 (1990)} have been used extensively in binding assays using isolated tubulin, these compounds bind noncovalently to tubulin.
One advantage of the amide derivatives of this invention over existing antitubulin compounds in competitive binding assays results from their unique ability to bind covalently in a highly specific manner to tubulin, specifically to the beta-subunit of tubulin. (A covalent bond is a nonionic chemical bond characterized by the sharing of electrons by two atoms). In binding assays it is necessary to measure the amount of the probe which is bound to tubulin, and this generally involves separating the tubulin-bound probe from unbound probe. In the case of the amides, since binding is covalent, the tubulin-bound probe is chemically stable allowing easy separation from the unbound probe by methods such as filtration or centrifugation. This enables their use not only in assays using isolated tubulin but also in assays using whole cells, crude cell extracts, and partially purified tubulin preparations, thus obviating the need for isolated tubulin and enabling tubulin-binding assays to be carried out in many different types of cell or cell extract.
One aspect of the present invention involves use of amide probes in binding assays to screen large numbers of compounds in order to identify those compounds with antitubulin activity using whole cells, cell extracts or isolated tubulin. For example, test compounds which bind to plant or fungal tubulin may be detected in assays using plant or fungal cells, thus providing a means of detecting antitubulin compounds with herbicidal or fungicidal activity. Similarly, amide probes may be used to detect compounds which bind to tubulin in mammalian cells or cell extracts, thus providing a means of detecting antitubulin compounds with anticancer activity.
A second aspect of the current invention involves use of amide probes in binding assays to evaluate the sensitivity of a cell population to an antitubulin compound. For example, the current invention can be used to evaluate the sensitivity of a tumor cell population to an antitubulin drug such as paclitaxel, vincristine or vinblastine, thus providing a means of predicting drug sensitivity of a patient""s tumor at the time of diagnosis or relapse using cells isolated by biopsy, and consequently guiding selection of the optimal chemotherapy regimen. Frequently, treatment of neoplasms with a particular antitubulin drug results in resistance development due to a reduced accumulation of drug in the cell. The current invention also provides a method for determining sensitivity of such resistant cells to antitubulin drugs. Various types of in vitro drug sensitivity tests have been used to select drugs more likely to be effective against tumor cells of a particular patient prior to their in vivo application {Cortazar, P. et al., Clinical Cancer Research, 3, 741-747 (1997), Arps, H. et al., Int. J. Immunotherapy, III, 229-235 (1987)}. Such assays typically involve cell culture of the isolated tumor cells or xenotransplantation using transplant-bearing mice, and require several days to multiple weeks to obtain results. In the current invention, the sensitivity of isolated tumor cells to antitubulin drugs can be determined by measuring the ability of said antitubulin drugs to influence binding of an amide probe to the cells, cell extracts or isolated tubulin. Since this method does not require culture of the isolated cells, it can provide sensitivity data within a few hours allowing drug sensitivity to be determined more rapidly.
A third aspect of the present invention involves another approach to the use of amide probes in binding assays to evaluate sensitivity of eukaryotic cells to pesticides or drugs which act by binding to tubulin. Specifically, this approach is useful in resistance monitoring for antitubulin pesticides or drugs to detect cells which show altered sensitivity to said antitubulin pesticides or drugs due to modifications in tubulin. Resistance to antitubulin compounds due to modifications in tubulin have occurred in fungal pathogens {Davidse, L. C. and Ishi, H. in xe2x80x9cModern Selective Fungicidesxe2x80x9d, ed. by H. Lyr, 305-322 (1995)}, algae {James, S. W. et al., Journal of Cell Science, 106, 209-218 (1993)} and helminths {Beech, R. N. et al., Genetics, 138, 103-110 (1994)}. Resistant cells containing modified tubulin may show a difference in binding affinity for amides, allowing amide probes to be used in binding assays to detect such mutants. Such an assay can be carried out by comparing the rate of binding of an amide probe to cells or extracts of cells previously exposed to the antitubulin pesticide or drug with the rate of binding to untreated control cells or cell extracts.
For example, benzimidazole and thiophanate fungicides such as benomyl (methyl 1-(butylcarbamoyl)benzimidazol-2-ylcarbamate), fuberidazole (2-(2xe2x80x2-furyl)benzimidazole), thiabendazole (2-(4-thiazolyl)benzimidazole), carbendazim (methyl benzimidazol-2-ylcarbamate), thiophanate-methyl (1,2-bis(3-methoxycarbonyl-2-thioureido)benzene, and thiophanate (1,2-bis(3-ethoxycarbonyl-2-thioureido)benzene are known in the art for use against plant pathogenic fungi. However, the use of benzimidazole and thiophanate fungicides over a period of time can result in the development of fungal strains having reduced sensitivity to these fungicides, whereby the fungicides are much less effective in controlling a particular fungal disease. Such xe2x80x9cresistantxe2x80x9d fungi when isolated as pure cultures typically are from 10-fold to  greater than 1,000-fold less sensitive to benzimidazoles and thiophanates than fungi from locations which have not been exposed to these fungicides. Moreover, fungi which develop reduced sensitivity to one benzimidazole or thiophanate fungicide frequently also show reduced sensitivity to other benzimidazole or thiophanate fungicides. The N-phenylcarbamate fungicide diethofencarb is used commercially to control benzimidazole-resistant fungi such as Botrytis cinerea. However, its use has led to the development of fungal strains resistant to both benzimidazoles and diethofencarb. Current methods to detect fungal strains resistant to benzimidazoles, thiophanates or diethofencarb are labor-intensive and time-consuming. Some methods involve isolation of pure test cultures followed by in vitro assays of mycelial growth using fungicide-amended agar plates, or in vivo assays involving fungicide-treated leaves. Alternatively, slide germination tests of spores may be carried out in the presence of fungicide. Fungal strains which are resistant to diethofencarb and/or benzimidazoles and thiophanates typically contain modified tubulin proteins {see for example, Koenraadt, H. et al., Phytopathology, 82, 1348-1354 (1992) and Yarden, O. and Katan, T., Phytopathology, 83, 1478-1483 (1993)}. Benzimidazole-resistant, diethofencarb-sensitive fungal strains typically show enhanced sensitivity to amide derivatives of the present invention, whereas benzimidazole-resistant, diethofencarb-resistant fungal strains typically show reduced sensitivity. While not wishing to be bound by theory, it is believed that amide probes can be used in binding assays to differentiate benzimidazole-resistant, diethofencarb-sensitive fungal strains which show enhanced ability to bind amide probes in assays using whole cells or cell extracts, or benzimidazole-resistant, diethofencarb-resistant fungal strains which show reduced ability to bind amide probes, from strains which are not resistant. Such assays may be less labor-intensive and time-consuming, and may also provide information as to whether the resistance mechanism involves a change in tubulin. Information about the mechanism of resistance may be useful in designing a resistance management strategy.
A fourth aspect of the present invention involves the use of amide probes in binding assays to detect and quantitate tubulin in cells or cell extracts. Tubulin is the subject of intense research due to its success as a target for drugs and pesticides and its important cellular functions. In such studies it is often desirable to detect and quantitate tubulin in cells or cell extracts. At present this is accomplished by various immunoassays {D. Thrower et al., Methods in Cell Biology, vol. 37, pp. 129-145 (1993)}, sodium dodecyl sulfate polyacrylamide gel electrophoresis {B. M. Spiegelman et al., Cell, vol. 12, pp. 587-600 (1977)}, binding to DEAE-cellulose {J. C. Bulinski et al., Analytical Biochemistry, vol. 104, 432-439 (1980)}, or by measuring colchicine-binding activity {Wilson, L., Biochemistry, vol. 9, pp. 4999-5007 (1970)}. Amide probes offer an alternative method to detect and quantitate tubulin based on measurement of amide-binding activity. Use of amide probes obviates the need for antibodies against tubulin, provides a simpler and more rapid method than either sodium dodecyl sulfate polyacrylamide gel electrophoresis or binding to DEAE-cellulose, and is applicable to measurement of tubulin levels in a variety of cells such as plant or fungal cells which are not sensitive to colchicine.
Various methods known to those with skill in the art can be used to detect the binding of amide probes to tubulin in assays using whole cells, crude cell extracts, partially purified tubulin preparations or isolated tubulin. This may, for example, involve the use of radiolabeled or fluorescent amide probes. Typically, the probe is incubated with cells, cell extracts or tubulin preparations and the amount of bound probe is determined following its separation from unbound probe by various separation techniques or a combination of such techniques. Separation techniques include, but are not limited to, centrifugation, chromatography, phase separation, precipitation of either the bound or unbound probe, or adhesion of either the bound or unbound probe to a solid substrate. Scintillation proximity assay technology (U.S. Pat. No. 4,568,649) provides another potential method to measure binding of the probe to tubulin. Yet another method involves detection of amide-bound tubulin, or amide-bound peptides released from tubulin by chemical or enzymatic treatment, by mass spectroscopy techniques.
One embodiment of this invention is a method for carrying out binding assays, which are useful for screening test compounds for antitubulin activity, comprising (i) incubating eukaryotic cells, cell extracts or isolated tubulin with the said test compound, (ii) adding an amide probe to the eukaryotic cells, cell extracts or isolated tubulin either simultaneously with the addition of the said test compound or subsequent to the addition of the said test compound and measuring the rate of binding of the said amide probe to tubulin in the eukaryotic cell, cell extract or isolated tubulin sample, and (iii) determining the antitubulin activity of the said test compound as indicated by a reduction or enhancement of the rate of binding of the said amide probe to tubulin in the sample containing the said test compound relative to the rate of binding of the said amide probe to tubulin in a control sample lacking the said test compound; said method using the said amide that binds covalently to tubulin and that inhibits the growth of eukaryotic cells, said amide having the structural formula
wherein
A is phenyl, pyridyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrrolyl, isothiazolyl, thiazolyl, pyrazolyl, imidazolyl, (C3-C7)cycloalkyl, pyrimidinyl, quinolyl, isoquinolyl, naphthyl, pyridazinyl, pyrazinyl, benzothienyl, indolyl, benzofuranyl or benzyl; or phenyl, pyridyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrrolyl, isothiazolyl, thiazolyl, pyrazolyl, imidazolyl, (C3-C7)cycloalkyl, pyrimidinyl, quinolyl, isoquinolyl, naphthyl, pyridazinyl, pyrazinyl, benzothienyl, indolyl, benzofuranyl or benzyl substituted with up to three substituents each independently selected from halo, cyano, (C1-C4)alkyl, halo(C1-C4)alkyl, (C2-C4)alkenyl, halo (C2-C4) alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C1-C4)alkylthio, halo(C1-C4)alkylthio, nitro, xe2x80x94NR6R7, xe2x80x94CR8xe2x95x90NOR9, xe2x80x94NHCOOR10, xe2x80x94CONR11R12, and xe2x80x94COOR13; or when A is an unsaturated ring and is substituted with two or more substituents which are adjacent to one another, two of said substituents may form a fused 5, 6 or 7 membered ring containing up to two heteroatoms selected from oxygen, nitrogen, sulfur and phosphorous;
R1 and R2 are each independently a hydrogen atom, (C1-C4)alkyl, halo(C1-C4)alkyl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl or halo(C2-C4)alkynyl, provided that both R1 and R2 are not a hydrogen atom;
R6 and R7 are each independently a hydrogen atom, (C1-C4)alkyl or (C1-C4)alkylcarbonyl;
R8 is a hydrogen atom, (C1-C4)alkyl, (C2-C4)alkenyl or (C2-C4)alkynyl;
R9 is a hydrogen atom, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl or (C1-C4)alkylcarbonyl;
R10, R11, R12 and R13 are each independently a hydrogen atom, (C1-C4)alkyl, (C2-C4)alkenyl or (C2-C4)alkynyl; and
X, Y and Z are each independently a hydrogen atom, halo, cyano, thiocyano or isothiocyano, provided that at least one of X, Y and Z is not a hydrogen atom; or
the optical enantiomers thereof.
A second embodiment of this invention is a method for evaluating the sensitivity of a test cell population to an antitubulin compound comprising (i) incubating cells, cell extracts or isolated tubulin of the said test cell population with the said antitubulin compound, (ii) adding an amide probe to the cells, cell extracts or isolated tubulin of the said test cell population either simultaneously with the addition of the said antitubulin compound or subsequent to the addition of the said antitubulin compound and measuring the rate of binding of the said amide probe to tubulin in the cells, cell extracts or isolated tubulin of the said test cell population, and (iii) determining the sensitivity of the said test cell population to the said antitubulin compound by comparing the ability of the said antitubulin compound to affect binding of the said amide probe in the cells, cell extracts or isolated tubulin of the said test cell population with its ability to affect binding of the said amide probe in cells, cell extracts or isolated tubulin from cell populations of known sensitivity to the said antitubulin compound, said method using the said amide that binds covalently to tubulin and that inhibits the growth of eukaryotic cells, said amide having the structural formula
wherein
A is phenyl, pyridyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrrolyl, isothiazolyl, thiazolyl, pyrazolyl, imidazolyl, (C3-C7)cycloalkyl, pyrimidinyl, quinolyl, isoquinolyl, naphthyl, pyridazinyl, pyrazinyl, benzothienyl, indolyl, benzofuranyl or benzyl; or phenyl, pyridyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrrolyl, isothiazolyl, thiazolyl, pyrazolyl, imidazolyl, (C3-C7)cycloalkyl, pyrimidinyl, quinolyl, isoquinolyl, naphthyl, pyridazinyl, pyrazinyl, benzothienyl, indolyl, benzofuranyl or benzyl substituted with up to three substituents each independently selected from halo, cyano, (C1-C4)alkyl, halo(C1-C4)alkyl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C1-C4)alkylthio, halo(C1-C4)alkylthio, nitro, xe2x80x94NR6R7, xe2x80x94CR8xe2x95x90NOR9, xe2x80x94NHCOOR10, xe2x80x94CONR11R12, and xe2x80x94COOR13; or when A is an unsaturated ring and is substituted with two or more substituents which are adjacent to one another, two of said substituents may form a fused 5, 6 or 7 membered ring containing up to two heteroatoms selected from oxygen, nitrogen, sulfur and phosphorous;
R1 and R2 are each independently a hydrogen atom, (C1-C4)alkyl, halo(C1-C4)alkyl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl or halo(C2-C4)alkynyl, provided that both R1 and R2 are not a hydrogen atom;
R6 and R7 are each independently a hydrogen atom, (C1-C4)alkyl or (C1-C4)alkylcarbonyl;
R8 is a hydrogen atom, (C1-C4)alkyl, (C2-C4)alkenyl or (C2-C4)alkynyl;
R9 is a hydrogen atom, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl or (C1-C4)alkylcarbonyl;
R10, R11, R12 and R13 are each independently a hydrogen atom, (C1-C4)alkyl, (C2-C4)alkenyl or (C2-C4)alkynyl; and
X, Y and Z are each independently a hydrogen atom, halo, cyano, thiocyano or isothiocyano, provided that at least one of X, Y and Z is not a hydrogen atom; or
the optical enantiomers thereof.
A third embodiment of this invention is a method for carrying out binding assays, which are useful for resistance monitoring for antitubulin drugs or pesticides to detect cells which show altered sensitivity to said antitubulin pesticides or drugs due to modifications in tubulin, comprising (i) measuring the rate of binding of an amide probe to tubulin in a test sample of eukaryotic cells, cell extracts or isolated tubulin from a cell population of unknown sensitivity to the antitubulin drug or pesticide and (ii) determining resistance as indicated by a reduction or enhancement of the rate of binding of the said amide probe to tubulin in the said test sample relative to the rate of binding of the said amide probe to tubulin in a corresponding control sample of known sensitivity to the said antitubulin drug or pesticide; said method using the said amide that binds covalently to tubulin and that inhibits the growth of eukaryotic cells, said amide having the structural formula
wherein
A is phenyl, pyridyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrrolyl, isothiazolyl, thiazolyl, pyrazolyl, imidazolyl, (C3-C7)cycloalkyl, pyrimidinyl, quinolyl, isoquinolyl, naphthyl, pyridazinyl, pyrazinyl, benzothienyl, indolyl, benzofuranyl or benzyl; or phenyl, pyridyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrrolyl, isothiazolyl, thiazolyl, pyrazolyl, imidazolyl, (C3-C7)cycloalkyl, pyrimidinyl, quinolyl, isoquinolyl, naphthyl, pyridazinyl, pyrazinyl, benzothienyl, indolyl, benzofuranyl or benzyl substituted with up to three substituents each independently selected from halo, cyano, (C1-C4)alkyl, halo(C1-C4)alkyl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C1-C4)alkylthio, halo(C1-C4)alkylthio, nitro, xe2x80x94NR6R7, xe2x80x94CR8xe2x95x90NOR9, xe2x80x94NHCOOR10, xe2x80x94CONR11R12, and xe2x80x94COOR13; or when A is an unsaturated ring and is substituted with two or more substituents which are adjacent to one another, two of said substituents may form a fused 5, 6 or 7 membered ring containing up to two heteroatoms selected from oxygen, nitrogen, sulfur and phosphorous;
R1 and R2 are each independently a hydrogen atom, (C1-C4)alkyl, halo(C1-C4)alkyl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl or halo(C2-C4)alkynyl, provided that both R1 and R2 are not a hydrogen atom;
R6 and R7 are each independently a hydrogen atom, (C1-C4)alkyl or (C1-C4)alkylcarbonyl;
R8 is a hydrogen atom, (C1-C4)alkyl, (C2-C4)alkenyl or (C2-C4)alkynyl;
R9 is a hydrogen atom, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl or (C1-C4)alkylcarbonyl;
R10, R11, R12 and R13 are each independently a hydrogen atom, (C1-C4)alkyl, (C2-C4)alkenyl or (C2-C4)alkynyl; and
X, Y and Z are each independently a hydrogen atom, halo, cyano, thiocyano or isothiocyano, provided that at least one of X, Y and Z is not a hydrogen atom; or
the optical enantiomers thereof.
A fourth embodiment of this invention is a method for carrying out binding assays, which are useful for determination of tubulin content in eukaryotic cells, cell extracts or isolated tubulin, comprising (i) incubating the cells, cell extracts or isolated tubulin preparations of unknown tubulin content with an amide probe and (ii) comparing the rate of binding or maximum extent of binding of the said amide probe to tubulin in the sample of said unknown tubulin content with the rate of binding or maximum extent of binding of the said amide probe to tubulin in a sample of known tubulin content; said method using the said amide that binds covalently to tubulin and that inhibits the growth of eukaryotic cells, said amide having the structural formula
wherein
A is phenyl, pyridyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrrolyl, isothiazolyl, thiazolyl, pyrazolyl, imidazolyl, (C3-C7)cycloalkyl, pyrimidinyl, quinolyl, isoquinolyl, naphthyl, pyridazinyl, pyrazinyl, benzothienyl, indolyl, benzofuranyl or benzyl; or phenyl, pyridyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrrolyl, isothiazolyl, thiazolyl, pyrazolyl, imidazolyl, (C3-C7)cycloalkyl, pyrimidinyl, quinolyl, isoquinolyl, naphthyl, pyridazinyl, pyrazinyl, benzothienyl, indolyl, benzofuranyl or benzyl substituted with up to three substituents each independently selected from halo, cyano, (C1-C4)alkyl, halo(C1-C4)alkyl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C1-C4)alkylthio, halo(C1-C4)alkylthio, nitro, xe2x80x94NR6R7, xe2x80x94CR8xe2x95x90NOR9, xe2x80x94NHCOOR10, xe2x80x94CONR12, and xe2x80x94COOR13; or when A is an unsaturated ring and is substituted with two or more substituents which are adjacent to one another, two of said substituents may form a fused 5, 6 or 7 membered ring containing up to two heteroatoms selected from oxygen, nitrogen, sulfur and phosphorous;
R1 and R2 are each independently a hydrogen atom, (C1-C4)alkyl, halo(C1-C4)alkyl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl or halo(C2-C4)alkynyl, provided that both R1 and R2 are not a hydrogen atom;
R6 and R7 are each independently a hydrogen atom, (C1-C4)alkyl or (C1-C4)alkylcarbonyl;
R8 is a hydrogen atom, (C1-C4)alkyl, (C2-C4)alkenyl or (C2-C4)alkynyl;
R9 is a hydrogen atom, (C1-C4)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl or (C1-C4)alkylcarbonyl;
R10, R11, R12 and R13 are each independently a hydrogen atom, (C1-C4)alkyl, (C2-C4)alkenyl or (C2-C4)alkynyl; and
X, Y and Z are each independently a hydrogen atom, halo, cyano, thiocyano or isothiocyano, provided that at least one of X, Y and Z is not a hydrogen atom; or
the optical enantiomers thereof.

Use of certain amides as probes for detection of antitubulin activity and resistance monitoring

Abstract: wherein

Abstract: A is cycloalkyl, alkyl, haloalkyl, alkylthio, haloalkylthio, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, haloalkoxy, or phenyl, pyridyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrrolyl, isothiazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrimidinyl, quinolyl, isoquinolyl, naphthyl, pyridazinyl, pyrazinyl, benzothienyl, indolyl, benzofuranyl or benzyl, all optionally substituted in an acceptable manner with up to 4 substituents;

Abstract: R1 and R2 are each independently a hydrogen atom, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl or haloalkynyl, provided that both R1 and R2 are not a hydrogen atom; and

Abstract: X, Y and Z are each independently a hydrogen atom, halo, cyano, thiocyano, isothiocyano or alkylsulfonyloxy, provided that at least one of X, Y and Z is not a hydrogen atom; or

Abstract: the optical enantiomers thereof.


Provided herein are crystalline forms of a triazolopyrimidine compound, which is useful for treating a PRC2-mediated disease or disorder.

Polycomb group (PcG) proteins are chromatin modifying enzymes that are dysregulated in many human cancers. The Polycomb Repressive Complex 2 (PRC2), which includes SUZ12 (suppressor of zeste 12), EED (embryonic ectoderm development) and the catalytic subunit, EZH2 (enhancer of zeste homolog 2), represses genes by methylating the core histone H3 lysine 27 (H3K27me3) at and around the promoter regions of target genes. PRC2 is the critical component of cellular machinery involved in the epigenetic regulation of gene transcription and plays critical function in development and tissue differentiation and regeneration. Although EZH2 is the catalytic subunit, PRC2 requires at least EED and SUZ12 for its methyltransferase activity. EED, SUZ12 and EZH2 are overexpressed in many cancers, including but not limited to breast cancer, prostate cancer, hepatocellular carcinoma and etc. EZH2 activating mutations have been identified in DLBCL (diffused large B cell lymphoma) patients and FL (follicular lymphoma) patients. Inhibition of PRC2 methyltransferase activity by compounds competing with the cofactor S-adenosyl methionine (SAM) in DLBCL reverses H3K27 methylation, re-activates expression of target genes and inhibits tumor growth/proliferation. Therefore, PRC2 provides a pharmacological target for DLBCL and other cancers.
In preparing a pharmaceutical composition, a form of the therapeutic agent is sought that has a balance of desired properties, such as, for example, dissolution rate, solubility, bioavailability, and/or storage stability. The existence of multiple solid forms, often referred to as polymorphs, is well known for solid pharmaceutical compounds, and the chemical and physical stability as well as handling properties of such compounds often depend on which solid form is used. Accordingly, the selection of a particular solid form of the active drug substance (e.g., a salt form, hydrated or solvated form, or polymorphic form) is often very important in the design of a reliable and reproducible production process, and in storage, handling and distribution of a safe and effective form of the drug substance.
"Impurities: Guideline for Residual Solvents", is a guidleline on amounts of residual solvents tolerated in pharmaceuticals, which was produced by the the International Council for Harmonisation of of Technical Requirements for Pharmaceuticals for Human Use (ICH). This Guideline recommends the use of less toxic solvents in the manufacture of drug substances and dosage forms, and sets pharmaceutical limits for residual solvents (organic volatile impurities) in drug products. This guidance divides solvents into three risk-based classes: Class 1 solvents, which are known to cause unacceptable toxicities; Class 2 solvents, which are associated with less severe toxicity; and Class 3 solvents, which have low toxic potential.
According to the ICH Guidance, residual amounts of Class 3 solvents of 50 mg per day or less (corresponding to 5000 ppm or 0.5%) would be acceptable without justification. The concentration limits are calculated using the equation below by assuming a product mass of 10 g administered daily:Concentration (ppm)=(1000×PDE)/dosePDE (permitted daily exposure) is given in terms of mg/day and dose is given in g/day. Higher amounts of Class 3 solvents may also be acceptable provided they are realistic in relation to manufacturing capability and good manufacturing practice.
Patent application number U.S. Ser. No. 14/977,273, which is herein incorporated by reference, discloses certain triazolopyrimidine compounds for treating PRC2-mediated diseases or disorders. This patent application was published on 23 Jun. 2016 as US 2016-0176882. One compound disclosed in that application is N-((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)-8-(2-methylpyridin-3-yl)-[1,2,4]triazolo[4,3-c]pyrimidin-5-amine (free form) and its hydrochloride salt. The free form (referred to herein as Compound A) has the following structure:

The hydrochloride salt (referred to herein as Compound X) has the following structure:

The free form, Compound A, displays low aqueous solubilities both at physiologically relevant pH level of 7.4 and in simulated gastric fluid (SGF). It was found that exposures of Compound A were under-proportional at higher doses in rodent pharmacokinetic studies, which may lead to insufficient and variable exposures in clinical settings. Experiments were carried out to find an appropriate salt to improve aqueous solubility. It was discovered that only the hydrochloric salt provides the necessary improvement in solubility, and demonstrates the dose-proportional exposure in rodent after testing a number of salts that also included phosphate, furmarate, tartarate, succinate, maleate and mesylate.
The procedure described in U.S. Ser. No. 14/977,273 to produce Compound X uses isopropanol (IPA, a Class 3 solvent) as the medium. Variable amounts of IPA were observed in different batches of Compound X obtained by the procedure described in U.S. Ser. No. 14/977,273 as determined by 1H NMR (exemplified by entry 1 in table 2 below), with the amount of IPA in some batches being more than 0.5% by weight. It has also been very difficult to remove the residual IPA from the final product. Additionally, Compound X thus obtained showed low and variable crystallinities, as judged from the XRPD spectra. Efforts were made to remove the residual IPA and improve crystallinality without much success. Therefore, the need exists for methods that can consistently produce Compound X in the desired form, i.e., a form that is substantially free of residual organic solvent and which shows improved and reliable crystallinity.

Crystalline forms of a triazolopyrimidine compound


A ferroelectric memory device that has a first bit line and a first plate line includes a first ferroelectric capacitor group having a plurality of ferroelectric capacitors coupled in series and in a ring shape. A switching means switches whether a ferroelectric capacitor out of the first ferroelectric capacitor group is electrically coupled to the first bit line and the first plate line.

1. Field of the Invention
The present invention relates to a ferroelectric memory device and an electronic apparatus.
2. Related Art
A conventional ferroelectric memory is disclosed in Japanese Unexamined Patent Publication No. H4-42498 (Japanese Unexamined Patent Publication No. H4-42498).
However, in the conventional ferroelectric memory disclosed in Publication No. H4-42498, a predetermined voltage is applied to a ferroelectric capacitor in a non-selected memory cell which is coupled to the same plate line as that of a selected memory cell. There are cases when the predetermined voltage becomes as large as a fifth of the driving voltage depending on the junction capacitance of a cell transistor in the memory cell. Therefore, in the conventional ferroelectric memory, there is a problem that the polarized information recorded on the ferroelectric capacitor of the non-selected memory cell degrades gradually and may eventually be destroyed.
Therefore, the present invention is intended to provide a ferroelectric memory device and an electronic apparatus, which can solve the above described problem.

Ferroelectric memory device and electronic apparatus


The present invention relates to antimicrobial formulations. More particularly, the invention relates to monovalent copper-containing and/or monovalent copper-generating products for healing wounds and burns, and particularly for chronic wounds, prevention of wound infections and infections in various implants as well as medical/surgical devices.

Copper (Cu) is an essential trace element for most living organisms. However, in high concentration it can exert biocidal effect in various mechanisms, most of them are yet not fully understood (Grass Get al., Appl. Environ. Microbiol., 2011; 77(5):1541-1547). First mentioned in an Egyptian papyrus dated back to 2600-2200 BC, the antimicrobial properties of copper have been well recognized and documented throughout history (Dollwet H. et al., Trace Elements Med. 1985; 2(2):80-87).
Over recent decades, copper has regained scientific interest due to its possible applications in the healthcare setting. One of the most common and established medical applications of copper is the addition of ionized copper-silver in hospital water systems as an effective method to control Hospital-acquired Legionella infection (Stout J. E. et al., Infect. Control Hosp. Epidemiol., 2003; 24(8):563-568). Various studies have demonstrated the effective impact of copper biocidal surfaces in reducing the spread of various bacteria, yeasts and viruses, a conclusion that was later on supported in clinical trials.
The mechanisms behind copper toxicity are still a subject of ongoing research, but a number of contributing factors have already been established. A major factor is the ability to act as a catalyst for oxidative damage to tissues through cyclic redox reactions, alternating between Cu(I) and Cu(II). The reactive oxygen species generated in these reactions directly damage essential cell components like nucleic acids, proteins, and lipids. Intracellular free copper ions also contribute to cell death through protein inactivation. The significance of the effect of copper on DNA degradation is still controversial, with different mechanisms of toxicity observed in different types of microorganisms. In several studies that involved enterococci DNA degradation as a result of copper ionic species and the generation of superoxides was a key factor in cell death process (Warnes S L et al., Appl. Environ. Microbiol., 2010 August; 76(16): 5390-401; Warnes S L et al., Appl. Environ. Microbiol., 2011 September; 77 (17): 6049-6059). In contrast, other studies that explored copper toxic effects on Gram-negative bacteria such as Escherichia coli and yeasts suggested that depolarization of the cytoplasmic membrane is the main target, while DNA degradation occurs only after cell death (Macomber L. et al., J. Bacteriol. 2007, March; 189(5):1616-26; Quaranta D. et al., Appl. Environ. Microbiol., 2011, January; 77(2):416-26).
The two most common ions formed by copper are the +1 (cuprous) and +2 (cupric) ions. The cuprous ion is the chemically more active and less stable of the two oxidation states, and is easily oxidized in an aqueous environment. However, it is possible to maintain high concentration of cuprous ions in aqueous environment by adding reagents which form a very stable complex with the cuprous ion, such as acetonitrile (CH3CN) (Parker A. J. et al., Journal of Solution Chemistry, November 1981, Volume 10, Issue 11, pp 757-774) or benzoic acid (C6H5COOH) (Saphier M. et al., J. Chem. Soc., Dalton Ttans., 1845-1849, 1999). Keeping the environment anaerobic also helps in stabilizing the cuprous form.
Currently, Ag (I) (Silver) ions are used to treat wound infection in burn victims as well as in chronic wounds. The present invention demonstrates that the use of Cu (I) ions, rather than Ag (I) ions or Cu (II) and metallic copper, is more efficient in eliminating Bacteria (such as Escherichia coli, Staphylococcus aureus) and yeast (such as Saccharomyces cerevisiae).

Topical antimicrobial formulations containing monovalent copper ions and systems for generating monovalent copper ions


A remote control for programming a hearing instrument includes a housing and a mechanism associated with the housing for mechanically generating an acoustical pulse for effecting control of a hearing instrument. The remote control is passive. A hearing instrument system includes a hearing instrument having a microphone and programming, and the remote control. The programming is configured to interpret the acoustical pulse generated by the mechanism to effect control of the hearing instrument.

Hearing instruments are currently programmable and include instrumentation or programming for volume control and program or mode selection, such as directional/non-directional usage, musical usage, quiet listening usage, etc. Other options may also be programmed into a hearing instrument, as known by those of skill in the art. An audiologist typically initially programs the hearing instrument based upon user preferences. User's also may program the devices themselves. For example, users may desire to increase or decrease the volume of the hearing instrument, or to select different modes based upon their field of usage.
Because of the small size of hearing instruments, user activated controls are difficult to provide. Where controls are provided, they are often difficult to use because of the small size of the hearing instrument, especially for users having limited dexterity. Many companies are researching the use of radio-frequency wireless remote controls. These devices, however, require significant changes to the design of the hearing instrument, including the addition of antennae and RF circuitry. In addition, the remote control device used for programming requires a radio-frequency transmitter that can consume significant electrical power and suffer from short battery life. One company utilizes a wrist watch remote control that transmits RF signals to a hearing instrument.

Wireless remote control for a hearing instrument


A circuit may include one or more transistors connected directly to an output, and a biasing network connected to at least one of a substrate, a well, and a back-gate of at least one of the transistors. The biasing network may bias the at least one of the substrate, the well, and the back-gate to a virtual floating bias, such that the virtual floating bias shifts in voltage level based upon an AC input signal of the circuit, to reduce the parasitic capacitance of the output node of the circuit.

In an amplifier, there may be a non-dominant frequency pole whose frequency value is proportional to gm/C, where gm is the transconductance of the output stage and C is the total capacitance at the output node (for example, C may include the capacitance of the load at the output node, the capacitance of the output node itself, and parasitic capacitances).
For high speed applications, the non-dominant pole may need to be pushed out to high frequencies. A low non-dominant pole frequency can lead to bad phase margin (under-damped behavior) and low bandwidth. To increase the frequency of the non-dominant pole, the amplifier may be designed with increased current in the output stage of the amplifier to increase the gm of the output stage. This, however, may lead to increasing power consumption. Additionally, as gm/C may be inherently limited by manufacturing process, increasing current may not be sufficient to increase the non-dominant pole of the output stage.
Accordingly, there is a need for an amplifier with increased or improved non-dominant pole frequencies with improved bandwidth and settling time, without increasing the current of the output stage.


A hydraulic damper with one end connected to the body of a vehicle and a second end connected to a suspension system of a vehicle. The mechanism allows for multiple hydraulic-fluid metering valve positions to control piston resistance based on a variable pressure input using pressurized gas. The use of compressed gas to mechanically control a valve position allows changes to the piston resistance to be made quickly and to be increased or decreased as desired. The hydraulic damper features a control piston which in turn mechanically controls a valve needle within a hydraulic suspension piston. The position of the valve needle controls the damping characteristics of the suspension piston. When the control piston moves, the position of the valve needle is proportionally adjusted.

Hydraulic dampers are used in conjunction with automotive suspension systems to absorb unwanted vibrations caused by the force applied from a road or rough terrain while traveling over it. To absorb the unwanted vibrations, dampers are generally connected between the body and the suspension of the automobile. A piston, including a piston head and a piston rod, is located within a pressure tube of the damper and the pressure tube is normally attached to the suspension portion of the vehicle. The piston head is often attached to the piston rod which extends through the pressure tube to be connected to the body of the vehicle. The piston head divides the pressure tube into an upper working chamber and a lower working chamber both of which are typically filled with hydraulic fluid. Valve shims on the piston head define a fluid flow path through the piston head. As used herein, fluid can mean either a liquid or a gas. Because the piston limits the flow of the hydraulic fluid between the upper and the lower working chambers when the damper is compressed or extended, the damper is able to produce a damping force which counteracts the force which would otherwise be transmitted from the suspension to the body of the vehicle and felt by the passengers of the vehicle. The valve shims can be asymmetric for expansion and contraction, for example by using check valves. A piston with less fluid flow provides a firmer suspension and more control while a piston with more fluid flow leads to a softer ride but less control.
Some prior dampers are adjustable. Prior adjustable suspension dampers are only mechanically adjustable or only single time adjustable. For instance, certain prior dampers use air pressure to hold the damper in a first position. When a timer elapses, the air pressure is released, allowing the damper to move to a second position where it remains until the system is reset. These systems are not dynamically adjustable. Additionally, loss of control pressure causes such dampers to default to an open position with more fluid flow, which can lead to less suspension control. In racing, dynamic control is especially desired. Due to the fast pace and frequent turns, it is desirable to have a suspension system with a quick response time capable of keeping up with the constant vibrations and bumps involved.
Some adjustable dampers have multiple position adjustment mechanisms which rely on stepper or servo-motor controls to move the metering valve into different positions. However, these are typically limited by a relatively slow response time.
It is desirable to provide dynamically adjustable hydraulic suspension dampers capable of constant adjustment.
Thus, there is a need for improvement in this field.


A contention control system unitarily manages a plurality of data transmissions so as to avoid contention therebetween. Data transmission command sending equipment of a data receiver continuously sends data transmission commands to a data sender according to a data transmission request. Data transmission-command receive control equipment receives the first valid one of the continuously-delivered data transmission commands therein and delivers it to data transmission control equipment. Correspondingly, data sending equipment starts to transmit data. Data transmission monitoring equipment of the data receiver monitors the state of transmission of the data. When the data transmission corresponding to the data transmission commands is made, the data transmission monitoring equipment detects it and notifies the result of detection to data transmission-command transmit control equipment, which in turns terminates the notification of the data transmission commands in response to its notification delivered from the data transmission monitoring equipment. Thus, a reduction in the efficiency of bandwidth utilization at the time that transmission errors are produced in the notification of the above commands can be restrained.

1. Field of Invention
The present invention relates to a data transmission apparatus for controlling contention between a plurality of data transmissions when the data transmissions are performed on a shared sending medium in a computer network, and a method therefor.
2. Description of Related Art
A computer network comprises a sending medium and a plurality of terminals electrically connected to the sending medium. The transfer of data between the respective terminals is performed through the sending medium. Transmission capability of the sending medium is expressed in the form of the amount of transmit data per unit time. This will be referred to as "transmission bandwidth unit: bit/sec!". A plurality of data transmissions shares the use of the same sending medium by using the transmission bandwidth in divided form. The transmission bandwidth is a finite shared resource.
A bandwidth or bit rate to be used for the transmission of data changes momentarily according to the demand of each application. When the sum of bit rate used for respective data transmissions at arbitrary times is greater than the transmission bandwidth of the sending medium, the shortage of the transmission bandwidth is produced. Thus, this cannot satisfy all the data transmissions and hence a struggle for the transmission bandwidth occurs between the respective data transmissions. This will be called "contention between the transmission bandwidth" When the contention takes place, data incapable of acquiring a necessary bandwidth are dropped or lost without transmission.
When the data has dropped, the corresponding data is normally transmitted again for its recovery. This will be referred to as "redelivery or retransmission". Namely, since the term "retransmission" means that the same data is transmitted plural times to make a success of the data transmission, an increase in transmission delay time and a reduction in the efficiency =the amount of transmitted effective or valid data/(bandwidth necessary for the transmission of the valid data.times.time required to transmit the data)! of utilization of the transmission bandwidth occur. Accordingly, a contrivance to avoid the contention beforehand is necessary. This will be called "contention control".
If attention is given to file transfer, print service, etc. of various applications for performing data transmissions, then the following features are brought about:(1) Data to be transmitted exists at a sending terminal or end before the commencement of the data transmission and the amount of its data is already known.(2) Data transmission control information such as the amount of data is generally exchanged between sending and receiving terminals before the commencement of the data transmission.(3) Since data to be transmitted already exists within a sending terminal, a transmission bandwidth to be used can be controlled.(4) The allowable range of a transmission delay is relatively large.(5) In client/server type applications such as a file service/print service, etc., all the data transmissions are concentrated on a server.
Therefore, the present applicant has proposed a contention control method which has focused attention on the above-described features (see Japanese Patent Application No. Hei 8-17989) According to the present proposal, for, example, the sequence of data transmissions and bandwidth used for the data transmissions are unitarily controlled based on control information about the data transmissions concentrated on a server beforehand to thereby avoid contention between the data transmissions.
A contention control operation of the data transmission apparatus described in Japanese Patent Application referred to above will be described by one example comprising a data sender, a data receiver and a sending medium In the present example, the data receiver controls the sequence of the data transmissions, the bandwidth used for the data transmissions and the like on a unitary basis. FIG. 1 shows the configuration of the present example. FIG. 2 is a diagram for describing the operation of the present example.
(1) Data receiver 2: PA1 (2) Data sender 1: PA1 1) A system for sequentially feeding back the success or failure of a data transmission (see FIG. 3) PA1 2) A retransmission or redelivery requesting system (see FIG. 4) PA1 The time required to generate a response or retransmission request indicative of the success or failure of data transfer at the receiving end. PA1 The time required to transmit the response or retransmission request indicative of the success or failure of the data transfer from the receiving end to the sending end (transmission delay time). PA1 A timeout interval for avoiding the deadlock when no data drop is detected. PA1 means for monitoring a form of the transmission of the data from the data sender to the data receiver; PA1 means for controlling the transmission of the data transmission commands, based on the result of monitoring by the monitoring means; and PA1 means for detecting a transmission error in the data transmission commands and an duplicate thereof to thereby control the reception of the data transmission commands. PA1 a step for continuously sending data transmission commands from the data receiver to the data sender prior to the transfer of the data from the data sender to the data receiver; PA1 a step for starting the transmission of the data from the data sender without duplicating, based on the continuously-transmitted data transmission commands; PA1 a step for monitoring a form of the transmission of the data from the data sender to the data receiver; and PA1 a step for terminating the transmission of the data transmission commands, based on the result of the above monitoring.
The data receiver 2 comprises data transmission control information acquiring means 7, data transmission control means 8, data transmission command sending means 9, data receiving means 10, etc. The data transmission control information acquiring means 7 obtains necessary information from control information exchanged between the data sender and the data receiver before, between and after all the data transmissions. Before the data transmissions, for example, the data transmission control information acquiring means 7 acquires an identifier for a corresponding data sender 1, the amount of data to be transmitted, etc. The data transmission control means 8 determines the time at which a data transmission having the contents described in data transmission control information acquired by the data transmission control information acquiring means 7 is made possible, and an available transmission bandwidth, based on the data transmission control information and the use situation with regard to a bandwidth according to a data transmission being in execution. The data transmission command sending means 9 transmits data transmission commands including the contents determined by the data transmission control means 8 to the data sender 1. Further, the data receiving means 10 receives therein framed data transmitted from the corresponding data sender 1.
The data sender 1 comprises data transmission command receiving means 4, data transmission control means 5, data sending means 6, etc. The data transmission command receiving means 4 receives therein data transmission commands sent from the data transmission command sending means 9 of the data receiver 2. The data transmission control means 5 controls the start/end of the transmission of data by the data sending means 6, the bit rate for its data transmission, etc. in accordance with the data transmission commands received by the data transmission command receiving means 4. Further, the data sending means 6 transmits data to the data receiver 2 under the control of the data transmission control means 5.
On the other hand, when the data is transmitted over the sending medium, there is a possibility that a signal error will take place due to noise or the like, or data will drop due to a signal error, buffer overflow in a repeater and the like. This will be called "transmission error". There may be cases in which the transmission error is detectable and undetectable. When the transmission error is detected, data subjected to the transmission error is recovered. This will be called "error correction". As an error correcting system, there are known an FEC (Forward Error Correction) system and a reforward or retransmission system. However, the RETRANSMISSION system can effect a 100% correction on the transmission error in principle. Since a transmission error in transmitted data can be detected only at a receiving terminal or end, whereas the corresponding data can be retransmitted only from a sending terminal or end at which it holds the data, feedback for confirming the delivery of the data from the receiving end to the sending end is essential to the retransmission system.
A handshake procedure for confirming the delivery of data by the conventional retransmission control system includes two systems shown below.
At this time, the following overhead times will be produced.
When no transmission error is detected, there is a danger that an event that the receiving side will cause a malfunction and an event, a so-called "deadlock" that the sending side continues to eternally wait for a response issued from the receiving side or vice verse, will occur. Thus, when one of the sending end and the receiving end does not receive a response to be expected from the other thereof within a predetermined time, either one of them performs the retransmission or redelivery of data to the other or discontinues the transfer of data to the other to thereby notify it to an application, whereby the deadlock is avoided. Such a timeout process is shown in FIG. 5. At this time, the following overhead time is produced.
Since the transmission bandwidth of the sending medium, the transmission delay time, the processing times in the repeater and the sender and receiver, etc. are not yet known at the instant of the timeout, the timeout interval is generally set to a time interval sufficiently longer than the time necessary for the normal transmission of data.
Referring back to the example shown in FIG. 1, when the transmission error is produced in the data transmission commands sent from the data transmission command sending means 9 upon transmission of the data transmission commands thereof, it is erroneously received or not received at all by the data transmission command receiving means 5. Accordingly, the data sender 1 does not comply with the unitary decision made by the data transmission control means 8, thus resulting in the failure of control on contention between the data transmissions. In this case, there is a danger that an event that the transmission of data is not started eternally due to the occurrence of the deadlock, will occur as well as no hope in the improvement in the efficiency of utilization of a bandwidth. Therefore, there is a demand for applying reliability against the transmission error to the data transmission commands so as to avoid the failure of the contention control.
However, when one attempts to correct the transmission error by the conventional retransmission system to avoid it, a non-used bandwidth at which no data transmission is actually done, is produced within the above overhead time even though the bandwidth used for the transfer of data from the sender to the receiver has been ensured. A penalty against the occurrence of the transmission error is large, so that a reduction in the efficiency of utilization of the bandwidth is caused.

Apparatus for and method of transmitting data


Tooth-shaped link member (1) for a transport tooth chain (11) with apertures (2) and two end-terminal toes (3) for the form-fitting engagement with a gear 99), which is geometrically adapted to the configuration of the gear (9), and which in addition each exhibit a lower contact surface (6) for gliding on a gliding surface of a guide body (8), wherein as an additional means for reducing the wear on the link member (1) a third gliding toe (4) is provided with does not come in form-fitting contact with the gear (9) which is arranged centrally between the end-terminal toes (2) of the link member 91) in order to enlarge the total surface of the link member on the gliding surface (7).

The invention refers to a tooth shaped link member of a tooth chain with apertures and two end terminal toes for form-fitting engagement with a toothed gear and having an outer contour corresponding to the toothed gear, and wherein the toes are provided with a contact surface for gliding on a gliding surface of a guide body. Furthermore, the invention refers to a transport tooth chain comprising a plurality of these link members and a transport conveyer comprising at least a plurality of these transport tooth chains.
These types of link members, transport tooth chains and transport conveyors are normally utilized in the conveying industry. Thus, for the formation of a linear conveying line with a transport conveyor which is according to a type of conveyor belt, transport tooth chains comprised of links are guided in an endless manner across an elongated conveying device with end terminal diverting—and/or driving rollers. Thereby, at least the driving roller which is configured as a toothed gear engages with the corresponding toes of the link member, respectively the tooth chain. An arrangement of this type is normally operated in environments where high temperatures exist—such as for example during production of hollow glass bodies. These parts of the tooth chain, which are manufactured entirely from steel, reliably withstand the very high temperatures that are generated during such work operations.
A tooth chain of the type referred to is known from DE 198 44 304 C1. The transport tooth chain consists of single link members linked to each other by means of round bolts or by cradle-type joints. A cradle-type joint consists of two parts as compared to a round bolt, namely a cradle pin and a support pin. The support pin is riveted end-terminally with a rivet washer in order to hold the link members together. Both profile pins are held in the apertures of the link member. During movement of the joint, both profile pins are rolling off each other. Thus, as compared to a pin support, no sliding friction occurs in the joint, thereby drastically reducing wear in that area.
In contrast thereto, chain conveyors that do not incorporate similar supplementary parts are also generally known in the prior art. In such conveyors, the tooth chain is conducted within a guiding device formed in the elongated support device similar to a type of gliding bed. The guiding device consists normally of a bottom portion laterally flanked with adjacent vertically extending wall portions. The width of the guiding device is dimensioned in such a manner that the tooth chain is guided therein with little lateral play.
All of the afore-discussed types of tooth chains suffer from the drawback, that the wear on the tooth shaped driving links are very heavy due to the gliding friction between the toes of the link and the guiding device. Optimization of the wear areas has been tried in order to realize a longer serviceable life.
For example, it has been tried to receive the arrangement of the bolts, which extend beyond the outer link members of the tooth chain in a recess in the sidewall of the guiding device, so that the sidewall area can operatively engage directly with the outer link member of the tooth chain.
There were also attempts to reduce the wear on the link members, more precisely the gliding surface of the toes of the link member. Accordingly, the link members were configured shorter, whereby the contact surface was enlarged which reduced the surface pressure between the contact surface and the gliding surface. This configuration leads inevitably too more building parts and to a change in the geometry of the gearing as well as to the division thereof.

Transport tooth chain with reduced wear on the vertical dimension of its link members


The present invention relates to a parallel electricity-storage system that includes: a plurality of DC buses; a number of sets of battery banks formed by serially connecting one or a plurality of battery cells capable of charging and discharging, the number thereof being larger than number of the DC buses; a switch provided for each of the battery banks and serially connected to the battery bank to switch connection between the battery bank and each of the DC buses; charge/discharge circuits as many as the number of the DC buses that charge the respective battery banks via the DC buses or supply discharged power from the respective battery banks received via the DC buses to a load device; a voltage detector that detects a voltage of the respective battery banks; and a controller that controls the switch based on at least a voltage detected by the voltage detector.

Conventionally, for example, Patent Literature 1 discloses a technique of preventing occurrence of problems such as overcurrent and abnormal heat generation resulting from a large cross current at the time of parallel input, in a parallel-connected electricity-storage system in which one or a plurality of electricity storage elements capable of charging and discharging are serially connected to form an electricity-storage element array, and a plurality of electricity-storage element arrays are connected in parallel. In the parallel-connected electricity-storage system, a cutoff switch is provided in each electricity-storage element array, and when there is one or a plurality of electricity-storage element arrays in which a voltage difference detected by a voltage monitoring unit is within a predetermined value, only a switch corresponding to the electricity-storage element array is closed to prevent the occurrence of problems (see, for example, Patent Literature 1 mentioned below).
Patent Literature 2 discloses a secondary battery with units including unit cells and charge/discharge circuits serially connected, in which DC/DC converter operating as a charge/discharge circuit are provided for each unit cells; while discharging, an output current of the DC/DC converter connected to a unit cell having a high SOC is set to be larger than that of a unit cell having a low SOC, so that the variations in the SOC are decreased; and while charging, an output current of the DC/DC converter connected to a unit cell having a high SOC is set to be less than that of a unit cell having a low SOC, so that the variations in the SOC are decreased.

Parallel electricity-storage system and control method thereof


The present invention relates to a game calling holder which when combined with a game calling unit and secured to a hunter's body at a predetermined aiming mount position will allow the hunter to simultaneously call the game while aiming the weapon. The game calling holder may appropriately include an elastic sleeve sized to elastically conform to the game calling unit configuration and a badge pin which retains the elastic sleeve and game calling unit in longitudinal alignment with the badge pin alignment when mounted onto a hunter's garment at a predetermined aiming mount position. The game calling holder when mounted appropriately to an aiming arm of a bow and arrow hunter and a triggering wrist of a firearm hunter accordingly allows the hunter to simultaneously aim and call the hunted prey.

It is conventional for game hunters to use game callers to call prey. Air activated game callers by mouthing (vacuum or air blown) the game caller by the hunter have been used for decades to call hunted game. Most game callers are designed to be hand held when used to call prey even though some are also designed to be clinched between the hunter's teeth if desired. Game callers, such as frequently used in hunting water fowl hunters, may be hand held or mouthed by clinching the duck caller between one's teeth to call the hunted waterfowl while somewhat awkwardly aiming a firearm at the prey. Game calling for a bow and arrow hunter is even more difficult. The manner in which a bow and arrow is placed in a targeting position does not permit a bow hunter such a simultaneous use of the game caller. It would be particularly advantageous (especially for bow and arrow hunters) to be able to simultaneously aim the arrow at the prey while calling the prey such as a deer. Currently, this is a tedious if not almost impossible task to perform with existing technology.
Except for the mouth held calling devices, most animal or prey calling devices must be operated independently of the weapon. Consequently, the normal use of hand held animal calling devices is to initially call the hunted prey (e.g. animal or bird) and then dispense with the prey calling device while aiming the weapon at the targeted prey. Many prey calling devices are equipped with a lanyard which allows the hunter to grasp the prey calling device when calling the prey and then drop the hung device about the neck when aiming the weapon at the targeted prey. The problem of being able to call the prey while aiming or targeting the animal or bird prey is further compounded when a bow and arrow is used as the weapon. Conventional lanyard hung calling devices can become a lethal hunting hazard if it becomes entangled in the released bow strings. Placement of the calling device further removed from the hunter's mouth can create excessive movement which often alarms the called prey.
Prey calling devices are also manufactured in various different shapes and forms. It would be particularly advantageous if there existed a more universal holder which would hold or retain a vast majority of the prey calling devices while also enabling the hunter to aim at the targeted prey while still maintaining a call to the prey. Further benefits would be achieved if the prey calling device could be emplaced upon the hunter at a position requiring a minimum amount of movement to activate the prey calling device so as to thereby alleviate potential spooking of the prey.
Certain body-mounted game callers have heretofore been proposed such as U.S. Pat. No. 6,514,116 B2 to Abbas which discloses a vacuum activated game caller which includes a garment mounted caller for mounting to a mid-section of a wearer's garment and a long air tube mounted onto the wearer's lapel. The patented Abbas game caller system is tailor made to only apply to a specially designed game caller and calling apparatus. The long, circuitous and small air tubes of the Abbas game calling apparatus further limits its usefulness to the Abbas system. Other game animal callers include a caller mounted to a bow or firearm (e.g. see U.S. Pat. No. 5,035,390 to Sanders and U.S. Pat. No. 5,431,590 to Abbas), a bellowed foot pouch (e.g. see U.S. Pat. No. 5,613,891 to Lamo), a belt or thigh mounted turkey call of U.S. Pat. No. 5,988,469 to Musacchina and clanging antler horns suspended from a deer stand as disclosed in U.S. Pat. No. 5,555,664 to Shockley.
It would be desirable to be able to position an air activated prey caller so that it could be used to simultaneously call the prey while also taking aim at the called prey with a weapon. This would be particularly useful for bow and arrow hunters since it would enable the hunter to concentrate upon aiming at the targeted prey while manipulating the bow and arrow to the targeting position. The fluid movement required for an accurate bow aim would not then be disrupted by the prey calling. It would be even more desirable if the game hunter would not need to hold or gain hand held access to the prey caller until it was time to use the prey caller. Since hunted prey typically possess extraordinary instincts to perceive motion or sense motion danger especially by movements of a hunter, a game calling device which would provide ready access to the prey hunter for the prey calling while requiring minimal movement to engage the call would be highly advantageous in order to avoid potential spooking of the hunted prey. A game call holding device which would firmly retain the prey caller at the precise position needed to sound the prey call but yet allow the game hunter full freedom to draw an arrow, aim and discharge the arrow at the prey while easily or continuously calling the hunted prey would fulfill a long felt need. A game call holding device which would enable the game hunter to blow or suck a required volume of air directly into the game caller while simultaneously drawing aim at a targeted prey would also be particularly useful to bow and arrow deer hunters. A prey calling holder adapted to fit most prey callers and mountable upon an aiming shoulder in juxtaposition to the hunter's mouth would enable the hunter to call prey while targeting prey with most prey calling devices.


A touch structure, a method of manufacturing same, a touch device, and a method for determining a touch position are provided. The touch structure includes a first touch unit and the first trace. The first touch unit includes a first touch electrode and a second touch electrode that are adjacent to each other and insulated from each other. The first touch electrode and the second touch electrode are both self-capacitance electrodes and both have a thin end and a thick end that are arranged opposite to each other. The first trace includes a first sub-trace and a second sub-trace is coupled to the first touch electrode and the second sub-trace is coupled to the second touch electrode.

Touch technologies include single touch technology and multi-touch technology. Upon each touch, single touch can be used to identify only one touch point, and multi-touch technology can be used to identify at least two touch points simultaneously.
Capacitive touch technology is widely used due to its high sensitivity, long life, and high light transmittance. The capacitive touch technology may be divided into touch technology using the mutual-capacitance principle and touch technology using the self-capacitance principle. Compared with the touch technology using the mutual-capacitance principle, the touch sensing technology using the self-capacitance principle has higher accuracy and higher signal-to-noise ratio.
At present, the multi-touch technology using the self-capacitance principle has gradually become a new research hotspot.

Touch structure, method for manufacturing same, touch device, and method for determining touch position

Hefei Xinsheng Optoelectronics Technology Co., Ltd.

Beijing BOE Technology Development Co., Ltd.


A computer readable recording media, having at least one program code recorded thereon, an image adjusting method can be performed when the program code is read and executed. The image adjusting method comprises: catching a current image; computing at least one kind of brightness information of the current image; respectively setting corresponding threshold values to different kinds of the brightness information; and determining if a contrast enhancing operation should be performed to the current image to generate an adjusted image according to a number that the brightness information is over the threshold value.

1. Field of the Invention
The present invention relates to an image adjusting method and an optical navigating apparatus utilizing the image adjusting method, and particularly relates to an image adjusting method and an optical navigating apparatus utilizing the image adjusting method, which can perform contrast enhancing according to various brightness information of the image.
2. Description of the Prior Art
An optical navigating apparatus, such as an optical mouse, utilizes an image sensor to catch continuous images, and then utilizes the features of these images (ex. brightness) to compute displacement of the optical navigating apparatus. However, the caught images may be affected by some factors such that the images are out of focus or have indefinite features, thus the computing for displacement may have error.
For example, the printed circuit board thickness which the image sensor is provided on must be controlled to fall in a predetermined range, or the caught image may be out of focus. Alternatively, the surface that the optical navigating apparatus passes may have no apparent features, such that the image may have indefinite features.

Image adjusting method and optical navigating apparatus utilizing the image adjusting method


An electrical connector includes a electrical connector extending between a pair of mechanical connectors to electrically couple circuits, and a supporting member between the mechanical connectors to reduce twisting of the electrical connector. The supporting member cambered to permit the mechanical connectors to translate with respect to one another. A clamping member includes a tapered clamping surface in an undeformed, unclamped position. The clamping member bends when in a clamped position, resulting in approximately planar clamping surface. Resilient pressure pads on the clamping members bias the electrical connector to the circuit board. The pressure pads are mounted in wells in the clamping members to support a sidewall of the pressure pads. Frames provide additional support to the sidewalls of the pressure pads. The pressure pads include a raised edge along a periphery of a contact surface of the pressure pad. Additionally, or alternatively, a support shoulder in the well cooperates with a recess along a periphery of a mounting surface of the pressure pad to support the sidewall. Alignment structure on the frame cooperates with alignment structure on the clamping members, the printed circuit boards and the electrical connectors to align contacts on the electrical connectors with contacts on the printed circuit boards, and to further align the pressure pads with the contacts.

This invention relates to electrical connectors, and more particularly to an improved socket for electrical connectors coupled to printed circuit boards.
Many computing devices, such as desktop computers, workstations, mainframe and super-computers employ multiple printed circuit boards (xe2x80x9cPCBxe2x80x9d) that include various microprocessors, printed circuits and other components that must be electrically coupled together to transmit data and/or power. The electrical traces on one or more layers of the printed circuit board form the printed circuits and typically terminate in one or more terminals or contacts for making connections. Every decreasing element sizes, such a pitch (i.e., the spacing between successive components), width, and height, exacerbate the problem of providing secure and reliable connections between the printed circuits. Precise positioning on the order of thousandths of an inch is often necessary. Consistent pressure across each of the many contacts is also desirable to assure a reliable connection. A single failed or intermittent connection of a contact on a printed circuit board can result in large amounts of xe2x80x9cdown-timexe2x80x9d for the computing device, and costly troubleshooting by highly skilled technicians.
A reliable, precise, and highly manipulable electrical connector is required to couple printed circuits between printed circuit boards. Additionally the connection should be secure over a time period commiserate with the expected life of the computing device to avoid costly maintenance and should allow easy replacement and/or addition of various computer components such as printed circuit boards.
According to principles of the invention, a clamping member of an electrical connector is thicker in a central region than in the end region. The clamp includes a bar that is tapered from the center to the edges when in an undeformed state and unclamped position. The bar is deformed under a force applied at the ends as the clamping members are moved into a clamped position. The result is a generally planar clamping surface when the clamping members are in the clamped position.

Electrical circuit connector with tapered surface