The present invention provides methods and adjuvants for enhancing an immune response to RSV in a host, wherein the methods and adjuvants comprise a source of a CD40 binding protein. Preferably, the CD40 binding protein is CD40L and the source is a vector comprising a promoter operatively linked to a CD40L coding region. The enhanced immune response produced by the adjuvants and methods of the current invention includes both increased expression of Th1 cytokines and increased production of antibody.

Worldwide, the most important cause of bronchiolitis and serious lower respiratory tract disease in infants and young children is respiratory syncytial virus (RSV) (Collins et al., "Respiratory syncytial virus," IN: Fields B, Knipe, D., Howley P., eds. Fields Virology. 3rd ed. 1. Philadelphia: Lippencott-Raven Publishers:1313 (1996); Crowe, J. E., Jr., "Current approaches to the development of vaccines against disease caused by RSV and parainfluenza virus (PIV)," Meeting Report, WHO Programme for Vaccine Development. Vaccine 13:415 (1995); and Welliver et al., "Clinical and laboratory diagnosis of respiratory syncytial virus infection," Critical Reviews in Clinical Laboratory Sciences 13:213 (1981)). Natural infection with RSV provides limited protection from reinfection and disease as demonstrated by recurrence of severe RSV infections throughout life (Hall et al., "Immunity to and frequency of reinfection with respiratory syncytial virus," J. Infect. Dis. 163:693 (1991); and Henderson et al., "Respiratory syncytial virus infections, reinfections and immunity: a prospective. Longitudinal study in young children," N. Engl. J. Med. 300:530 (1979)). Moreover, the peak incidences of serious RSV disease are in young infants who have maternally-acquired neutralizing RSV antibodies. Thus, the development of RSV vaccines has long been a priority for infants and young children (Crowe, J. E. Jr., "Current approaches to the development of vaccines against disease caused by respiratory syncytial virus (RSV) and parainfluenza virus (PIV). A meeting report of the who programme for vaccine development," Vaccine 13:415 (1995); "New vaccine development: establishing priorities; diseases of importance in the United States," Washington D.C., Institute of Medicine National Academy Press (1985); "New vaccine development: establishing priorities, diseases of importance in developing countries," Washington D.C. National Academy Press II (1986); Doherty P. C., "Vaccines and cytokine-mediated pathology in RSV infection," Trends in Microbiology 2:148 (1994); and Murphy et al., "Current approaches to the development of vaccines effective against parainfluenza and respiratory syncytial viruses," Virus Research 11:1 (1988)). More recently, vaccines are being developed for older children at risk for serious complications of infection and for the elderly (Piedra et al., "Purified fusion protein vaccine protects against lower respiratory tract illness during respiratory syncytial virus season in children with cystic fibrosis," Pediatric Infectious Disease Journal 15:23 (1996); Han et al., "Respiratory syncytial virus pneumonia among the elderly: an assessment of disease burden," Journal of Infectious Diseases 179:25 (1999); and Falsey et al., "Safety and immunogenicity of a respiratory syncytial virus subunit vaccine (PFP-2) in ambulatory adults over age 60," Vaccine 14:1214 (1996)).
RSV vaccine development has been focused toward live, temperature sensitive, attenuated vaccines and subunit vaccines based on the F and/or G glycoproteins (Groothuis et al., "Safety and Immunogenicity of a purified F protein respiratory syncytial virus (PFP-2) vaccine in seropositive children with bronchopulmonary dysplasia," Journal of Infectious Diseases 177:467 (1998); Neuzil et al., "Adjuvants influence the quantitative and qualitative immune response in BALB/c mice immunized with respiratory syncytial virus FG subunit vaccine," Vaccine 15:525 (1997); and Siegrist et al., "Protective efficacy against respiratory syncytial virus following murine neonatal immunization with BBG2NA vaccine: influence of adjuvants and maternal antibodies," Journal of Infectious Diseases 179:1326 (1999)). In animal model systems, the F glycoprotein is generally the most effective with the G glycoprotein being the next most effective in inducing neutralizing antibodies and protective immunity. Vaccination with the G glycoprotein, however, generally induces only limited protection (Stott et al., "Immune and histopathological responses in animals vaccinated with recombinant vaccinia viruses that express individual genes of human respiratory syncytial virus," J. Virol. 61:3855 (1987); and Connors et al., "Respiratory syncytial virus (RSV) F, G, M2 (22K), and N proteins each induce resistance to RSV challenge, but resistance induced by M2 and N proteins is relatively short-lived," Journal of Virology 65:1634 (1991)). In clinical studies, no vaccine has yet proven safe and efficacious, mainly because candidate live virus vaccines have been under or over attenuated or have reverted to wildtype phenotype (Karron et al., "Evaluation of two live, cold-passaged, temperature-sensitive respiratory syncytial virus vaccines in chimpanzees and in human adults, infants, and children," Journal of Infectious Diseases 176:1428 (1997)). However, the recent availability of an RSV infectious clone has expanded the options in developing live virus candidate vaccine strains, and renewed hope that a safe and efficacious live virus vaccine can be developed (Teng et al., "Altered growth characteristics of recombinant respiratory syncytial viruses which do not produce NS2 Protein," Journal of Virology 73:466 (1999); Skiadopoulos et al., "Attenuation of the recombinant human parainfluenza virus type 3 CP45 candidate vaccine virus is augmented by importation of the respiratory syncytial virus CPTS530 L polymerase mutation," Virology 260:125 (1999); and Whitehead et al., "Addition of a missense mutation present in the 1 gene of respiratory syncytial virus (RSV) CPTS530/1030 to RSV vaccine candidate CPTS248/404 increases its attenuation and temperature sensitivity," Journal of Virology 73:871 (1999)). Nevertheless, there remains a need for efficacious methods and adjuvants for enhancing the safety and efficacy of RSV vaccines.
Development of subunit vaccines, in particular, has been hindered by concerns about the enhanced lung disease that occurred in young children who received a formalin-inactivated RSV (FI-RSV) vaccine, and then had natural RSV infection (Chin et al., "Field evaluation of a respiratory syncytial virus vaccine and a trivalent parainfluenza virus vaccine in a pediatric population," Am J Epidemiol 89:449 (1969)). Although the reasons for this vaccine-augmented disease remain uncertain, evidence in the BALB/c mouse model suggests that a heightened Th2 cytokine response may in part be responsible (Anderson et al., "Cytokine Response to respiratory syncytial virus stimulation of human peripheral blood mononuclear cells," Journal of Infectious Diseases 170:1201 (1994); Connors et al., "Enhanced pulmonary histopathology induced by respiratory syncytial virus (RSV) challenge of formalin-inactivated RSV-immunized BALB/c mice is abrogated by depletion of interleukin-4 (IL-4) and IL-10," Journal of Virology 68:5321 (1994); and Waris et al., "Respiratory synctial virus infection in BALB/c mice previously immunized with formalin-inactivated virus induces enhanced pulmonary inflammatory response with a predominant TH2-like cytokine pattern," Journal of Virology 70:2852 (1996)). In these studies, enhanced lung pathology in FI-RSV vaccinated mice challenged with live RSV was shown to be mediated by Th2-type CD4+ T cells expressing IL-4, IL-5, IL-6, and IL-10. In contrast, mice immunized and challenged with live RSV do not develop extensive lung pathology and respond with a mixed Th1/Th2 immune response (Anderson et al. (1994); Graham et al., "Priming immunization determines T helper cytokine mRNA expression patterns in lungs of mice challenged with respiratory syncytial virus," Journal of Immunology 151:2032 (1993); Hussell et al., "Th1 and Th2 cytokine induction in pulmonary T cells during infection with respiratory syncytial virus," Journal of General Virology 77:2447 (1996); and Srikiatkhachom et al., "Virus-specific memory and effector T lymphocytes exhibit different cytokine responses to antigens during experimental murine respiratory syncytial virus infection," Journal of Virology 71:678 (1997)). Based on this possible role of a heightened Th2 cytokine response in enhancing lung disease upon live RSV infection, there is a need for methods and/or reagents for promoting a Th1 response over a Th2 response to live viral challenge.
Since passive administration of high titered neutralizing RSV antibodies can decrease the risk of serious RSV disease, one of the best indicators of protection from RSV disease is high titers of neutralizing antibodies (Groothuis et al., "Use of intravenous gamma globulin to passively immunize high-risk children against respiratory syncytial virus: safety and pharmacokinetics. The RSVIG study group," Antimicrobial Agents & Chemotherapy 35:1469 (1991); and Hemming et al., "Hyperimmune globulins in prevention and treatment of respiratory syncytial virus infections," Clinical Microbiology Reviews 8:22 (1995)). Unfortunately, both attenuated live and subunit candidate vaccines induce only modest increases in antibodies (Dudas et al., "Respiratory syncytial virus vaccines," Clinical Microbiology Reviews 11:430 (1998); and Murphy et al., "An update on approaches to the development of respiratory syncytial virus (RSV) and parainfluenza virus type 3 (PIV3) vaccines," Virus Research 32:13 (1994)). As evidenced by the variety of adjuvants that are being evaluated for their ability to enhance the immune response to subunit vaccines (See e.g., Xin et al., "Immunization of rantes expression plasmid with a DNA vaccine enhances HIV-1-specific Immunity," Journal of Applied Biomaterials (Orlando) 92:90 (1999); Ciupitu et al., "Immunization with a lymphocytic choriomeningitis virus peptide mixed with heat shock protein 70 results in protective antiviral immunity and specific cytotoxic T lymphocytes," Journal of Experimental Medicine 187:685 (1998); and Hancock et al., "Formulation of the purified fusion protein of respiratory syncytial virus with the saponin QS-21 induces protective immune responses in BALB/c Mice that are similar to those generated by experimental infection," Vaccine 13:391 (1995)), there remains a need for an adjuvant that is effective at enhancing immune responses to RSV vaccines, especially subunit vaccines.
One potential immune-enhancing molecule is CD40L which is important to productive interactions between T cells and antigen presenting cells (Armitage et al., "CD401: a multi-functional ligand," Seminars in Immunology 5:401 (1993); Grewal et al., "The CD40 Ligand. At the center of the immune universe?" Immunologic Research 16:59 (1997); Laman et al., "Functions of CD40 and its ligand, GP39 (Cd401)," Critical Reviews in Immunology 16:59 (1996); Ramshaw et al., "Cytokines and immunity to viral infections," Immunological Reviews 159:119 (1997); van Kooten et al., "Functional role of CD40 and its ligand," International Archives of Allergy & Immunology 113:393 (1997); van Kooten et al., "Functions of CD40 on B cells, dendritic cells and other cells," Current Opinion in Immunology 9:330 (1997); Bennett et al., "Help for a cytotoxic-T-cell response is mediated by CD40 signaling," Nature 393:478 (1998); and Ridge et al., "A conditioned dendritic cell can be a temporal bridge between a CD4+T-helper and a T-killer," Nature 393:474 (1998)). CD40L has been shown to enhance both humoral and cellular immune responses (Grewal et al. (1997); Laman (1996); Gurunathan et al., "CD40 ligand/trimer DNA enhances both humoral and cellular immune responses and induces protective immunity to infectious and tumor challenge," Journal of Immunology 161:4563 (1998); and Durie et al., "The role of CD40 in the regulation of humoral and cell-mediated immunity," Immunology Today 15:406 (1994); Klaus et al., "CD40 and its ligand in the regulation of humoral immunity," Seminars in Immunology 6:279 (1994); and Noelle et al., "CD40 and its ligand in cell-mediated immunity," Agents & Actions—Supplements 49:17 (1998)). For example, CD40L expression has been shown to enhance T cell and APC activation and signaling, the importance of which has been revealed by studies of CD40L−/− mice (Borrow et al., "CD40L-deficient mice show deficits in antiviral immunity and have an impaired memory CD8+ CTL response," Journal of Experimental Medicine 183:2129 (1996); Castigli et al., "CD40-deficient mice generated by recombination-activating gene-2-deficient blastocyst complementation," Proceedings of the National Academy of Sciences of the United States of America 91:12135 (1994); Cosyns et al., "Requirement of CD40-CD40 ligand interaction for elimination of Cryptosporidium parvum from mice," Infection & Immunity 66:603 (1998); Grewal et al., "Impairment of antigen-specific T-cell priming in mice lacking CD40 ligand," Nature 378:617 (1995); Kawabe et al., "The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation," Immunity 1:167 (1994); Kennedy et al., "CD40/CD40 ligand interactions are required for T cell-dependent production of interleukin-12 by mouse macrophages," European Journal of Immunology 26:370 (1996); Lei et al., "Disruption of antigen-induced inflammatory responses in CD40 ligand knockout mice," Journal of Clinical Investigation 101:1342 (1998); Soong et al., "Disruption of CD40-CD40 ligand interactions results in an enhanced susceptibility to Leishmania amazonensis infection," Immunity 4:263 (1996); and Stout et al., "Impaired T cell-mediated macrophage activation in CD40 ligand-deficient mice," Journal of Immunology 156:8 (1996)) and in CD40L−/− humans (Allen et al., "CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome," Science 259:990 (1993)). Coincident expression of CD40L has been shown to promote T cell mediated immunity (Ramshaw et al. (1997); Yang et al., "Transient subversion of CD40 ligand function diminishes immune responses to adenovirus vectors in mouse liver and lung tissues," Journal of Virology 70:6370 (1996); Ruby et al., "CD40 ligand has potent antiviral activity," Nature Medicine 1:437 (1995); Couderc et al., "Enhancement of antitumor immunity by expression of CD70 (CD27 ligand) or CD154 (CD40 ligand) costimulatory molecules in tumor cells," Cancer Gene Therapy 5:163 (1998); and Brown et al., "Thymic lymphoproliferative disease after successful correction of CD40 ligand deficiency by gene transfer in mice," Nature Medicine 4:1253 (1998)). Administering anti-CD40 monoclonal antibody to mice together with pneumococcal polysaccharide generated strong, isotype-switched antibody responses (Dullforce et al., "Enhancement of T cell-independent immune responses in vivo by CD40 antibodies," Nature Medicine 4:88 (1998)). Immunization of BALB/c mice with DNA plasmids expressing β-galactosidase and a protein consisting of CD40L linked to a leucine zipper motif increased the Th1-type immune response to β-galactosidase (Gurunathan et al. (1998)). The importance of CD40L expression in the development of Th1 cytokine responses was also demonstrated by antibody inhibition studies in which anti-CD40L antibody decreased Th1-mediated autoimmune diabetes in NOD mice by reducing IL-12 secretion and slightly increasing IL-4 production (Balasa et al., "CD40 ligand-CD40 interactions are necessary for the initiation of insulitis and diabetes in nonobese diabetic mice," Journal of Immunology 159:4620 (1997)).
Several studies that utilized CD40L deficient mice reveal a role for CD40L in both humoral and cellular immune responses to viruses. Constitutive retroviral expression of CD40L restored antigen-specific cytolytic and humoral immune responses in CD40L−/− mice infected intranasally with the HKx31 strain of influenza (Brown et al. (1998)). Infection of mice with recombinant vaccinia virus that expressed CD40L markedly enhanced viral clearance by both an IFNγ-dependent mechanism and a novel CD40L-dependent mechanism (Ruby et al. (1995)). In studies that examined the anti-adenovirus response in CD40L−/− mice, diminished CD4+ T cell priming and reduced IL4, IL-10 and IFNγ cytokine expression occurred in the absence of CD40L (Yang et al. (1996)). A role for CD40L in antiviral B and T cell immune responses was also shown in CD40L−/− mice challenged with lymphocytic choriomeningitis virus (LCMV), (Borrow et al. (1996); Oxenius et al., "CD40-CD40 ligand interactions are critical in T-B cooperation but not for other anti-viral CD4+ T cell functions," Journal of Experimental Medicine 183:2209 (1996)). CD40L−/− mice infected with LCMV were capable of generating primary CTL responses, but had defective memory CTL responses. Furthermore, primary anti-LCMV IgG1 antibody responses were severely impaired in the absence of CD40L. Although an involvement of CD40L in immune responses has been established, it has not been established or suggested that CD40L, or vectors capable of expressing CD40L, are effective in enhancing an immune response, especially a Th1 cytokine immune response, to RSV.
Li et al. ("Nucleic Acid Respiratory Syncytial Virus Vaccines," U.S. Pat. Nos. 5,880,104 (1999) and 5,843,913 (1998)) describe vaccines for RSV that utilize the RSV F protein expressed from the cytomegalovirus promoter.
Brams et al. ("Neutralizing High Affinity Human Monoclonal Antibodies Specific to RSV F-Protein and Methods for their Manufacture and Therapeutic Use Thereof," U.S. Pat. Nos. 5,939,068 (1999) and 5,811,524 (1998)) describe methods for producing antibodies against the RSV F protein, and describe several antibodies developed using these methods.
Gurunathan et al., ("CD40 Ligand/Trimer DNA Enhances Both Humoral and Cellular Immune Response and Induces Protective Immunity to Infectious and Tumor Challenge," J. Immunol. 161, 4563 (1998)), describes the use of plasmids encoding a protein containing the CD40L coding region fused to a leucine zipper motif, called the CD40 ligand/trimer, to enhance Th1 and cytotoxic T-lymphocyte responses.
Alderson et al., ("Method for Stimulating an Immune Response," WO96/26735 (1996)), describes the use of a soluble, trimer-forming fragment of CD40L to enhance production of interleukin 12 in vitro, and to treat infection with Leishmania or Pneumocystis in CD40L-deficient mice.
The current invention provides adjuvants and methods that utilize a source of a CD40 binding protein, such as a vector operatively linked to CD40L, to enhance an immune response, especially a Th1 cytokine immune response, to an RSV vaccine.

Cd40 ligand adjuvant for respiratory syncytial virus

The United States of America as represented by the Department of Health and Human Services


A developer container includes a conductive member containing a resin configured to detect a developer amount using capacitance, and a frame member having the conductive member configured to store the developer. The conductive member is provided on a first side of the frame member contacting the developer and on a second side of the frame member, the second side is the back of the first side, and the conductive member provided on the first side and the conductive member provided on the second side are connected with each other within the frame member.

Field of the Invention
The present invention relates to a developer container, a development device, a process cartridge, and an image forming apparatus.
A development device includes a developer bearing member, and the device is used to visualize an electrostatic latent image with developer. A process cartridge includes an image bearing member for bearing the developer image and a process unit acting on the image bearing member. The image bearing member and the process unit are integrated as a cartridge.
Description of the Related Art
In electrophotographic image forming apparatuses using electrophotographic imaging process, a process cartridge method has been employed. In the process cartridge method, an electrophotographic photosensitive member and a process unit acting thereon are combined into one cartridge to provide the cartridge detachable from the electrophotographic image forming apparatus body.
Such a process cartridge method enables users to perform maintenance of the apparatuses by themselves without relying on service staff, and this significantly increases the apparatus operability. For this reason, the process cartridge method has been widely used in the electrophotographic image forming apparatuses.
Process cartridges include toner, to provide the color, and developer, which consists of magnetic particles that carry the color on an outside of a magnetic developer drum. The developer allows a latent electrostatic image on the photoconductor to take up sufficient toner to give a properly colored image. In the electrophotographic image forming apparatuses employing the process cartridge method as described above, the users can replace the process cartridges by themselves. Consequently, the electrophotographic image forming apparatuses are often provided with a means for detecting toner consumption amount and notifying the users of the timing of replacement, that is, a toner remaining amount detection unit. Toner consumption amount can be based on electrical resistance properties since electrical resistance properties will change depending on the developer-toner mix.
As examples of the remaining toner amount detection unit, Japanese Patent Application Laid-Open No. 2003-248371 and Japanese Patent Application Laid-Open No. 2012-168241 discuss systems for detecting change in capacitance between a plurality of electrodes disposed in a process cartridge, and notifying a remaining toner amount. In the system in Japanese Patent Application Laid-Open No. 2003-248371, a developer bearing member is used as an input side electrode, and a capacitance detection member is used as an output side electrode. The capacitance detection member is disposed to face the developer bearing member in the development device, and capacitance is detected by applying an alternating current bias to the developer bearing member. In this structure, the process cartridge is provided with a contact member for electrically connecting the capacitance detection member and a conductive member (hereinafter, referred to as a body side remaining toner amount contact) having spring properties, the conductive member being provided in the image forming apparatus body. The application of the AC bias to the developer bearing member induces an electric current corresponding to the capacitance (remaining toner amount) between the developer bearing member and the capacitance detection member. The current value is measured, through the contact member provided at the process cartridge side, and the body side toner remaining contact, by the remaining toner amount detection unit of the image forming apparatus body and thereby the remaining toner amount can be sequentially detected.

Developer container, development device, process cartridge, and image forming apparatus


A method for producing an oxide superconductor by partially melting and solidifying the precursor of the oxide superconductor is a method wherein the precursor is placed on a substrate material containing pure metal or a compound which is meltable in the precursor when the precursor is in a partially molten state, and partially melting and solidifying the precursor in said state.

When a large, bulk-shaped oxide superconductor having a diameter of several tens of millimeters or more is solidified by slow-cooling from a partially molten state to promote crystal growth, for example, methods like that described below are generally employed. One example thereof is that a bulk-shaped precursor of an oxide superconductor is formed, and then it is supported by a rod-shaped material, a substrate or a sheet-shaped material which is placed below the precursor and is composed of a heat-resistant material such as Al2O3, YSZ (yttrium stabilized zirconia) or MgO. Alternatively, a method is employed in which a mixed powder of a superconducting powder having the composition of YBa2Cu3O7-x (so-called Y123 powder) and an oxide powder having the composition of Y2BaCuO5 (so-called Y211 powder), or a mixed powder of a superconducting powder having the composition of YbBa2Cu3O7-x (so-called Yb123 powder) and an oxide powder having the composition of Yb2BaCuO5 (so-called Yb211 powder), which has a peritectic temperature equal to a peritectic temperature of a precursor of a superconductor or lower, is placed on a metal mount or the like.
When a precursor of an oxide superconductor is placed directly on a support member such as a dish or crucible composed of a heat-resistant material such as platinum or Al2O3 (alumina) and heated to a temperature at which the precursor is partially molten, the precursor in the partially molten state reacts with materials comprised in the heat-resistant material and adheres to the dish or crucible. When the precursor is solidified, the precursor is subjected to large stress due to the difference in thermal expansion coefficient between the precursor and the dish or crucible, resulting in the formation of cracks which are undesirable for an oxide superconductor. The aforementioned general methods are used to avoid these problems.
Namely, in the aforementioned methods, the precursor in partially molten and solidified state is supported with a support member wherein the composition thereof is as close as possible to the composition of the oxide superconductor. As a result, stress loading caused by the difference in thermal expansion coefficient when the precursor is solidified, is reduced, and crack formation is prevented as much as possible in the oxide superconductor obtained with these methods.
In addition, as described in Japanese Unexamined Patent Application, First Publication No. Hei 5-229820, a technology is provided in which a precursor in a partially molten state is supported by floating on molten silver in a metal dish, and then the precursor is solidified from this partially molten state. Here, the silver hardly reacts with an oxide superconductor. It is described in the document that, due to the above characteristic, the resulting oxide superconductor can be easily removed from a solid of the silver after a melting and solidifying the precursor.
However, in the previously described methods using the rod-shaped material, a substrate or a mixed powder which consists of a material having a composition which is similar to the composition of the oxide superconductor, there was still the problem of susceptibility to formation of cracks by reason explained below, although the risk of crack formation is lower than the method using a support member such as a dish or crucible composed of platinum or Al2O3 (alumina).
Here, when considering the partially molten state of an oxide superconductor, a superconductor powder having the composition of YBa2Cu3O7-x decomposes at the peritectic temperature or higher as in the manner of the following formula (I).2YBa2Cu3O7-x (Y123)=Y2BaCuO5 (Y211)+L(3BaCuO2+2CuO)  (I)
In this formula (I), L represents a liquid phase. X represents the amount of oxygen deficiency in the lattice thereof.
The superconductor in the partially molten state has a liquid phase. Accordingly, when the supporting methods of the prior art are used, problems are thought to occur such that deformation of a lower portion of a precursor in the partially molten state is caused due to its weight when the precursor supported by several rod-like support members is softened, or the bottom of the precursor adheres to the support member as a result of a reaction between the precursor and the support member, or the like. In addition, in the methods in which an oxide superconductor is supported by a support member or mixed powder which has a composition similar to that of the oxide superconductor, a solidified portion (portions in which a reaction has proceeded spontaneously) forms easily that consists of a composite oxide having a composition that contains rare earth elements, and a subtle difference in the coefficients of thermal expansion between the solidified portion and an oxide superconductor which is surrounding the solidified portion is easily formed. In actuality, the inventors of the present invention obtained experimental results demonstrating that cracks form easily in the vicinity of the interface between the aforementioned solidified portion composed from composite oxide (portions in which a reaction has proceeded spontaneously) and the oxide superconductor portion which is surrounding the solidified portion, when this type of oxide superconductor was attempted to be produced by a partial melting and solidification method wherein solidification is conducted from a partially molten state. Here, in the present invention, "partially molten" state means a state in which the 123 phase is melted, while the 211 phase remains in the solid phase and is dispersed in the molten 123 phase.
Among the various types of oxide superconductors, RE-Ba—Cu—O based oxide superconductors (where RE contains a rare earth element) have a high critical temperature and are widely known.
In this type of oxide superconductors, an oxide superconductor wherein Y is used as a rare earth element thereof and the composition thereof is YBa2Cu3O7-x is considered that it has a low risk of crack propagation throughout entire bulk of the oxide superconductor, even if fine cracks are partially formed, when the bulk of the oxide superconductor is produced by a partial melting and solidification method. In actuality, a bulk of a Y—Ba—Cu—O based superconductor has been produced having a high critical current density and a diameter of about 100 mm.
However, for example, in the case of an oxide superconductor in which Nd is used as the rare earth element, when fine cracks are formed, the cracks easily propagate throughout the oxide superconductor. Accordingly, if partial cracks form in the oxide superconductor, the cracks propagate throughout the oxide superconductor and break the oxide superconductor, or the oxide superconductor tends to have remarkably low superconductivity characteristics and large cracks penetrating through the entire superconductor. For example, when a Nd based bulk having superior superconductivity characteristics is produced using the partial melting and solidification method, a current production limit is a production of a bulk having a diameter of about 30 mm. However, such a bulk having the diameter is unable to be produced at satisfactory yield due to the presence of cracks.
It is understood from documents describe below regarding the difficulty in obtaining large, bulk-shaped oxide superconductors that are free of cracks and other defects, that "As the size of bulk materials made to undergo crystal growth becomes larger, the length of time required for crystal growth increases. As a result, prolonged heat treatment is conducted in the partial molten state, and compositional variations and the like are caused due to a loss in liquid phase components, or contamination caused from materials contained in the substrate or the like, thereby making it difficult to obtain high-quality crystals." Examples of these documents include a document published by D. A. Cardwell entitled "Processing, microstructure and characterization of artificial joint in top seeded melt grown Y—Ba—Cu—O" in "Institute of Physics Publishing Superconductor Science and Technology, 15 (2002) 639-647", a document published by Lihua Chen entitled "Joining of melt-textured YBCO: A direct contact method" in "Institute of Physics Publishing Superconductor Science and Technology, 15 (2002) 672-674", and a document described by Naomichi Sakai, et al. entitled "Microgravity Superconductor Production Project" in "Cryogenics, 34, 11 (1999) p. 563".
In consideration of the aforementioned problems, an object of the present invention is to provide a technology which enables a production of a large, bulk-shaped oxide superconductor that is free of defects, wherein cracks which are caused by a difference in the coefficients of thermal expansion between an oxide superconductor and a support member are not formed when a production of an oxide superconductor is carried out using a partial melting and solidification methods.
Another object of the present invention is to provide a preferable substrate material for supporting a precursor of an oxide superconductor, which is usable for producing a large, bulk-shaped oxide superconductor free from cracks by using a partial melting and solidification method.
In addition, another object of the present invention is to provide a large, bulk-shaped oxide superconductor free from cracks by using a partial melting and solidification method.
Moreover, another object of the present invention is to provide a technology that enables a production of a bulk-shaped Nd based oxide superconductor having a diameter of about 30 mm or more, which is currently the largest size in the world.

Method for producing oxide superconductor, oxide superconductor and substrate material for supporting precursor of the same


An overload protective circuit breaker switch including: a first fixed contact and a second fixed contact adapted to connect an electric appliance to power supply; a movable contact adapted to form with the first fixed contact and the second fixed contact a normal open contact; an actuator controlled by the user to turn about an axis; a lever coupled to and turned with the actuator, the lever being turned about a first bearing point, when the overload protective circuit breaker switch is not at an overload status, to move the movable contact between a normal open contact position in which the movable contact form with the first fixed contact and the second fixed contact a normal open contact, and a normal close contact position in which the movable contact form with the first fixed contact and the second fixed contact a normal close contact; and a release mechanism adapted to move the lever, the release mechanism releasing the lever from the first bearing point to a second bearing point upon an overload, causing the lever to release the movable contact and to let the movable contact return to the normal open contact status.

The present invention relates to an overload protective circuit breaker switch, and more particularly to such an overload protective circuit breaker switch that is specifically designed for use in a small electric appliance to automatically cut off power supply in case of an overload.
Using a fuse or fuseless circuit breaker to protect an electric appliance against overload has been well known. Various circuit breaker means have been disclosed. Exemplars are seen in U.S. Pat. No. 5,223,813, entitled "Circuit breaker rocker actuator switch"; U.S. Pat. Nos. 4,528,538; 4,833,439, etc. These disclosures teach the installation of circuit breaker means with bimetal contact means which automatically cuts off power supply in case of an overload or overcurrent. These circuit breaker means are functional, however they are complicated in structure.

Overload protective circuit breaker switch


An algorithm executed in an implantable cardiac rhythm management device (CRMD) automatically adjusts the time that an atrial pace (AP) and/or a ventricular pace (VP) pulse is generated by a pulse generator when the expected time of occurrence of the AP pulse falls within a predetermined interval referred to as the “lowest tachy zone”. By delaying the generation of the AP pulse until outside of the lowest tachy zone, undersensing of ventricular tachycardia depolarizations due to cross-channel refractory and VP refractory is avoided.

I. Field of the Invention
This invention relates generally to cardiac rhythm management devices, and more particularly to a method and apparatus for avoiding undersensing of episodes of tachycardia due to brady/tachy crossover in the device.
II. Discussion of the Prior Art
Many rate enhancements found in state-of-art multi-chamber pacemakers and pacemaker/defibrillators may cause the device to pace the heart at rates in the excess of a programmed Lower Rate Limit (LRL). For example, features now commonly found in CRMDs, such as rate smoothing, rate adaption, ventricular rate regulation, etc., may cause the device to generate pace pulses faster than the programmed LRL and as fast as a programmed Upper Rate Limit (URL). For devices that detect and/or treat tachyarrhythmias, it often happens that the heart rate due to the tachycardia episode and the programmed URL share a common range of heart rate. That is, at rates near or at the URL, the atrial pace can be inside the lowest tachy zone (LTZ) as a condition referred to as "brady/tachy cross-over".
For situations of brady/tachy crossover, if the CRMD is pacing the heart at a fast rate when a ventricular tachyarrhythmia occurs, then detection and possible treatment of the tachyarrhythmia is often delayed or sometimes completely inhibited due to undersensing of the tachyarrhythmia caused by ventricular sense channel refractory periods initiated by atrial pacing.
In accordance with the present invention, a pacing mode switch algorithm is implemented in the software/firmware of the microprocessor-based controller used in implementing the CRMD that addresses incidences of brady/tachy crossover whereby undersensing of the tachyarrhythmia due to ventricular sensed channel refractory periods initiated by atrial pacing is avoided. The algorithm operates such that whenever the device is scheduled to deliver an atrial pace pulse at an interval relative to the previous ventricular sense or pace that is shorter than the longest known interval of the tachyarrhythmia, the device delays generation of the atrial pace pulse. The next scheduled ventricular pace pulse would still be delivered so long as it is not inhibited by a ventricular sensed event.
The mode switch is only applied on those cardiac cycles where the V-to-A pace interval is shorter than a programmed ventricular tachycardia interval referred to as the "lowest tachy zone". The algorithm of the present invention also helps reduce undersensing of atrial arrhythmias due to atrial sensed channel refractory periods that are initiated by atrial pacing, although it will not eliminate that phenomenon entirely.

Dynamic mode switch for early detection of tachyarrhythmia


A fluid control valve includes a valve housing having an inlet and an outlet. A metering plug is located within the valve housing, and is configured to move linearly within the valve housing along a valve axis between an open position to allow fluid flow between the inlet and the outlet, and a closed position to block fluid flow between the inlet and the outlet. A reference plane is oriented perpendicular to the valve axis. The metering plug includes a nose portion having a sensing port in fluid communication with fluid flow at the outlet. The sensing port is oriented perpendicular to the valve axis and generally parallel to the reference plane.

A plug valve, particularly a contoured plug valve, may require a high actuation force to move the valve because of the fluid pressure acting on an end face of the valve. It is known that high actuation forces may lower the dynamic response of the valve. Therefore, the plug valve may include a passageway that is drilled from the nose of the valve to an internal cavity of the valve. Pressure in this internal cavity generates a pressure force on a shoulder of the valve that urges the valve in one direction and, therefore, counteracts the force of the fluid acting on the end face of the valve, which tends to urge the valve in an opposite direction.
By reducing the actuation force, a valve used in high performance applications such as, for example, a valve used for turbine fuel metering, may be actuated with a relatively inexpensive, fast acting electric actuator having a high dynamic response.


The present prevention provides an effective, fast acting method of vaccination useful in suppressing gonadotropic hormone release. The vaccine utilizes LHRH conjugated at its amino terminus to a protein carrier and can be mixed with either adjuvants or detergents in order to provide an effect vaccine.

The possibility of developing an antifertility vaccine for male mammals based on active immunization against Luteinizing Hormone Releasing Hormone (LHRH) is currently under investigation in several laboratories. These studies are based on the findings that antibodies against LHRH prevent gonadotropin release. Prevention of gonadotropin release causes regression of Leydig cells and suppression of testosterone production and spermatogenesis with subsequent infertility. See e.g. Fraser et al., "Effect of Active Immunization to Luteinizing Hormone Releasing Hormone on Serum and Pituitary Gonadotropins, Tests and Accessory Sex Organs in Male Rat", J. Endocrinol., 63:399-405 (1974); Fraser et al., "LHRH Antibodies: Their Use in the Study of Hypothalamic LHRH and Testicular LHRH-like Material, and Possible Contraceptive Applications", In: Sandlet, ed Progress Toward a Male Contraceptive. New York, John Wiley, (1982) pp. 41-78.
Production of anti-LHRH antibodies would also be useful to treat certain forms of cancer such as prostate cancer where such therapy could replace orchiectomy or LHRH analogue treatment.
Recurrent or metastatic cancer of the prostate is a major cause of cancer mortality in the United States with more than 25,000 deaths occurring annually because of this malignancy. Silverberg and Lubera, "Cancer Statistics", CA 38:1-19 (1988). It is the most common malignancy in men older than 70. Carcinoma within the prostate is a common finding at autopsy, being found in 20-40% of men between 70-79 years of age. Unfortunately, approximately one third of all prostate cancers are diagnosed only after the patient has clinically apparent disseminated disease with bone or visceral metastases outside the pelvis.
For patients with disseminated disease at the time of diagnosis the classical treatment is surgical orchiectomy. Huggins and Hodges, "Studies of Prostatic Cancer. Effect of Castration, Estrogen, and Androgen Injection of Serum Phosphatases in Metastatic Carcinoma of the Prostate", Cancer Res., 1:293-297 ( 1941 ). This procedure decreases serum testosterone levels by 95% and causes objective tumor regression in approximately 40% of cases and disease stabilization in an additional 40% of cases. Alternative strategies to surgical orchiectomy include treatment with diethylstilbestrol (DES) or with LHRH analogues. These strategies also seem to work by decreasing serum testosterone levels, and have similar response rates to those seen with orchiectomy. Results of first line single agent hormonal manipulations are favorable but average response durations are less than one year and actuarial survival less than 2 years. Seftel et al., "Hormonal Therapy for Advanced Prostatic Carcinoma", J. Surg. Onc. Suppl., 1: 14-20 ( 1989 ).
Recent results have suggested that the addition of an anti-androgen to initial orchiectomy or an LHRH antagonist may improve response rates. Using combined androgen blockade in patients with stage D2 prostate cancer, Labtie initially reported a 90% survival rate at 2 years. When this therapy was tested in a Canadian double-blinded randomized trial, the results still statistically significantly favored combined therapy although the improvement in survival was less striking (52% survival at 18 months with simple orchiectomy versus 66% survival with combined therapy). Beland et al., "Total Androgen Blockade for Metastatic Cancer of the Prostate", Am. J. Clin. Onc., 11 (Suppl. 2):S18714 S190 (1988) This modest but statistically significant improvement in survival provided by combined therapy was also seen in an American randomized study. Thus the optimal therapy for cancer of the prostate at this time seems to be a combination of orchiectomy and therapy that blocks peripheral androgen action.
Current therapies for the suppression of androgen production are not universally acceptable to all patients. Orchiectomy is psychologically unacceptable to many patients. The user of LHRH analogues is dependent on repetitive application of the analogue and involves long term inconvenience and expense. Use of estrogens such as DES is generally considered inferior to the other two treatment modalities due to cardiovascular complications and side effects such as gynecomastia.
Immunization against LHRH has been proposed as an alternative anti-neoplastic strategy for sex steroid dependent tumors. Raydin and Jordan, "Active Immunization to Luteinizing Hormone to Inhibit the Induction of Mammary Tumors in the Rat", Life Sci., 43:117-123 (1988). This strategy has been shown to be effective in animal models, and depends on the immunoneutralization of LHRH after active immunization of the host. This blockade of LHRH causes decreased production of gonadotropins and then secondarily decreased sex steroid production by the ovaries or testes. It would be of great significance in the treatment of this disease to have a LHRH vaccine capable of rapidly stimulating production of high titers of anti-LHRH antibodies.
The availability of synthetic LHRH has provided anti-LHRH antisera, needed for development of radioimmunoassays and immunocytochemistry. Unfortunately, the use of synthetic LHRH in humans to induce production of anti-LHRH antibodies is precluded by the necessity of using adjuvants not suitable for use in humans in order to achieve an effective titer within an acceptable time period. In the majority of the reported experiments, Freund's complete adjuvant (FCA) was used as an immune enhancer to obtain anti-LHRH antisera. Chappel et al., "Active Immunization of Male Rhesus Monkeys Against Luteinizing Hormone Releasing Hormone", Biol. Reprod., 22:333-342 (1974); Fraser et al., "Preparation of Antisera to Luteinizing Hormone Releasing Factor", J. Endocrinol , 61:756-769 (1974); and Awoniyi et al., "Changes in Testicular Morphology in Boars Actively Immunized Against Gonadotropin Hormone-Releasing Hormone", J. Androl., 9:160-171 (1988).
In developing vaccines for man, only materials permitted for use in humans can be utilized. This criterion eliminates FCA, the most potent immune enhancer. Thus other methods of inducing highly effective anti-LHRH antibody in the shortest possible time are necessary to enable anti-LHRH production in man. Steblay, "Glomerulonephritis Induced in Sheep By Injections of Heterologous Glomerular Basement Membrane and Freund's Complete Adjuvant", Exp. Med., 116:253-172 (1962); Thau et al., "Effects of Immunization with the 8-Subunit of Ovine Luteinizing Hormone on Corpus Luteum Function in the Rhesus Monkey", Fertil. Steril., 31:200-204 (1979); and Dalsgaard, "Adjuvants", Vet. Immunol. Immunopathol., 17:145-152 (1987).
The studies described below were designed to examine the ability of LHRH conjugated to tetanus toxoid (TT) either at the N-terminal, C-terminal, or mid-section of the LHRH to induce biologically effective antibodies in the shortest possible time.
It has now been shown that conjugating a protein carrier to LHRH enhances immunogenicity in a site specific manner. Carriers such as TT and purified protein derivative (PPD, derived from tuberculin) which are suitable for use in man and have been shown to stimulate the immune response are useful as the protein carrier. Fraser et al., (1982); Shastri et al., (1981); Talwar, "Immunobiology of Gonadotropin-Releasing Hormone", J. Steroid Biochem., 23: 795-800 ( 1985 ); and Ellouz et al., "Minimal Structural Requirements for Adjuvant Activity of Bacterial Peptidoglycan Derivative", Biochem. and Biophys. Res. Comm.,59:1317-1325 (1974).

[Gln']-luteinizing hormone releasing hormone conjugate of tetanus vaccine and its uses


A semiconductor device package such a as Ball Grid Array (BGA), includes a die attached to a substrate. The substrate has a series of plated through holes (PTH) that include a copper pad at each of their ends. The PTH are located in a mold gate region at a corner of the substrate beyond the periphery of the die. Each PTH contains a rivet. The PTH with the pads and rivets stabilize the substrate at the mold gate region, which reduces the possibility of substrate delamination upon degating following an encapsulation process.

The present invention relates to semiconductor device manufacturing and packaging and more particularly to delamination-resistant array type packages and their method of manufacture.
One type of known semiconductor package includes a multi-layer circuit board comprising a core and one or more dielectric layers, conducting layers and pads. A semiconductor die may be flip-chip connected to external conductive layers of the board with solder balls. Vias (small openings) are made in the dielectric layers to allow conductive connections between layers and typically comprise two pads on different layers of the board that are electrically connected by a drilled hole. The hole is made conducting by electroplating or by it lining with a conducting tube or a rivet. A so-called "plated through hole" (PTH) typically provides vertical connections through the core to the conductive layers of the circuit board. Plated through holes are drilled using lasers or a mechanical drill.
A known array type manufacture of multiple devices is used on BGA (Ball Grid Array) packages where a plurality of dies is disposed on a substrate in the arrangement of a matrix array. The substrate may be a copper clad glass fiber laminate. The dies are connected to signal terminals of the substrate by wirebonds and then the dies are encapsulated in a protective coating using a molding process. In the molding process, a plurality of substrates with the dies is placed between upper and lower molds. When the upper and lower molds are combined, gaps between the two molds and the die substrates are reserved as runners and gates. Colloidal particles are placed at the center of the mold which are subsequently melted to produce a compound flow which is injected into the mold cavities through the runners and gates so as to cover the dies. FIG. 1 shows two die substrates 100 (in plan view) on completion of the molding process. FIG. 2 shows an end view of the substrates and dies. Sealing compound regions 101 (covering the individual dies), runner regions 102, mold gate regions 103, and a residue 104 are formed after the compound flow is cured. The runner regions 102, the mold gates 103 and the residue 104 comprise a cull which needs to be stripped by a degating process. In a typical degating process, a plunger exerts a force on the residue 104 which results in the cull breaking away. A problem of the degating process is delamination of the substrate at the regions of the mold gates 103. For instance, an outer copper layer of the substrate may stick to the mold gate region and peel way on degating, leaving fibers of the substrate exposed. Delamination can even occur when the mold gate region of the substrate has been gold plated in an attempt to aid mold gate release. Delamination is undesirable as it can lead to moisture ingress into the package with a resulting degradation of performance or even failure of the packaged semiconductor device.
Thus it would be advantageous to provide a package which is less susceptible to delamination on degating.

Semiconductor device with plated through holes


An intelligent framework is provided that is disposed between a high-level language environment and a database system environment. According to one embodiment, the framework programmatically receives information regarding definitions of data structures of objects participating in a software application and information regarding relationships among the objects. Based upon the particular request from the high-level language environment and upon the definitions and relationships, the framework programmatically and dynamically generates appropriate statements associated with the database system environment that accomplish the request. For example, the framework may issue statements to define the structure of a database, access information from the database, and/or manipulate information within the database.

1. Field of Invention
Embodiments of the present invention generally relate to design and implementation of database applications. More particularly, embodiments of the present invention relate to methods and techniques of programmatically managing the creation of database structure, populating the database structure, and accessing and/or manipulating data stored in a database.
2. Description of the Related Art
Development of database applications currently involves two distinct skill sets typically requiring the involvement of both database engineers and software engineers. An example of current database modeling activities may include the following: (1) One or more database engineers capture the requirements of the database application in an entity relationship diagram (ERD); (2) manually or with the assistance of a database tool, such as Oracle9i Designer of Oracle Corporation, the database engineer(s) create an appropriate database schema to support the relationships presented by the ERD; (3) the database engineer(s) convey the requirements of the database application to one or more software engineers; (4) the software engineer(s) capture the requirements in an appropriate form, such as uniform modeling language (UML) diagrams, for development of needed data structures, e.g., class definitions; and (5) the software engineer(s) create the data structures. Other tasks, such as provisioning and providing for access and manipulation of the database typically require similar interactions among the database engineers and the software engineers.
As can be appreciated, a software development team composed of both database engineers and software engineers implementing the above database modeling process is costly both in terms of communication overhead and payroll. Consequently, a need exists to reduce the complexity of and/or automate database design and development tasks thereby allowing application developers with limited or no database skills to efficiently and effectively perform such tasks.

Software framework that facilitates design and implementation of database applications


A transparent adhesive unit for a touch screen is provided. The transparent adhesive unit includes a transparent film, a noise-blocking layer located on a first surface of the transparent film and formed of a conductive material, a first adhesive layer located on a surface of the noise-blocking layer, and a second adhesive layer located on a second surface of the transparent film, in which the second surface is positioned in opposition to the first surface.

1. Field of the Invention
The present invention relates to a touch screen. More particularly, the present invention relates to a capacitive type touch screen.
2. Description of the Related Art
Generally, the term "touch screen" refers to a device in which an input detection means is integrated with a display means. The touch screen may include a display unit, such as a Liquid Crystal Display (LCD), and a touch panel disposed on the display unit.
When a person's finger tip or an object touches a character or a particular position on a touch screen, the touch screen recognizes the touch position, thus receiving a user's input through the screen touch, without the use of a keypad.
Despite its low precision, the implementation of a touch screen eliminates the need for a keypad while increasing the ease of use of a device. Thus, the touch screen is often used as a display device in public places, that is, a subway, a department, a bank, etc., and is also widely used for commercial terminals in various shops. Recently, the touch screen has been used for portable terminals such as a cellular phone, a Digital Multimedia Broadcasting (DMB) receiver, a vehicle navigation, and so forth.
Types of a touch panel (or touch screen) may include a resistive type, a capacitive type, a surface acoustic wave type, an infrared beam type, and so forth.
In a typical touch panel of a capacitive type, a first electrode line and a second electrode line are respectively formed on a first film and a second film, and the first electrode line and the second electrode line are electrically connected with a controller through connection terminals. The controller senses a change in capacitance of a corresponding touch region of the touch panel, caused by a touch with an input means (e.g., a finger, a stylus pen, or the like), and determines a position of the touch region.
However, as the thickness of a portable terminal having the touch screen mounted thereon tends to be reduced and a distance between the touch panel and the display unit also tends to decrease, noise (e.g., electromagnetic waves) from the display unit causes malfunction of the touch panel.
Moreover, the conventional capacitive touch screen has a large thickness and a low transmissivity because of having a plurality of films.
That is, the conventional capacitive touch screen, because of having a plurality of films, has a large thickness and a low transmissivity, such that visibility of the screen degrades and reduction in the size of a product becomes difficult to achieve.

Transparent adhesive unit and touch screen having the same


The present invention provides simple and inexpensive assays for the detection of virtually any analyte in any sample that is in liquid form or that can be solubilized. The assays utilize the fluid dynamics of drop evaporation whereby soluble materials, including analytes and particles binding thereto, are drawn to the edge of the drop and ultimately form a concentrated residual ring. The presence or absence of certain reagents can then be detected through a number of different approaches.

I. Field of the Invention
The present invention relates to the fields of biology and diagnostics. More specifically, the invention deals with "drop"-based technologies that permit simple, fast and accurate detection of most any analyte in environmental, plant, medical and other samples.
II. Related Art
A major stumbling block to low resource and/or home diagnostics is simplicity of design. Complex designs drive up the cost of manufacturing and limit distribution. But even clearing this hurdle is no guarantee, since complex designs also fail with improper use by those unskilled in their principles of operation. Thus, a diagnostic design that is inexpensive to manufacture, is simple to operate and can be readily interpreted by the unskilled end-user at home would be highly desirable. The desperate need for such an assay is well-demonstrated by the continuing health management issues surrounding malarial infections, with 250 million cases of malaria being reported in 2006, and having with a mortality rate of 881,000 individuals (FIG. 1) (WHO, 2006)
Traditionally, the "gold standard" for malarial detection has been microscopic examination of thick and/or thin blood films, where an experienced microscopist counts the number of parasites found per unit volume of blood (Warhurst & Williams, 1996). Other methods have also been developed, including fluorescence staining (Gay et al., 1996; Cooke et al., 1992; Srinivasan et al., 2000), amperometric immunosensing (Sharma et al., 2008), and single and multiplexed PCR techniques (Snounou et al., 1993). Recently, a new strategy using an enzyme-linked immunosorbent assay (ELISA) has been reported that detects the presence Histidine-Rich Protein 2 (pfHRP2), which is found specifically in P. falciparum induced malarial infection (Kifude et al., 2008; Martin et al., 2009). Although all of these techniques have limits of detection of <100 parasites/μl, they are limited primarily to the laboratory due to their sensitivity to environmental changes, requirements for specialized reagents, slow developing time, and reliance on sophisticated equipment for an interpretable readout. This is problematic since a majority of malarial infections occur in regions where advanced scientific technology and personnel are not readily available. Therefore, diagnostic strategies that are simple to use and require reagents and equipment that are easy to transport and stable in a variety of environmental conditions must be developed.
To circumvent these challenges, rapid diagnostic tests (RDTs) have been developed over the last two decades (Moody, 2002; Quintana et al., 1998; Singh et al., 2000). Although these techniques have performed well in laboratory testing, show high sensitivity, and acceptable limits of detection (<100 parasites/μL), these techniques have not performed well when subjected to variable temperature and humidity conditions due to their reliance on antibodies with small stability ranges (Ochola et al., 2006). In addition, there have been reports that mutations of pfHRP2 found in the Asia-Pacific region reduce the sensitivity of antigen detection due to the antibodies high specificity in the RDTs (Baker et al., 2005). Thus, even further improved and more effective diagnostic assays are needed.


A method of manufacturing a multi-layer board is disclosed. The method may include forming a detachable separation layer over a support; forming a first solder resist layer over the separation layer; stacking a metal foil over the first solder resist layer; forming a circuit pattern over the metal foil; forming an insulation part over the first solder resist layer such that the circuit pattern is covered; forming a second solder resist layer over the insulation part; and separating a circuit stack unit, which includes the first solder resist layer, the metal foil, the circuit pattern, the insulation part, and the second solder resist layer, from the support by disconnecting the separation layer and the support. This method uses a simple process to reduce manufacture costs and shorten manufacture times.

1. Technical Field
The present invention relates to a multi-layer board and a method of manufacturing a multi-layer board.
2. Description of the Related Art
In accordance with the trends towards compact sizes in current electronic products, the parts included in the electronic products are also being fabricated in smaller sizes. This in turn may require smaller sizes in the packages mounted with component chips, as well as thinner substrates for the packages. A small thickness in the substrate is also important in terms of minimizing loop inductance, which depends on the physical distances within a circuit. The need to develop a multi-layer circuit board for use in thin, minute semiconductor devices is continuously increasing, especially in the field of semiconductors, where miniaturization is of critical importance.
However, the thin multi-layer circuit board currently under development may entail a complicated manufacturing process and high production costs, while the finished product may not provide high levels of reliability.

Method of manufacturing a multi-layer board


Methods and apparatuses for removing contaminants. A plurality of injection wells are drilled through the vadose zone to a depth below the water table defining the upper boundary of the aquifer. A plurality of venting wells or venting laterals are established to a depth above the water table sufficient to discourage fouling by contaminated water or condensate, and oxygenated gas is injected under pressure through the injection wells. Additional biochemical cleansing may occur at ground level prior to venting of contaminated air. Microbes natural to the contaminated site may be extracted, analyzed, fermented, and reintroduced to enhance biodegradation, and nutrients, food, or both, may be supplied to the microbial population to sustain high levels of degradation activity. Relatively pure liquid contaminant may be separated from other fluids, such as water.

Field of the Invention (Technical Field)
The present invention relates generally to methods and apparatuses for in situ remediation of organic contaminants, such as hydrocarbons, and inorganic contaminants, such as metals, from subsurface soil and ground water. In situ remediation of excavated materials and surface spills of liquid contaminants also may be conducted utilizing the present invention.

Contaminant remediation, biodegradation and removel methods and apparatus

Environmental Improvement Technologies, Inc.


Methods of determining which kinematic model an autonomous vehicle (AV) should use to predict motion of a detected moving actor are disclosed. One or more sensors of the AV sensors will detect a moving actor. The AV will assign one or more probable classes to the actor, and it will process the information to determine a kinematic state of the actor. The system will query a library of kinematic models to return one or more kinematic models that are associated with each of the probable classes. The system will apply each of the returned kinematic models to predict trajectories of the actor. The system will then evaluate each of the forecasted trajectories of the actor against the kinematic state of the actor to select one of the returned kinematic models to predict a path for the actor. The system will then use the predicted path to plan motion of the AV.

Autonomous vehicle (AV) control systems rely on a complex system of sensors to detect, classify, and predict actions of other movers in the environment. Whether the AV is fully autonomous or semi-autonomous, the vehicle's autonomous functions will consider the likely trajectories of other actors when planning a path for the vehicle and/or initiating a reactive measure in response to the other actor.
To predict the trajectory of another actor, the AV will select a kinematic model that is appropriate for the other actor. Kinematic chain motion models, commonly referred to simply as kinematic models, are mathematical models that describe the motion of objects, regardless of force. The AV can use a kinematic model to predict the actor's position and orientation over time in view of various parameters.
An AV will store various kinematic models in its onboard or remotely accessible memory, and each model will be associated with one or more different classes of actors. For example, a kinematic model for a pedestrian will typically be different from the model for a bicyclist, which will typically be different from the model for a sedan, which will typically be different from the model for a tractor-trailer, etc. When the AV perceives an actor, it will classify the actor, and it will then use the classification to select the appropriate kinematic model that the AV will apply to predict the actor's motion. However, there may be times in when a particular actor could fall within two or more classifications. For example: a person who is walking a bicycle could be classified as a pedestrian or a cyclist; a person on roller skates be classified as a pedestrian or as something else such as a scooter operator, skateboarder or cyclist. If the AV does not select the appropriate kinematic model for a particular actor, the AV's ability to forecast that actor's motion will be less reliable.
This document describes methods and systems that are directed to addressing the problems described above, and/or other issues.

Method and system for determining a mover model for motion forecasting in autonomous vehicle control


The present disclosure relates to car seat control assembly having a car seat control module installable in a motor car seat and a cable set for components of the seat. The car seat control module is non-separably connected with the cables of the cable set. Each of the respective cables has a plug connector for connection to the component associated with the cable on a terminal end opposite the car seat control module. In this arrangement, the assembly requires minimal packaging space enabling the arrangement to be installed in the motor car seat in a quick and simple manner, for a secure connection between car seat control module and components of the seat.

An arrangement for a car seat control module installable in a motor car seat and a cable set for components of the seat is known from practice. With this arrangement the cables of the cable set are connected with the car seat control module via plug connectors, and the cables are further connected with the components of the car seat via plug connectors in the area of their ends facing away from the car seat control module.


A liquid in which fine solid Sn particles are dispersed in a resin is accommodated inside the heated tank 4. The resin pressurized by a pressurizing pump is conducted to a nozzle 1, so that a liquid-form resin is caused to jet from the tip end of the nozzle 1 that is disposed inside a vacuum chamber 7. The liquid-form resin which is caused to jet from the nozzle 1 assumes a spherical shape as a result of surface tension, and is solidified by being cooled in a vacuum, so that a solid-form target 2 is formed. A laser introduction window 10 used for the introduction of laser light is formed in the vacuum chamber 7, and laser light generated from a laser light source 8 disposed on the outside of the vacuum chamber 7 is focused by a lens 9 and conducted into the vacuum chamber 7, so that the target is converted into a plasma, thus generating EUV light.

As the degree of integration of semiconductor integrated circuits has increased, circuit patterns have become finer, and the resolution has become insufficient in the case of conventionally used exposure apparatuses utilizing visible light or ultraviolet light. As is universally known, the resolution of an exposure apparatus is proportional to the numerical aperture (NA) of the transfer optical system, and is inversely proportional to the wavelength of the light that is used for exposure. Accordingly, as one means of increasing the resolution, there have been attempts to use a short-wavelength EUV light source (also called a "soft X-ray" light source) for exposure and transfer instead of visible light or ultraviolet light.
Light sources that are considered to be especially promising as EUV light generating devices used in such exposure and transfer apparatuses are laser plasma EUV light sources (these may be referred to below as "LPP (laser produced plasma)") and discharge plasma EUV light sources.
In LPP, pulsed laser light is focused on a target material inside a vacuum vessel so that this target material is converted into a plasma, and the EUV light that is radiated from this plasma is utilized. Such devices have a brightness comparable to that of an undulator, while at the same time being compact.
Furthermore, EUV light sources using a discharge plasma such as dense plasma focus (DPF) are compact, produce a large amount of EUV light, and are inexpensive. In recent years, these light sources have attracted attention as light sources for EUV exposure apparatuses using EUV light with a wavelength of 13.5 nm.
An outline of such an EUV exposure apparatus is shown in FIG. 6. In this figure, IR1 through IR4 are reflective mirrors of an illumination optical system, and PR1 through PR4 are reflective mirrors of a projection optical system. W is a wafer, and M is a mask.
Laser light emitted from a laser light source L is focused on a target S, and X-rays are generated from the target S by the plasma phenomenon. These X-rays are reflected by reflective mirrors C and D, and are incident on the illumination optical system as parallel X-rays. Then, the X-rays are successively reflected by the reflective mirrors IR1 through IR4 of the illumination optical system, and illuminate an illuminated region on the mask M. The X-rays reflected by the pattern formed on the mask M are successively reflected by the reflective mirrors PR1 through PR4 of the projection optical system, so that an image of the pattern is focused on the surface of the wafer W.
As EUV light sources with a wavelength of 13.5 nm that is thus used in EUV exposure apparatuses (both laser plasma light sources and discharge plasma light sources), EUV light source utilizing an Xe plasma using Xe gas or liquefied Xe as target substance have been widely researched and developed. The reasons for this are that a relatively high conversion efficiency (ratio of EUV light intensity obtained to input energy) is obtained, and that the problem of debris (scattered particles) tends not to occur since Xe is a gaseous material at ordinary temperatures.
However, in the case of techniques using Xe gas as a target, there are limits to how far a higher output EUV light source can be obtained, so that there is a demand for the use of other substances. In particular, it is known that Sn is effective in obtaining a high conversion efficiency.
However, if Sn is used "as is" as a solid target, the density of the plasma that is generated also becomes too high, so that the exciting laser is absorbed by the generated plasma, or so that the EUV light itself that is generated from the plasma is also absorbed. Accordingly, there is a problem in that the EUV light conversion efficiency cannot be increased as might be thought.
Furthermore, since Sn is a low melting point metal, the following problems are encountered:
(1) In the case of a laser plasma light source, a large amount of debris is generated when the solid Sn target is irradiated with the laser. If the Sn is supplied after being heated and converted into a vapor in order to avoid this problem, the density is reduced, so that a sufficiently high conversion efficiency cannot be obtained. Furthermore, solidification occurs in the low-temperature peripheral areas, so that there is a large amount of adhesion in these areas.(2) In the case of a discharge plasma light source, it is difficult to supply a material in a solid state to the discharge space (the space where the plasma is generated between the electrodes). If the material is supplied after being heated and vaporized, the material solidifies in the peripheral low-temperature areas, so that large amounts of material adhere in these areas.
Accordingly, although it is known that Sn is a high-efficiency material, it has been difficult to use Sn "as is" as a target substance in EUV light sources.

EUV light source, EUV exposure equipment, and semiconductor device manufacturing method


An integrated circuit chip is fabricated as several circuit modules that are synchronized with a clock signal, by the following steps. Initially, a hardware description language is used to describe a functional behavior for a first module on the chip which generates an intermodule signal, and describe a functional behavior for a second module on the chip which processes the intermodule signal. Thereafter, a slow circuit embodiment of the first module is synthesized with port timing constraints which permit the intermodule signal to be generated in twice the cycle time T.sub.CY of the clock signal, and a slow circuit embodiment of the second module is synthesized with port timing constraints which permit the intermodule signal to be processed in twice the cycle time of the clock. Then, a timing analysis program is run on the slow circuit embodiment of the first and second modules to thereby obtain a first delay .DELTA..sub.1 in which the intermodule signal is actually generated, and obtain a second delay .DELTA..sub.2 in which the intermodule signal is actually processed. Subsequently, a fast circuit embodiment of the first module is synthesized which generates the intermodule signal within a delay of (T.sub.CY)(.DELTA..sub.1).div.(.DELTA..sub.1 +.DELTA..sub.2) and a fast circuit embodiment of the second module is synthesized which processes the intermodule signal within a delay of (T.sub.CY)(.DELTA..sub.2).div.(.DELTA..sub.1 +.DELTA..sub.2).

This invention relates to methods for synthesizing an integrated circuit chip as several circuit modules which are synchronized with a clock signal, and which are intercoupled by intermodule signals that are generated and processed in different modules within a single clock cycle.
In the prior art, various hardware description languages have been developed for use in synthesizing integrated circuit chips. One example of such a hardware description language is the language called Verilog. Using such a language, the functional behavior of an integrated circuit chip can be specified by an engineer; and that functional behavior can then be sent as an input to a circuit synthesizer program which in turn generates circuitry on a chip that performs the specified behavior.
With a hardware description language, the functional behavior for an entire chip can be described as a single module. However, as the number of transistors on a chip increases, describing the chip as a single module becomes impractical. Synthesizing a chip as a single module which contains over a million transistors can take several weeks to run. This problem is avoided by partitioning a chip into multiple modules which are synchronized with a clock signal, and by synthesizing each module separately.
However, when the functional behavior of a chip is partitioned into multiple modules, then a new problem inherently occurs. Due to the partitioning, a large number of intermodule signals will arise which are generated in one module and processed in one or more different modules. In a practical chip, thousands of these intermodule signals can exist; and, in order to synthesize the circuitry for any one module, timing constraints must be specified for all ports on which the intermodule signals enter or exit that module.
Since all of the modules in an actual chip together can generate and process thousands of intermodule signals, the task of specifying the timing constraints properly for all of the intermodule ports is horrendous. If the timing constraint for a port is made too small, then the synthesizer program will have to spend too much time trying to synthesize a circuit which meets the constraint; and that adds to the cost of the synthesis. Further, if a port timing constraint is too small, the synthesizer program may not be able to synthesize a circuit which meets the constraint, in which case the synthesizer program will eventually stop trying and simply report the failure.
Also, whenever the timing constraint for a first port on one module is too small, then it follows that the timing constraint for a second port on another module which is connected to the first port will be too large. This large constraint is a problem because synthesizer programs work on meeting the timing constraint of just one port at a time; and they sequentially select the port which has the worst timing constraint violation. Thus, when the timing constraint for the second port is too large, the synthesizer program will never even select the second port and try to speed up the circuitry which connects to it. Instead, the synthesizer program will only try to speed up the circuitry which connects to the first port where the timing constraint is too small. Consequently, the probability that the synthesized circuits will generate and process the intermodule signal on the first and second ports within the cycle time of the clock is greatly reduced.
Accordingly, a primary object of the present invention is to provide a novel method of fabricating an integrated circuit chip by which the above problems are overcome.

Method of synthesizing synchronized circuit modules in an integrated circuit chip


A method for refractive correction of the eye in order to improve the vision of the eye while not adversely affecting its natural asphericity is described. The method involves determining the amount of correction necessary, selecting an intrastromal corneal ring (ICR) of appropriate thickness to obtain the necessary correction from a selection of ICRs of varying thickness, and inserting the ICR into the corneal stroma. The method may be useful for the correction of myopia and excessive astigmatism.

Anomalies in the shape of the eye can cause visual disorders. Hyperopia occurs when the eyeball is too short. In such a case, parallel rays from greater than 20 feet focus behind the retina. Myopia, on the other hand occurs when the eyeball is too long. The focus of parallel rays in this case is in front of the retina. Astigmatism is a condition in which the parallel rays of light do not come to a single point, but rather have a variable focus due to the fact that the cornea is aspherical and refracts light in a different meridian at different distances. Some degree of astigmatism is normal, but where it is too high, it must often be corrected.
Hyperopia, myopia and astigmatism are usually corrected by glasses or contact lenses. Surgical methods for the correction of such disorders have been cited in the literature and include radial keratotomy (see e.g. U.S. Pat. Nos. 4,815,463 and 4,688,570) and laser corneal oblation (see e.g. U.S. Pat. No. 4,941,093). Further, the general method of implanting rings in the corneal stroma to change the curvature of the cornea is known. Previous work involving the implantation of polymethylmethacrylate (PMMA) rings, allograft corneal tissue and hydrogels is well documented. One of the ring devices involves a ring design that allows a split ring to be inserted into a channel dissected in the stromal layer of the cornea using a minimally invasive incision through which the channel for the implant is created and through which the implant is inserted and adjusted. Adjustment of the device normally involves an adjustment of ring size or diameter.
U.S. Pat. No. 4,452,235, which is herein incorporated by reference in its entirety, describes a method and apparatus for corneal curvature adjustment. The method involves inserting one end of a split end adjusting ring into the cornea of the eye and moving the ring in a circular path until its ends meet. The ends are thereafter adjusted relative to each other until the shape of the eye has assumed a desired curvature whereupon the ends are fixedly attached to maintain the desired curvature of the cornea.
The present invention describes a method that allows for the refractive correction of the eye wherein the curvature of the cornea is changed by inserting rings of varying thickness into the corneal stroma.


A semiconductor memory device is disclosed that can be operated in a speed test mode. The memory device includes an array of memory cells capable of storing data, a control circuit receiving a signal from an external system clock and controlling data transfer operations between the memory device and an external data bus, and a test mode circuit receiving the external clock signal. When operated in speed test mode, the control circuit, provides a signal to the test mode circuit enabling its function. A predetermined data pattern is first written to one or more cells, and then subsequently accessed during a read cycle. The enabled test mode circuit compares the contents of an internal data bus to the predetermined data pattern at a time referenced to the system clock signal. In the case of a failed comparison, the test mode circuit produces a signal that places the external data bus in a high impedance state. The disclosed memory device is therefore capable of itself providing some of the test functions previously provided by external testing equipment, and speed testing equipment in particular.

This invention relates generally to electronic devices, and more particularly to memory devices and methods of testing such devices.
Computer designers desire fast and reliable memory devices that will allow them to design fast and reliable computers. Manufacturers of memory devices, such as random access semiconductor memories, must test a full range of functionality and timing characteristics of the memory devices in order to provide a reliable product to their customers. Because each memory cell or bit of the memory device must be tested, the time and equipment necessary for testing memory devices of ever increasing cell number and density represents a significant portion of the overall manufacturing cost of such devices. Any reduction in the time to test each unit will reduce manufacturing costs.
Manufacturers of memory devices increasingly automate the testing procedure in order to save on testing time and cost. Automated testing is most easily accomplished after the memory device has been packaged as a semiconductor chip, because the chip can be inserted into a test socket. Automated testing circuitry then applies predetermined voltages and signals to the chip, writes test data patterns to the memory, reads data, and analyzes the results to detect memory speed, timing, failures, etc. The more chips that can be tested simultaneously, the greater testing time savings per chip.
Still more time can be saved if testing is performed simultaneously with other end-step manufacturing processes. For example, many manufacturers use a xe2x80x9cburn-inxe2x80x9d process to screen out devices that are likely to fail at an unacceptably early time following manufacture. During the burn-in process, memory chips are subject to elevated temperatures and voltages which then accelerate failures in any inherently weaker chips. The ability to automatedly and simultaneously test multiple chips during the burn-in process, rather than afterwards, saves time and reduces manufacturing cost.
While much of cell-to-cell defect and functionality testing can be accomplished during the bum-in process, speed testing memory chips has not been performed during burn-in. This is because speed testing today""s increasingly fast memory devices requires highly precise generation of timing signals and precise measurement of memory device response thereto. Currently available speed testers do not perform well in the extreme environment of the bum-in process. Also, current speed testing equipment tests very few memory chips at a time, because capacitive loading and signal delay effects must be minimized. Thus, current speed testing equipment and methods add disproportionately to the testing time and manufacturing cost per chip.
Unsuccessful attempts have been made to address the disproportionate time and cost of speed testing by fabricating circuitry, on the chip to be tested, capable of providing at least some of the test functions usually provided by external speed testing equipment. For example, a predetermined data pattern is first written to the memory device and then accessed during a read cycle. Comparator circuits fabricated on-chip compare the read data to the predetermined data pattern and indicate whether the data accessed matches the expected pattern. For purposes of speed testing, these comparator circuits must perform the comparison function at particular determined times to indicate whether the expected data has been successfully accessed at those particular times. On-chip delay circuits have been constructed to provide the precise clocking signals necessary to trigger the function of the comparator circuits.
Speed testing is performed to determine in which of a number of determined speed grades a particular memory device belongs. Because of manufacturing process tolerance and variations, one memory device of a particular design may be faster than another memory device of the very same design. Because the on-chip delay circuits are themselves subject to the same process variations as the rest of the circuitry on the chip, these delay circuits cannot reliably be used to measure the effects of those variations.
According to the present invention, a semiconductor memory device is provided that can be operated in a speed test mode. The memory device includes an array of memory cells capable of storing data. The memory device also includes a control circuit receiving a system clock signal and controlling data transfer operations between the array of memory cells and an external data bus. The memory device further includes a test circuit receiving the system clock signal and coupled to an internal data bus. When operated in the speed test mode, the control circuit provides a test enable signal to the test circuit. A predetermined data pattern is written to one or more cells and subsequently accessed during a read cycle. The enabled test circuit compares the contents of the internal data bus to the predetermined data pattern at a time referenced to the system clock signal. The test circuit then produces a signal that places the external data bus in one of two states corresponding to whether a passed or failed comparison has occurred.
In a preferred embodiment, the test circuit includes a data pattern circuit that stores the predetermined data pattern and provides this pattern to a data compare circuit. The data compare circuit receives the clock signal and the test enable signal, and compares the contents of the internal data bus to the predetermined data pattern at a time referenced to the clock signal. In the event of a failed comparison, the data compare circuit produces a signal that disables an output circuit coupling the internal data bus and the external data bus.

Self-test RAM using external synchronous clock


An example image capture device includes memory and one or more processors coupled to the memory and a camera sensor. The camera sensor is disposed to receive light through at least a portion of a display. The one or more processors are configured to determine an effective aperture for the camera sensor. The one or more processors are configured to apply a mask to one or more pixels in the at least a portion of the display, wherein the mask is based on the effective aperture. The one or more processors are configured to capture an image using the camera sensor.

Image capture devices (e.g., digital cameras) are commonly incorporated into a wide variety of devices. In this disclosure, an image capture device refers to any device that can capture one or more digital images, including devices that can capture still images and devices that can capture sequences of images to record video. By way of example, image capture devices may comprise stand-alone digital cameras or digital video camcorders, camera-equipped wireless communication device handsets such as mobile phones (including cellular or satellite radio phones), camera-equipped tablets or personal digital assistants (PDAs), computer devices that include cameras such as so-called "web-cams," or any devices with digital imaging or video capabilities.
Image capture devices may be capable of producing imagery under a variety of lighting conditions (e.g., illuminants). For example, image capture devices may operate in environments that include large amounts of reflected or saturated light, as well as in environments that include high levels of contrast. Some example image capture devices include an adjustment module for auto exposure control, auto white balance, and auto focus, in addition to other modules (e.g., a tint adjustment module), to adjust the processing performed by the imaging signal processor hardware.

Under-display camera systems and methods