An important large family of enzymes is the protein kinase enzyme family. Currently, there are about 500 different known protein kinases. However, because three to four percent of the human genome is a code for the formation of protein kinases, there may be many thousands of distinct and separate kinases in the human body. Protein kinases serve to catalyze the phosphorylation of an amino acid side chain in various proteins by the transfer of the γ-phosphate of the ATP-Mg2+ complex to said amino acid side chain. These enzymes control the majority of the signaling processes inside cells, thereby governing cell function, growth, differentiation and destruction (apoptosis) through reversible phosphorylation of the hydroxyl groups of serine, threonine and tyrosine residues in proteins. Studies have shown that protein kinases are key regulators of many cell functions, including signal transduction, transcriptional regulation, cell motility, and cell division. Several oncogenes have also been shown to encode protein kinases, suggesting that kinases play a role in oncogenesis. These processes are highly regulated, often by complex intermeshed pathways where each kinase will itself be regulated by one or more kinases. Consequently, aberrant or inappropriate protein kinase activity can contribute to the rise of disease states associated with such aberrant kinase activity. Due to their physiological relevance, variety and ubiquitousness, protein kinases have become one of the most important and widely studied family of enzymes in biochemical and medical research.
The protein kinase family of enzymes is typically classified into two main subfamilies: Protein Tyrosine Kinases and Protein Serine/Threonine Kinases, based on the amino acid residue they phosphorylate. The serine/threonine kinases (PSTK), includes cyclic AMP- and cyclic GMP-dependent protein kinases, calcium and phospholipid dependent protein kinase, calcium- and calmodulin-dependent protein kinases, casein kinases, cell division cycle protein kinases and others. These kinases are usually cytoplasmic or associated with the particulate fractions of cells, possibly by anchoring proteins. Aberrant protein serine/threonine kinase activity has been implicated or is suspected in a number of pathologies such as rheumatoid arthritis, psoriasis, septic shock, bone loss, many cancers and other proliferative diseases. Accordingly, serine/threonine kinases and the signal transduction pathways which they are part of are important targets for drug design. The tyrosine kinases phosphorylate tyrosine residues. Tyrosine kinases play an equally important role in cell regulation. These kinases include several receptors for molecules such as growth factors and hormones, including epidermal growth factor receptor, insulin receptor, platelet derived growth factor receptor and others. Studies have indicated that many tyrosine kinases are transmembrane proteins with their receptor domains located on the outside of the cell and their kinase domains on the inside. Much work is also under progress to identify modulators of tyrosine kinases as well.
Nuclear factor κB (NF-κB) belongs to a family of closely related dimeric transcription factor complexes composed of various combinations of the Rel/NF-κB family of polypeptides. The family consists of five individual gene products in mammals, RelA (p65), NF-κB1 (p50/p105), NF-κB2 (p49/p100), c-Rel, and RelB, all of which can form hetero- or homodimers. These proteins share a highly homologous 300 amino acid “Rel homology domain” which contains the DNA binding and dimerization domains. At the extreme C-terminus of the Rel homology domain is a nuclear translocation sequence important in the transport of NF-κB from the cytoplasm to the nucleus. In addition, p65 and cRel possess potent transactivation domains at their C-terminal ends.
The activity of NF-κB is regulated by its interaction with a member of the inhibitor IκB family of proteins. This interaction effectively blocks the nuclear localization sequence on the NF-κB proteins, thus preventing migration of the dimer to the nucleus. A wide variety of stimuli activate NF-κB through what are likely to be multiple signal transduction pathways. Included are bacterial products (LPS), some viruses (HIV-1, HTLV-1), inflammatory cytokines (TNFα, IL-1), environmental and oxidative stress and DNA damaging agents. Apparently common to all stimuli however, is the phosphorylation and subsequent degradation of IκB. IκB is phosphorylated on two N-terminal serines by the recently identified IκB kinases (IKK-α and IKK-β). IKK-β is also known as IKK2. Site-directed mutagenesis studies indicate that these phosphorylations are critical for the subsequent activation of NF-κB in that once phosphorylated the protein is flagged for degradation via the ubiquitin-proteasome pathway. Free from IκB, the active NF-κB complexes are able to translocate to the nucleus where they bind in a selective manner to preferred gene-specific enhancer sequences. Included in the genes regulated by NF-κB are a number of cytokines and chemokines, cell adhesion molecules, acute phase proteins, immunoregulatory proteins, eicosanoid metabolizing enzymes and anti-apoptotic genes.
It is well-known that NF-κB plays a key role in the regulated expression of a large number of pro-inflammatory mediators including cytokines such as TNF, IL-1β, IL-6 and IL-8, cell adhesion molecules, such as ICAM and VCAM, and inducible nitric oxide synthase (iNOS). Such mediators are known to play a role in the recruitment of leukocytes at sites of inflammation and in the case of iNOS, may lead to organ destruction in some inflammatory and autoimmune diseases.
The importance of NF-κB in inflammatory disorders is further strengthened by studies of airway inflammation including asthma, in which NF-κB has been shown to be activated. This activation may underlie the increased cytokine production and leukocyte infiltration characteristic of these disorders. In addition, inhaled steroids are known to reduce airway hyperresponsiveness and suppress the inflammatory response in asthmatic airways. In light of the recent findings with regard to glucocorticoid inhibition of NF-κB, one may speculate that these effects are mediated through an inhibition of NF-κB.
Further evidence for a role of NF-κB in inflammatory disorders comes from studies of rheumatoid synovium. Although NF-κB is normally present as an inactive cytoplasmic complex, recent immunohistochemical studies have indicated that NF-κB is present in the nuclei, and hence active, in the cells comprising rheumatoid synovium. Furthermore, NF-κB has been shown to be activated in human synovial cells in response to stimulation with TNF-α or IL-1β. Such a distribution may be the underlying mechanism for the increased cytokine and eicosanoid production characteristic of this tissue. See Roshak, A. K., et al., J. Biol. Chem., 271, 31496-31501 (1996). Expression of IKK-β has been shown in synoviocytes of rheumatoid arthritis patients and gene transfer studies have demonstrated the central role of IKK-β in stimulated inflammatory mediator production in these cells. See Aupperele et al. J. Immunology 1999. 163:427-433 and Aupperle et al. J. Immunology 2001; 166:2705-11. More recently, the intra-articular administration of a wild type IKK-β adenoviral construct was shown to cause paw swelling while intra-articular administration of dominant-negative IKKβ inhibited adjuvant-induced arthritis in rat. See Tak et al. Arthritis and Rheumatism 2001, 44:1897-1907.
The NF-κB/Rel and IκB proteins are also likely to play a key role in neoplastic transformation and metastasis. Family members are associated with cell transformation in vitro and in vivo as a result of over expression, gene amplification, gene rearrangements or translocations. In addition, rearrangement and/or amplification of the genes encoding these proteins are seen in 20-25% of certain human lymphoid tumors. Further, NF-κB is activated by oncogenic ras, the most common defect in human tumors and blockade of NF-κB activation inhibits ras mediated cell transformation. In addition, a role for NF-κB in the regulation of apoptosis has been reported strengthening the role of this transcription factor in the regulation of tumor cell proliferation. TNF, ionizing radiation and DNA damaging agents have all been shown to activate NF-κB which in turn leads to the upregulated expression of several anti-apoptotic proteins. Conversely, inhibition of NF-κB has been shown to enhance apoptotic-killing by these agents in several tumor cell types. As this likely represents a major mechanism of tumor cell resistance to chemotherapy, inhibitors of NF-κB activation may be useful chemotherapeutic agents as either single agents or adjunct therapy. Recent reports have implicated NF-κB as an inhibitor of skeletal cell differentiation as well as a regulator of cytokine-induced muscle wasting (Guttridge et al. Science; 2000; 289: 2363-2365.) further supporting the potential of NFκB inhibitors as novel cancer therapies.
Several NF-κB inhibitors are described in C. Wahl, et al. J. Clin. Invest. 101(5), 1163-1174 (1998), R. W. Sullivan, et al. J. Med. Chem. 41, 413-419 (1998), J. W. Pierce, et al. J. Biol. Chem. 272, 21096-21103 (1997).
The marine natural product hymenialdisine is known to inhibit NF-κB. Roshak, A., et al., JPET, 283, 955-961 (1997). Breton, J. J and Chabot-Fletcher, M. C., JPET, 282, 459-466 (1997).
Additionally, patent applications have been filed on aminothiophene inhibitors of the IKK2, see Callahan, et al., WO 2002030353; Baxter, et al., WO 2001058890, Faull, et al., WO 2003010158; Griffiths, et al., WO2003010163; Fancelli, et al., WO 200198290; Granetto, et al., WO 2003037886; imidazole inhibitors of IKK2, see Callahan, et al., WO 200230423; anilinophenylpyrimidine inhibitors of IKK2, see Kois, et al., WO 2002046171; β-carboline inhibitors of IKK2, see Ritzeler, et al, WO 2001068648, Ritzeler, et al, EP 1134221; Nielsch, et al. DE 19807993; Ritzeler, et al., EP 1209158; indole inhibitors of IKK2, see Ritzeler, et al., WO 2001030774; benzimidazole inhibitors of the IKK2, see Ritzeler, et al., DE 19928424; Ritzeler et al, WO 2001000610; Ritzeler, et al., WO 2004022553; aminopyridine inhibitors of IKK2, see Lowinger, et al, WO 2002024679; Murata, et al, WO 2002024693; Murata, et al., WO 2002044153; aminopyrimidine inhibitors of IKK2, see Bollbuck, et al., WO 2004089913; pyrazole inhibitors of IKK2, see Bergmanis, et al., WO 2003024935; Metz, et al., WO 2003024936; Geng et al., WO 2003027075; Stealey, et al., WO 2003035625; Xu, et al., WO 200307076; Lennon, et al., WO 2003095430; pyrazinone inhibitors of IKK2, see Boys, et al., WO 2005035527; pyrazolaquinazoline inhibitors of IKK2, see Beaulieu, et al., WO 2002028860; Burke et al, WO 2002060386; Burke, et al. US 20030022898; thiophene tricyclic inhibitors of IKK2, see Belema, et al., WO 2003084959; pyrazolopurine inhibitors of IKK2, see Qiu, et al., WO 2004075846; oxazolo and thiazolo pyridine inhibitors of IKK2, see Pitts, et al., WO 2004106293; quinoline inhibitors of IKK2, Browner, et al., WO2002041843, Browner, et al., US 20020161004 and pyridylcyanoguanidine inhibitors of IKK2, see Bjorkling, et al., WO 2002094813, Binderup et al, WO 2002094322 and Madsen, et al., WO 200294265; thienopyridine inhibitors of IKK2, see Cywin, et al., WO 2003103661; Liu, et al., WO 2005035537; benzothiophene inhibitors of IKK2, see Chen et al., WO 2005012283. The natural products staurosporine, quercetin, K252a and K252b have been shown to be IKK2 inhibitors, see Peet, G. W. and Li, J. J. Biol. Chem., 274, 32655-32661 (1999) and Wisniewski, D., et al., Analytical Biochem. 274, 220-228 (1999). Synthetic inhibitors of IKK2 have also been described, see Burke, et al. J. Biol. Chem., 278, 1450-1456 (2003), Murata, et al., Bioorg. Med. Chem. Lett., 13, 913-198 (2003), Murata, et al., Bioorg. Med. Chem. Lett., 14, 4013-4017 (2004), and Murata, et al., Bioorg. Med. Chem. Lett., 14, 4019-4022 (2004) have described IKK2 inhibitors.
Thus, attempts have been made to prepare compounds that inhibit IKK2 activity and a number of such compounds have been disclosed in the art. However, in view of the number of pathological responses that are mediated by IKK2, there remains a continuing need for inhibitors of IKK2 which can be used in the treatment of a variety of conditions.
The present inventors have discovered novel indole carboxamide compounds, which are inhibitors of kinase activity, in particular inappropriate IKK2 activity. Such indole carboxamide derivatives are therefore useful in the treatment of disorders associated with inappropriate kinase, in particular inappropriate IKK2 activity in particular in the treatment and prevention of disease states mediated by IKK2 mechanisms including inflammatory and tissue repair disorders, particularly rheumatoid arthritis, inflammatory bowel disease, asthma, rhinitis, and COPD (chronic obstructive pulmonary disease); osteoarthritis, osteoporosis and fibrotic diseases; dermatosis, including psoriasis, atopic dermatitis and ultraviolet radiation (UV)-induced skin damage; autoimmune diseases including systemic lupus erythematosus, multiple sclerosis, psoriatic arthritis, alkylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, atherosclerosis, restonosis, diabetes, glomerulonephritis, cancer, including Hodgkins disease, cachexia, inflammation associated with infection and certain viral infections, including acquired immune deficiency syndrome (AIDS), adult respiratory distress syndrome, and Ataxia Telangiestasia.


There are numerous diseases and disorders that can effect corneal tissue and which can, as a result, adversely effect or eliminate vision. For example, allergies, conjunctivitis, corneal infections, Fuchs' dystrophy (deterioration of corneal endothelial cells), varicella-zoster virus, iridocomeal endothelial syndrome, keratoconus, ocular herpes and a number of other conditions, as well as congenital corneal abnormalities can be responsible for corneal damage or irregularity that may affect vision. In an endeavour to restore sight or improve vision in people suffering from corneal abnormalities it has become particularly common to perform corneal transplant operations where the abnormal corneal tissue is removed and replaced using fine sutures with normal corneal tissue obtained from a donor. Although corneal transplant operations enjoy a high rate of success there are nonetheless some problems which can occur, such as rejection of the replacement cornea and ocular fibrosis or scarring. Even in the case of a successful corneal transplantation it is necessary for subsequent administration of immunomodulatory agents. Non-compliance by the patient with prescribed dosing regime of immunomodulating agents may give rise to tissue rejection. There is, accordingly, a need for improved means of prolonging corneal graft survival and preventing tissue rejection as well as for the provision of approaches for therapy of ocular infection, wounds and fibrosis and for therapy of other ocular disorders, for example.
The cornea is a highly organised group of cells and proteins which unlike most tissue is clear, and does not contain blood vessels to nourish or protect against infection. The cornea receives nutritional supply from tears and the aqueous humor found in the anterior chamber located behind it. The cornea is composed of five basic layers, namely the protective external epithelium, Bowman's layer which is located below the epithelial basement membrane and is composed of collagen fibers, the stroma which consists primarily of water and collagen and is located beneath Bowman's layer; and Descemet's membrane located beneath the stroma, which is composed of collagen fibers produced by the endothelial cells located in the lower endothelium. The endothelial cells are essential in maintaining clarity of the cornea by removing excess fluid from the stroma.
Irreversible immunological rejection is the major cause of human corneal graft failure (1), despite the immunologically privileged nature of the eye (2). The histological correlates of rejection include local upregulation of major histocompatability complex and adhesion molecules, an influx of mononuclear cells into the cornea and anterior chamber, and local production of some inflammatory cytokines (3-7). The major target of corneal graft rejection is the corneal endothelium. Human (but not rodent) corneal endothelium is essentially amitotic (8), so that damage to the monolayer during graft rejection cannot be repaired.
Gene therapy has the potential to influence an allograft response through local expression of a modulatory gene product within transplanted donor tissue. The present inventors consider that the cornea may be uniquely amenable to such an approach because of its small size, which may allow modification of the whole tissue, and because of the ease with which a donor cornea may be manipulated in vitro and stored for a considerable period (for example, up to 28 days) prior to transplantation. The anatomical location and clarity of the cornea allow in vivo assessment of the entire graft in the post-operative period and loss of function is easy to detect. Furthermore, the cornea and anterior chamber are at least partially immunologically privileged sites (2), which may allow the use of otherwise immunogenic or pro-inflammatory vectors.


The ability to provide for the fuel and energy needs of the world's growing population has emerged as one of the great challenges of this century. Current fuel and energy needs are primarily met by non-renewable fossil fuels, a source that is both unsustainable and increasingly cost-inefficient. Therefore, new approaches to solving the world's energy needs are required to address these mounting concerns.
Among forms of plant biomass, lignocellulosic biomass is particularly well-suited for energy applications because of its large-scale availability, low cost, and environmentally benign production. In particular, many energy production and utilization cycles based on cellulosic biomass have very low greenhouse gas emissions on a life-cycle basis. The primary obstacle impeding the more widespread production of energy from biomass feedstocks is the general absence of low-cost technology for overcoming the recalcitrance of biomass feedstocks to conversion into useful products. Lignocellulosic biomass contains carbohydrate fractions (e.g., cellulose and hemicellulose) that can be converted into ethanol or other end-products including lactic acid and acetic acid. In order to convert the carbohydrate fractions, the cellulose or hemicellulose must ultimately be converted, or hydrolyzed, into monosaccharides. The hydrolysis of cellulose and hemicellulose has historically proven to be problematic.
Cellulose digesting anaerobic bacteria are of great potential utility because they can be used to produce ethanol or other fuels from abundant substrates such as forestry, municipal and agricultural waste. However, it has been challenging to realize the potential utility of biomass because of difficulty in the genetic manipulation of anaerobic bacteria and a lack of understanding of their metabolic biochemistry. Genome sequence data and recent advances in biotechnological tools for genetic modification of Clostridium thermocellum and other similar organisms have made it possible to make progress in the utilization of biomass for fuel, but the great complexity of metabolism makes it difficult to achieve a desired outcome such as near theoretical ethanol yield from cellulosic substrates.
Many microorganisms can metabolize glucose, cellulose or cellodextrins anaerobically, but they vary in the pathways utilized and the products generated. It has been demonstrated in genetically modified Thermoanaerobacterium saccharolyticum that glucose and cellobiose can be fermented to ethanol at very close to theoretical yield, but similar genetic manipulations in Clostridium thermocellum have not had the same outcome. Argyros et al. “High ethanol titers from cellulose using metabolically engineered thermophilic, anaerobic microbes.” Appl. Env. Microbiol., 2011 doi:10.1128/AEM.00646-11 (epub ahead of publication).
Clostridium thermocellum has both cellulolytic and ethanologenic fermentation capabilities and can directly convert a cellulose-based substrate into ethanol. However, C. thermocellum possesses a branched carbon utilization pathway that generates undesirable products, and thus its yield of ethanol is low. Furthermore, C. thermocellum is not as amenable to manipulation for ethanol production as T. saccharolyticum. The difficulty in manipulating C. thermocellum for ethanol production is exemplified more clearly when the carbon utilization pathways from C. thermocellum and T. saccharolyticum are compared. In homoethanologenic T. saccharolyticum, the carbon atoms from glucose flow down a linear central metabolic pathway to ethanol (FIG. 1A). In C. thermocellum, a different set of enzymes is present and thus the carbon utilization pathway (FIG. 1B) is different that the carbon utilization pathway in T. saccharolyticum. The difference in the carbon-utilization pathways of C. thermocellum compared to T. saccharolyticum makes it infeasible to produce ethanol at theoretical yield with the same modifications.
Many enzymes in carbon-utilizing metabolic processes use a nicotinamide adenine dinucleotide as a cofactor. There are two common types of nicotinamide adenine dinucleotide cofactors, NAD+ and NADP+. Each can exist in a reduced or oxidized form. In order to maintain steady state, each cofactor involved in a reaction must be regenerated at the same rate it is consumed. In other words, the cell must be reduction-oxidation (“redox”) balanced. Enzymes are typically specific for (i.e. react with) either the phosphorylated (NADP+, NADPH) or non-phosphorylated (NAD+, NADH) nicotinamide cofactors. The specificity of an enzyme can sometimes be switched from one nicotinamide cofactor to the other by mutations in the cofactor binding region of the protein. It is also possible to find different isoforms of an enzyme that carry out the same enzymatic activity, but use different cofactors (e.g. NAD+ instead of NADP+). Isoforms with altered cofactor specificity may be found for example in different species.
The T. saccharolyticum oxidation-reduction reactions in the metabolic pathway from cellobiose to ethanol are:
(1) D-glyceraldehyde 3-phosphate+phosphate+NAD+=3-phospho-D-glyceroyl phosphate+NADH+H+ (catalyzed by glyceraldehyde-3-phosphate dehydrogenase)
(2) pyruvate+CoA+oxidized ferredoxin=acetyl-CoA+CO2+reduced ferredoxin+H+ (catalyzed by pyruvate oxidoreductase)
(3) reduced ferredoxin+NADH+2 NADP++H+=oxidized ferredoxin+NAD++2 NADPH (catalyzed by NADH-dependent reduced ferredoxin:NADP+oxidoreductase)
(4) acetyl-CoA+NADPH+H+=acetaldehyde+CoA+NADP+ (catalyzed by acetaldehyde dehydrogenase)
(5) acetaldehyde+NADPH+H+=ethanol+NADP+ (catalyzed by alcohol dehydrogenase)
Reactions 1-5 above are redox and cofactor balanced. A single polypeptide called AdhE contains both catalytic activities of steps 4 and 5. Activity of AdhE is detectable with both NADH and NADPH cofactors (See Shaw et al., “Metabolic engineering of a thermophilic bacterium to produce ethanol at high yield.” PNAS 2008. 105(37): 13769-74). In C. thermocellum, activity can be detected for both cofactors in the alcohol dehydrogenase reaction, but the aldehyde dehydrogenase reaction is specific to NADH only (See Brown et al., “Mutant alcohol dehydrogenase leads to improved ethanol tolerance in Clostridium thermocellum.” PNAS 2011. 108(33): 13753-7 and Rydzak et al., “Growth phase-dependent enzyme profile of pyruvate catabolism and end-product formation in Clostridium thermocellum ATCC 27405.” J. of Biotech. 2009. 104(3-4): 169-75). Therefore, reaction 4 above cannot occur in C. thermocellum. Reaction 4 can occur with NADH as the cofactor, but use of NADH would lead to an overabundance of NADPH and depletion of NADH in the cell. The oxidation-reduction reactions in C. thermocellum in the pathway from cellobiose to ethanol are the same as 1-5 above, but with the addition of two more:
(6) oxaloacetate+NADH+H+=malate+NAD+ (catalyzed by malate dehydrogenase)
(7) malate+NADP+=pyruvate+CO2+NADPH (catalyzed by malic enzyme)
The net effect of these two additional reactions in C. thermocellum is that electrons are transferred from NADH to NADPH. This leads to a further accumulation of NADPH and makes the pathway from cellobiose to ethanol unbalanced for cofactors and therefore infeasible in this configuration. As a result, C. thermocellum strains lacking the ability to make other end products (e.g. mutants for lactate dehydrogenase and phosphotransacetylase) show poor ethanol productivity and secrete amino acids that consume NADPH during their biosynthesis.
Consequently, in order to optimize ethanol production in C. thermocellum, there is a need for mutant strains of C. thermocellum that are reduction-oxidation and cofactor balanced.
The present invention relates to cellulose-digesting organisms that have been genetically modified to allow the production of ethanol at high yield by changing cofactor usage and/or production at key steps of central metabolism.


1. Field of the Invention
This invention is related to a system, apparatus and method for the non-lethal restraint of a vehicle through the use of an entanglement device that will entangle such vehicle. The non-lethal entanglement device incorporates a plurality of tendrils, filaments, tentacles or straps, or a combination there of, that are propelled from a housing by compressed gas or by pressure generated by a gas generator of the type commonly used in air bag deployment apparatus. Filaments that are launched from the device may be attached to frangible balls carrying adhesive substances or barbed capture elements that will adhere or stick to a target surface. The filaments are designed to assist in entangling a target vehicle and restrain the entangled target.
2. Description of Related Art
Devices for stopping a fleeing vehicle include barriers, tire spike strips, caltrops, snares and electrical system disabling devices. The well-known spike strip, with spikes projecting upwardly from a base structure, usually an elongated structure, either a rolled up device or an accordion type device, is designed to be placed on a road in anticipation that a fleeing target vehicle will be driven over the spike strip. Once tire contact is made with the spike strip it will cause deflation of vehicle tires, and eventually cause the vehicle to stop due to the vehicle being difficult to control on flat tires. Barriers, such as concrete barricades, can be effective but to set them up is time consuming and barriers are not particularly portable. Barriers are normally used only in static, non-portable placements. Caltrops are small pyramid-like devices with four projections at about one hundred nine degrees offset to each other. When a caltrop is deployed it will have one of the projections, typically a spike, pointing vertically upward. A vehicle will have to drive directly over a caltrop so as to puncture a tire. Snares, such as a net that is stretched across a road, can also be effective in stopping a vehicle but such snares are time consuming to set up, are generally bulky and heavy and need to be anchored securely to restrain a moving vehicle.
It is also known that there are vehicle immobilization devices that depend on an electrical charge to disable the vehicle. These devices may work with vehicles that have electronic ignition, on-board engine and component control computers, microchip controlled systems, and other electrical control components that can be destroyed or made inoperative through the application of a voltage surge or other high energy electrical pulse or charge provided to a vulnerable electrical systems. Such electrical based-disabling devices may have limited or no effect on vehicles with shielded electrical systems or on vehicles that are not electronically dependent to operate.
Regardless of the type of vehicle stopping device used it is enlightening to realize that the energy needed to stop a fast moving vehicle is significant. Kinetic energy attained by a moving vehicle is on the order of one-half of the mass of the vehicle times the velocity squared. Thus a large truck, such as the well known Humvee (High Mobility Multipurpose Wheeled Vehicle (“HMMWM”), can exhibit more than ten times the kinetic energy of a small passenger car. Thus it is important to realize that a large amount of energy is needed to stop a moving vehicle and that any immobilization device will need to be effective against an array of vehicles to be capable of stopping heavy as well as light vehicles. In this invention the undercarriage immobilization device described herein is not intended to go “head-to-head” with the fleeing vehicle, but is designed to use motion of the vehicle components to assist in the restraint or capture of a target vehicle and thus render the vehicle immobile or significantly slowed to the point of being easily overtaken by law enforcement personnel.
To reduce the complexity and length of the Detailed Specification, and to fully establish the state of the art in certain areas of technology, Applicants herein expressly incorporate by reference material identified in the following publications:    National Institute of Justice, “Department of Defense Non-lethal Weapons and Equipment Review: A Research Guide for Civil Law Enforcement and Corrections,” October 2004, NCJ-205293.    Greg Lucas, “Bay Area's New Efforts in the War on Terror Coast Guard Weapon: High-tech net to keep boats from off-limits areas,” San Francisco Chronicle Article, Aug. 10, 2005. (Available on the Internet.).    MIL-HDBK 5 “Military Handbook Metallic Materials and Elements for Aerospace Vehicle Structures,” United States DOD, Dec. 1, 1998.    MIL-HDBK 17 “Military Handbook Composite Materials Handbook,” United States DOD, Dec. 12, 2002.    Honeywell Spectra Technical Bulletin, HON-PF-PS10, (Available on the Internet).    Steven H. Scott, “Sticky Foam as a Less-Than-Lethal Technology,” Sandia National Laboratory, US DOE Contract No DE-AC04-96AL8500, CIRCA 1994.    T. D. Goolby and K. J. Padilla, “Sticky Foam Restraining Effectiveness Human Subject Tests for the Less-Than-Lethal Foam Project,” Sandia Report, Jul. 8, 1994 UNCI (Available on the Internet).
The applicants believe that the material incorporated above is “non-essential” in accordance with 37 CFR 1.57, because it is referred to for purposes of indicating the background of the invention or illustrating the state of the art. However, if the Examiner believes that any of the above-incorporated material constitutes “essential material” within the meaning of 37 CFR 1.57(c)(1)-(3), applicants will amend the specification to expressly recite the essential material that is incorporated by reference as allowed by the applicable rules.


The present invention relates to rotary sprinklers, and is particularly directed to an improvement to the type of rotary sprinkler described in U.S. Pat. No. 4,261,515.
The above Application describes a rotary sprinkler comprising a nozzle having an inlet connectable to a source of pressurized water and formed with an axial bore through which the water exits in the form of an axial jet, a rotor in the path of the axial jet, and means for floatingly mounting the rotor for axial, lateral and rotary movements with respect to the nozzle bore, the underface of the rotor being formed with at least one groove (preferably two) extending from the rotor center to its outer edge for deflecting the jet laterally of the sprinkler and for imparting a rotory motion to the rotor.


The present invention relates to a dental handpiece for the polymerization of photosetting compounds or resins compatible with the power supply of other handpieces.
The invention refers in particular to an instrument employed by dental surgeons for the polymerization of photosetting compounds or resins utilised especially in dental prostheses,
Photosetting resins are applied in a semifluid state to patients"" dental prostheses and are then hardened by a polymerization process. Such a polymerization process involves heating the resins for a certain length of time, using a light source that emits blue light, i.e. having an emission spectrum with a wavelength centered around 470 nm.
Handpieces according to the prior art currently use halogen lamps as their light source. The light coming from the halogen lamps is filtered by dichroic filters, so that a blue light having a light spectrum with a wavelength between 430 and 510 nm is obtained. The light emerging from the dichroic filters is transported, through optic fibres, to the outlet of the dental handpiece, enabling the dentist to direct it onto the resin to be polymerized, applied to the patient""s dental prosthesis.
The known dental handpieces using halogen lamps as polymerizing lamps have various drawbacks.
In order to achieve polymerization of the resin, the light emerging from the dental handpiece must have a power of approximately 500 mW. Since halogen lamps have a very low power efficiency (efficiency value xcex7=0.5-1%), this results in a high energy dissipation by the polymizering lamps, which reaches values between 50 and 100 W.
For this reason, handpieces for the polymerization of photosetting compounds must have a special power supply, able to supply the polymerizing lamps with a power that ranges from 50 to 100 W. Consequently, the seats in which the patients sit, normally known as dental chair units, provide a connector element connected to the power supply and specifically designed for the polymerizing handpiece.
Furthermore, with the output power that can be obtained from halogen lamps, rather long resin polymerization times are required; this can be very tiresome both for the patient undergoing the procedure and for the dental surgeon who has to perform it.
In an attempt to reduce resin polymerization times, handpieces with different light sources have been put on the market. Handpieces are per se known that use as their light source gas-discharge lamps (plasma torches) that emit high-power white light, which is filtered in order to obtain a light beam with an emission spectrum centred on blue. Also known are dental handpieces using laser as their light source, which directly transmit a light beam with an emission spectrum centred on blue.
With this type of dental handpiece it is possible to obtain a light beam with a power output approximately ten times greater compared to that obtained with halogen lamps, therefore shorter polymerization times are achieved. However, such dental handpieces, apart from being very expensive, have the problem of needing to dissipate a large amount of heat and inevitably they must provide a heat dissipation or cooling system, making them excessively bulky and heavy. Furthermore, such heat dissipation systems often include fans driven by motors which must be powered by the dedicated electrical supply of the polymerizing handpiece.
Also known, especially at an experimental level, are handpieces for polymerization of photosetting compounds using as their light source LEDs that emit in the blue range.
All known handpieces using halogen lamps, plasma torches, laser or LEDs as their light source, have an independent electrical supply system, dedicated soleley to the electrical supply of said light sources. This makes the dental handpiece bulky and lacking in versatility because of the purpose-built circuitry provided for such light sources and also the need to provide the dental chair unit with special connectors for the power supply of such handpieces.
The object of the invention is to eliminate said drawbacks, providing a dental handpiece for polymerization of photosetting compounds or resins that is compatible with the power supply of other handpieces.
A further object of the present invention is to provide a handpiece of reduced dimensions and bulk that is versatile, economical and easy to produce.
The handpiece according to the invention comprises a connector element shaped so as to be able to connect to external electrical connectors utilised for other types of handpieces, such as for example the handpiece or ultrasound scaler for removal of plaque and caries, or the dental turbine for cleaning and washing dental prostheses.
This is made possible thanks to the fact that in the handpiece according to the invention LEDs that emit in the blue range are used as the light source. In fact LEDs require a decidedly lower power supply than halogen lamps, plasma torches or laser. This has made it possible to take the electrical supply for bias of the LEDs directly from the electrical supply circuit provided in the external connector of other types of handpieces.
In the case of connection of the handpiece for polymerization according to the invention to the connector of an ultrasound scaler, the electrical energy for bias of the LEDs is taken from the electrical circuit provided in the connector of the scaler and destined to supply the ultrasound transducer of the scaler.
For this purpose, in the handpiece according to the invention, an equivalent resonator circuit is provided that must tune the resonance frequency of the supply circuit provided in the external connector of the scaler. Downstream of the equivalent resonance circuit and upstream of the LED assembly of the polymerizing handpiece, a voltage and current stabilizer or regulator is provided in order to generate a constant voltage and direct current signal for correct bias of the LEDs.
Dental turbines include a light source to illuminate the work surface. For the electrical supply to this light source of the dental turbine, the external connectors of dental turbines carry an electrical supply signal taken from an electrical supply source. In the case of connection of the handpiece according to the invention to an external connector for dental turbines, the supply of the LEDs for polymerization is taken from the electrical supply carried by the external connector of the turbine.
In this case the voltage supplied by the external connector is too low to be able to supply the LEDs, therefore an electronic voltage booster or step-up transformer circuit capable of providing an adequate voltage to bias the LEDs is provided inside the handpiece according to the invention. Downstream of the step-up transformer circuit a voltage and current stabilizing circuit is provided to maintain a constant voltage and direct current during power supply of the LEDs.
The advantages of the handpiece for the polymerization of photosetting compounds according to the invention appear evident. Since it can adapt to the connectors used for the power supply of handpieces of other types, it allows the connectors and circuitry specifically dedicated to its supply to be eliminated from the dental chair unit, with considerable economic advantages as regards size and complexity.


1. Field of the Invention
This invention relates generally to the field of electrical connectors. More particularly, this invention relates to an electrical connector commonly used for audio and video applications which is commonly referred to as an audio jack connector, RCA connector or phono connector.
2. Background of the Invention
The term "audio jack connectors", "phono connectors", "RCA connectors" and the like are used synonymously herein. These terms are intended to generically embrace coaxial connectors which are commonly referred to by these names in the electronics industry as well as other coaxial connector devices which operate in a similar manner. These terms are not intended to restrict the usage of the connector to audio or phonograph applications since they are commonly used for other purposes including video, radio frequency (RF) and intermediate frequency (IF) applications.
Connectors such as those described above are commonly used for many electrical and electronic applications. These connectors are particularly popular in consumer electronics devices. As such, large quantities of these connectors are in use. In addition, there is a great deal of demand for such devices to be produced and installed in electronic systems at low cost to the manufacturer. Similar coaxial connection devices are also commonly used in radio frequency applications and the like which can benefit from decreased cost.
Traditionally, such connectors are installed manually by either soldering a pair of solder tabs to wires or cables which are connected to other electrical circuitry. Mechanical support is obtained by either a solder connection or by passing the connector through a hole in an electrical enclosure and securing the connector with a threaded nut and washer or similar connection procedures.
Obviously, such manufacturing techniques are labor intensive and result in higher product cost and lower reliability. It is thus desirable to provide a system for producing such connectors in a manner which is more conducive to automation in the manufacture of the end user product. In addition, existing connectors are made of several metal parts and insulators which are assembled together. It is also desirable to reduce the number of parts in the assembly to simplify the design and reduce or eliminate the possibility of assembly errors.
These and other drawbacks of the prior art connectors are ameliorated by the improved coaxial connector of the present invention.


In general, conventional rate converters include two major computation blocks, as illustrated in FIG. 1. A first block is a conversion rate tracking loop that determines the ratio between an input sample rate and output sample rate. Once the ratio is determined, the conversion rate tracking loop generates the corresponding input sample index for each output sample.
The second computation block is the sample interpolator. The function of this block is to interpolate the input data sample and to generate the output data sample with the real value index. One problem with conventional rate converters is that they create aliasing from the resampling, and it is relatively difficult to produce an output signal having a high Signal-to-Noise Ratio (SNR) and having a relatively flat frequency response within standard frequency ranges for audio signals.
Embodiments of the invention address this and other limitations of the prior art.


This invention relates generally to a fluid valve and more particularly to a switching logic element having a normally closed characteristic.
Switching logic elements utilize an unbalanced poppet which is spring loaded on a seat; however, without additional fluid pressure to bias the poppet against the seat, flow can occur between the input and output ports. These valves are called "normally open" because of the need for fluid pressure to close them. The complementary logic element--normally closed--has not previously been available. Such a normally closed logic element would require a positive or pilot pressure input to be opened and to remain open.
The need for a pilot pressure is an operating requirement for fail safe applications, i.e. if the source of fluid pressure is cut off either inadvertently or because of system shut down, the valve should close to prevent loss of load supporting pressure by flow through the logic element.


1. Field of the Invention
The present invention relates to a powered vehicle door closing system and specifically to a powered vehicle door closing system suitable for an automotive vehicle such as a van with a sliding door moveable between open and closed positions relative to a vehicle body opening, and more specifically to a system which is capable of forcibly and automatically moving a latch member employed in a lock unit from a half-latched position (a nearly-closed position of the sliding door) to a fully-latched position (a fully-closed position of the sliding door) by powering the final, low-displacement/high-force movement of the sliding door.
2. Description of the Prior Art
Recently, there have been proposed and developed various powered vehicle door closing systems which can automatically move a latch member from a half-latched position to a fully-latched position. One such powered vehicle door closing system has been disclosed in Japanese Patent Provisional Publication (Tokkai Heisei) No. 1-105886. The powered door closing system disclosed in the Japanese Patent Provisional Publication No. 1-105886 is applied to a door lock for an automobile sliding door. The prior art door closing system has three switches, namely a first switch for detection of a half-latched state of the latch member, a second switch for detection of a fully-latched state of the latch member, and a third member for detection of a stand-by position of a moveable drive lever (a portion of a force-transmitting linkage) by way of which the latch member can be shifted from the half-latched position to the fully-latched position. The first switch consists of a pair of electrical contacts, one being a stationary electrical contact provided in the vehicle body and the other being a spring-loaded, plunger-type electrical contact provided onto the door for contact with the stationary contact upon shift to the half-latched position of the latch member via the manual door operation. The first switch is responsive to the movement of the sliding door in such a manner as to rotate the drive lever away from its stand-by position by way of normal rotation (positive rotation) of a drive motor such as a reversible electric motor when the sliding door reaches the half-latched position of the latch member, and as a result the latch member is forcibly moved to its fully-latched position. The second switch is responsive to the movement of the latch member in such a manner as to rotate the drive lever toward the stand-by position by way of reverse-rotation (negative rotation) of the drive motor when the latch member reaches the fully-latched position. The third switch is responsive to the movement of the drive lever in such a manner as to stop the drive motor and consequently to maintain the drive lever at the stand-by position immediately when the drive lever reaches the stand-by position. Each of the second and third switches consists of an ordinary limit switch which is so designed to cut off power automatically at or near the limit of travel of a moving object controlled by electrical means. The conventional system requires an accurate installation of the first, second, and third switches, since respective spring-loaded switching contacts or points of the second and third switches are mechanically operated and additionally the stationary electrical contact (included in the first switch) is provided in the vehicle body, while the other plunger-type electrical contact is provided onto the door for contact with the stationary contact. When installing the three switches on the vehicle, the conventional system requires a complicated wiring harness. This results in an increased assembling time of the respective switches onto the vehicle. Due to a complicated, costly structure of the conventional system, total manufacturing costs of the automotive vehicle with an auto door closing system is increased. Owing to an inherent switching characteristic of the limit switch with the spring-loaded mechanical contact, there is a possibility that a switched-ON operation of the limit switch cannot be completed, particularly during manual quick door closing operation with great momentum. There is a possibility of malfunction of the system.


Refrigerator appliances generally include a cabinet that defines a chilled chamber for receipt of food items for storage. For example, the cabinet can define a fresh food chamber and a freezer chamber. The fresh food chamber can be maintained at a temperature greater than the freezing point of water. Conversely, the freezer chamber can be maintained at a temperature equal to or less than the freezing point of water.
Refrigerator appliances generally also include one or more shelf assemblies positioned within the fresh food chamber and/or the freezer chamber to facilitate storage and/or organization of any food items positioned therein. Typically, the shelf assemblies are adjustable in height using, e.g., a cantilevered track assembly. Accordingly, with such a configuration, the user may customize the fresh food chamber and/or the freezer chamber of the refrigerator appliance to meet their specific needs.
Modern refrigerator appliances can also include lighting systems attached to or embedded within the one or more shelf assemblies. The lighting systems can, e.g., illuminate the shelf assembly itself, or alternatively can illuminate a lower shelf assembly. However, in order for such refrigerator appliances to provide such lighting systems with electrical power, one or more electric wires are generally required to be disconnected and reconnected as the shelf assembly is adjusted. Certain consumers may find such electrical wires unsightly and may find the additional steps of disconnecting and reconnecting wires undesirable.
Accordingly, a refrigerator appliance having one or more shelf assemblies capable of connecting a lighting system to an electrical source without requiring disconnection and reconnection of electrical wires would be useful. Moreover, a refrigerator appliance having one or more shelf assemblies capable of connecting a lighting system to an electrical source without any visible connections would be particularly beneficial.


1. Field of the Invention
The present invention relates to an optical information recording medium being utilized for a recording and reproducing apparatus or a drive, which records an information in the optical information recording medium with moving the medium relatively and reads out the information from the medium, and a substrate and a manufacturing method for the optical information recording medium, particularly, relates to an optical information recording medium, which can be recorded and reproduced in a high density and a large capacity, and a substrate and a manufacturing method for the optical recording medium.
2. Description of the Related Art
Currently, there existed a system, which can optically record and reproduce information by using a disk shaped medium, as a system of an information recording medium for reading out information with moving the medium relatively. A disk system medium can be divided into several types such as a read only type or a ROM (read only memory) type, a recordable or a write once type or an “R” type and a rewritable type or a RW type. Generally, a recording density of a medium is high in a ROM type and low in “R” and RW types. For instance, in a DVD (digital versatile disk) system, which utilizes a laser beam having a wavelength of 635 through 650 nm, introduced into the market in 1996, a read only type disk such as a DVD-ROM disk and a DVD-Video disk was introduced first. A recording capacity of a read only type DVD disk is 4.7 GB. On the other hand, a recording capacity of a rewritable type DVD disk such as a DVD-RAM (DVD-Random Access Memory) disk is 2.6 GB, that is, the recording capacity of a DVD-RAM disk is almost 55% of that of a DVD-ROM disk. Researches and developments for increasing a recording capacity of a rewritable type disk are progressing. However, a system having a same capacity as that of a DVD-ROM disk has not been developed yet.
In the case of a rewritable type disk, a recording format on a disk and materials of recording medium are key technologies. In a DVD-RAM disk, a land-groove recording method, which is utilized for recording information on both land and groove of an optical information recording medium, has been used. In this method, an address necessary to recording and reproducing is recorded with cutting a land and a groove at each specific period of time.
FIG. 19 is a fragmentary plan view of a disk partially enlarging a microscopic construction 20, that is, a physical format construction of the land-groove recording method disk. In FIG. 19, the drawing shows an external appearance of the construction when the disk is not recorded and grooves 21a through 21c, hereinafter represented by the groove 21, are formed in parallel to each other. Lands 22a and 22b, hereinafter represented by the land 22, are allocated in between the grooves. An information is recorded on both the groove 21 and the land 22 when recording. A plurality of address pits 23a through 23n, which is necessary to recording and reproducing, is formed by cutting the groove 21 and land 22. The addresses occupy an area 24 in conjunction with an accompanied signal, so that the area 24 prevents a total capacity of a disk from increasing. In other words, a limited area of a disk can not be effectively utilized because of the area 24.
Further, with respect to recording material, in consideration of interchangeability with a read only type DVD disk drive, a phase change recording method, which does not utilize a magnetic head, is suitable. However, this method is defective in reflectivity, which is much inferior to a read only type disk or a write once type disk of utilizing dye. Accordingly, the low reflectivity results in that a recording capacity can not be increased.
By combining a microscopic construction or a physical format construction with a phase change material for high density recording and by optimizing them, a recording capacity equivalent to that of a read only type DVD disk can be realized.
An optical disk, which records addresses with scattering over a disk without having an inherent address area such as the area 24 shown in FIG. 19, is considered as a format for a large capacity optical disk. In other words, an address area such as the area 24 is not provided, so that a recording capacity can be increased as many as that of a DVD-ROM disk. However, in a case that a main recording signal is recorded in a vicinity area of an address signal, the main recording signal may interfere in the address signal and an error may occur by this method, and then rewriting can not be performed any more. Conversely, the address signal may leak into and interfere in the main recording signal and result in a reading out error.


This invention relates generally to an apparatus and method for an improved nanocalorimeter, and more specifically, to a system and method for an improved nanocalorimeter for measuring the heat released or absorbed during chemical reactions.
Calorimetry is used to measure enthalpic changes, including enthaplic changes arising from reactions, phase changes, changes in molecular conformation, temperature variations, and other variations of interest that may occur for a particular specimen. By measuring enthalpic changes over a series of conditions, other thermodynamic variables may be deduced. For example, measurements of enthalpy as a function of temperature reveal the heat capacity of a specimen, and titrations of reacting components can be used to deduce the binding constant and effective stoichiometry for a reaction. Calorimetry measurements are useful in a broad variety of applications, including, for example, pharmaceuticals (drug discovery, decomposition reactions, crystallization measurements), biology (cell metabolism, drug interactions, fermentation, photosynthesis), catalysts (biological, organic, or inorganic), electrochemical reactions (such as in batteries or fuel cells), and polymer synthesis and characterization, to name a few. In general, calorimetry measurements can be useful in the discovery and development of new chemicals and materials of many types, as well as in the monitoring of chemical processes. Standard calorimeters require relatively large samples (typically about 0.5 ml to 10 liters) and usually measure one sample at a time. As such, these systems cannot be used to measure very small samples, as might be desired for precious or highly reactive materials. Furthermore, standard calorimeters cannot be used effectively to monitor a large number of reactions of small sample size in parallel, as is required in order to perform studies using combinatorial chemistry techniques.
In recent years, researchers and companies have turned to combinatorial methods and techniques for discovering and developing new compounds, materials, and chemistries. For example, pharmaceutical researchers have turned to combinatorial libraries as sources of new lead compounds for drug discovery. As another example, Symyx Technologies® is applying combinatorial techniques to materials discovery in the life sciences, chemical, and electronics industries. Consequently, there is a need for tools that can measure reactions and interactions of large numbers of small samples in parallel, consistent with the needs of combinatorial discovery techniques. Preferably, users desire that these tools enable inexpensive measurements and minimize contamination and cross-contamination problems.
In some cases, the sample to be studied is precious, and it might not be acceptable to use the relatively large amount of material required by a standard microcalorimeter to perform only one measurement. For example, one may desire to study a natural extract or synthesized compound for biological interactions, but in some cases the available amount of material at concentrations large enough for calorimetry might be no more than a few milliliters. Performing a measurement in standard microcalorimeters, such as those sold, for example, by MicroCal® Inc. (model VP-ITC) or Calorimetry Sciences Corporation® (model CSC4500), requires about 1 ml of sample, which means that one would possibly be Faced with using a majority or all of the precious material for one or a small series of measurements. Tools that enable calorimetric measurements with much smaller sample sizes would be helpful in overcoming this limitation.
One of the most popular uses of combinatorial techniques to date has been in pharmaceutical research. Pharmaceutical researchers have turned to combinatorial libraries as sources of new lead compounds for drug discovery. A combinatorial library is a collection of chemical compounds which have been generated, by either chemical synthesis or biological synthesis, by combining a number of chemical “building blocks” as reagents. For example, a combinatorial polypeptide library is formed by combining a set of amino acids in every possible way for a given compound length (i.e., the number of amino acids in a polypeptide compound). Millions of chemical compounds can theoretically be synthesized through such combinatorial mixing of chemical building blocks.
Once a library has been constructed, it must be screened to identify compounds, which possess some kind of biological or pharmacological activity. For example, screening can be done with a specific biological compound, often referred to as a target, that participates in a known biological pathway or is involved in some regulation function. The library compounds that are found to react with the targets are candidates for affecting the biological activity of the target, and hence a candidate for a therapeutic agent.
Through the years, the pharmaceutical industry has increasingly relied on high throughput screening (HTS) of libraries of chemical compounds to find drug candidates. HTS describes a method where many discrete compounds are tested in parallel so that large numbers of test compounds are screened for biological activity simultaneously or nearly simultaneously. Currently, the most widely established techniques utilize 96-well microtitre plates. In this format, 96 independent tests are performed simultaneously on a single 8 cm×12 cm plastic plate that contains 96 reaction wells. These wells typically require assay volumes that range from 50 to 500 μl. In addition to the plates, many instruments, materials, pipettors, robotics, plate washers and plate readers are commercially available to fit the 96-well format to a wide range of homogeneous and heterogeneous assays. To achieve faster testing, the industry is evolving to plates that contain 384 and 1536 wells.
A variety of measurement approaches has been used to screen combinatorial libraries for lead compounds, one of which is the inhibitor assay. In the inhibitor assay, a marker ligand, often the natural ligand in a biological pathway, is identified that will bind well with the target protein molecule. The assay requires the chemical attachment of a fluorescent molecule to this marker ligand such that the fluorescent molecule does not affect the manner in which the marker ligand reacts with the target protein. To operate an inhibitor assay, the target protein is exposed to the test ligands in microtitre wells. After a time necessary for reaction of the test ligand to the target protein, the marker ligand is applied. After a time for reaction with the marker ligand, the wells are rinsed such that non-reacted marker ligand is washed away. In wells where the target protein and the test ligand have reacted, the test ligand blocks the active site of the target protein so the marker ligand cannot react and is washed away, while in cells where the target protein and test ligand have not reacted, the marker ligand reacts with the target protein and is not washed away. By investigating the wells for the presence of fluorescence after the washing, reactions of test ligands and target proteins can be determined as having occurred in wells where no fluorescence is observable.
However, the inhibitor assay requires time and expense to develop the assay. The principal components that need development are discovering a marker ligand and attaching a fluorophore to the marker in a manner that does not affect its reaction with the target protein. Attaching the fluorescent marker can often take 3 months of development or more and cost $250 k or more once the marker ligand is identified. An assay method that avoids such assay development, such as measuring the heat of the reaction with calorimetry, would eliminate this cost and lime delay in the discovery process.
Calorimetry measurements are commonly utilized in biophysical and biochemical studies to determine energy changes as indications of biochemical reactions in a media. Prior techniques for measurements include using electrodes, thermopiles, optical techniques, and microcalorimeters for measurements within a sampled media. There is a great interest in developing ultra-miniature microcalorimeter devices that require very small volumes of sampled media for accurate detection and measuring of biochemical reactions on, or in close proximity to, the microcalorimeter and which can be applied in a manner to quickly measure large numbers of reactions such that it can be as efficient as assays such as inhibitor assays which can be used in HTS to screen perhaps 100,000 test ligands a day.
The following disclosures may be relevant and/or helpful in providing an understanding of some aspect of the present invention:
In Plotnikov et al., U.S. Pat. No. 5,967,659 (“Ultrasensitive Differential Microcalorimeter with User-selected Gain Setting”), a differential calorimeter is disclosed that includes sample and reference cells, a thermal shield surrounding the cells, heating devices thermally coupled to the thermal shield and the cells, a temperature monitoring system, and a control system. The temperature monitoring system monitors the temperature of the shield, cell temperatures, and temperature differentials between the cells and the shield. The control system generates output signals for control of the heating devices, with a gain setting and scan rate selected by means of a user interface. Output control signals are functions of input temperature signals and the user-selected gain setting, as well as functions of input temperature signals and the user-selected scan rate using a mapping function stored in memory.
In Cavicchi et al., U.S. Pat. No. 6,079,873 (“Micron-scale Differential Scanning Calorimeter on a Chip”), a differential scanning microcalorimeter produced on a silicon chip enables microscopic scanning calorimetry measurements of small samples and thin films. The chip, fabricated using standard CMOS processes, includes a reference zone and a sample zone. The reference and sample zones may be at opposite ends of a suspended platform or may reside on separate platforms. Each zone is heated with an integrated polysilicon heater. A thermopile consisting of a succession of thermocouple junctions generates a voltage representing the temperature difference between the reference and sample zones.
In Thundat et al., U.S. Pat. No. 6,096,559 (“Micromechanical Calorimetric Sensor”), a calorimeter sensor apparatus utilizes microcantilevered spring elements for detecting thermal changes within a sample containing biomolecules which undergo chemical and biochemical reactions. The spring element includes a bimaterial layer of chemicals on a coated region on at least one surface of the microcantilever. The chemicals generate a differential thermal stress across the surface upon reaction of the chemicals with an analyte or biomolecules within the sample due to the heat of chemical reactions in the sample placed on the coated region. The thermal stress across the spring element surface creates mechanical bending of the microcantilever. The spring element has a low thermal mass to allow detection and measuring of heat transfers associated with chemical and biochemical reactions within a sample place on or near the coated region. Deflections of the cantilever are detected by a variety of detection techniques.
In Lieberman, U.S. Pat. No. 6,193,413 (“System and Method for an Improved Calorimeter for Determining Thermodynamic Properties of Chemical and Biological Reactions”) a microcalorimeter includes a thin amorphous membrane anchored to a frame within an environmental chamber. Thermometers and heaters are placed on one side of a thermal conduction layer mounted on the central portion of the membrane. Samples are placed on two such membranes; each sample is heated and its individual heat capacity determined. The samples are then mixed by sandwiching the two microcalorimeters together to cause a binding reaction to occur. The amount of heat liberated during the reaction is measured to determine the enthalpy of binding.


1. Field of the Invention
The present invention relates to the filed of the digital signal processing, and more specifically, to the field of phase equivocation in burst modems.
2. Discussion of the Prior Art
When the communication exists for a long period of time, it is possible to use a conventional phase-lock loop (PLL) in a receiver to recover the carrier from a continuously transmitted signal. The PLL that is specifically designed to recover the carrier is termed as a phase carrier loop.
However, in a time-division multiple access (TDMA) communication system, the available spectrum is used by letting each user to have access to the whole band for a short time (traffic burst), during which time the user transmits data as fast as the user can. The user's frequency allocation is shared with the other users who have time slots allocated at other times.
Thus, in a TDMA-type burst communication systems, the signals exist for a short period of time. Consequently, there is little time in which the phase carrier loop can slew to the proper phase in order to recover the carrier from the burst signal.
This situation is exacerbated for a TDMA-type burst commination system if the phase of the incoming symbol is very close to the border between the plant points. If this is the case, the slicer in the phase carrier loop can not determine to which quadrant the incoming symbol point having such phase should belong because such symbol can be equally located in either of two quadrants. Such symbol point is further referred to as a symbol point having a phase equivocation, and the phase carrier loop can not lock fast enough on an incoming signal having a phase equivocation characteristic.
What is needed is to design a carrier phase loop system that is capable of resolving the phase equivocation of the incoming symbols, thus placing any incoming symbol point to a certain quadrant for further processing by the loop, thus increasing the speed of locking of the carrier phase loop on the carrier.


A modern telecommunications system often comprises one or more switched telephone networks and one or more Internet Protocol-based packet networks. These two different types of networks are interconnected by a media gateway, which acts as a translator between the two types of networks. The media gateway enables multimedia communications, such as voice and video, over multiple transport protocols end to end.
Because the media gateway connects different types of networks, one of its main functions is to convert between the different transmission and coding techniques used across the different networks. For example, a Voice-over-Internet-Protocol-capable (VoIP-capable) media gateway performs the conversion between time division multiplexed voice media that originate at a switched telephone network telecommunications terminal and VoIP datagram media that is intended for an Internet Protocol network terminal, as part of a telephone conversation between two parties; of course, the media gateway has to perform the conversion in the other direction as well. Other functions that the media gateway provides are echo cancellation, tone detection, tone generation (e.g., dual tone multi-frequency tones, etc.), and conferencing.
Since a packet stream that is received from the Internet Protocol network comprises data packets and control packets, which contain addressing information, the VoIP media gateway converts the received packets to a time division multiplexed stream while processing the control packets. The media gateway must perform the conversion in a timely manner to minimize the possibility of packet loss, which the listening party on a call might perceive. To handle all of the packets responsively and without unacceptable delay or jitter, the media gateway uses digital signal processors, which are dedicated devices that are capable of the high-speed packet processing that is required for the conversion. Each digital signal processor comprises multiple processing resources, such as processing channels, to handle multiple calls and the different conversion formats across the calls. For example, the conversion formats might be distinguished from one another by codec type, encryption algorithm, payload values, addressing information, or redundancy in the information transmitted. Protocol standards and formulas exist that govern these properties, such as G.711 and G.729 compression/decompression algorithms. Similarly, the media gateway must also perform the conversion in the other direction from a time division multiplexed stream to Internet Protocol packets in a timely manner.
One or more media gateways are controlled by a media gateway controller, which provides the call control and signaling functionality for each media gateway and across media gateways. Communication between media gateways and media gateway controllers is achieved by means of protocols such as H.248, Media Gateway Control Protocol (MGCP), and so forth. During a call initialization that involves an Internet Protocol (IP) terminal, the media gateway controller provides to the IP terminal the IP address of the media gateway resource that is handling the call. This enables the IP terminal to specify the proper destination address of the packets that it originates and to recognize the packets that are being sent to the terminal. Alternatively, instead of a call involving an IP terminal, the call could involve another media gateway that exchanges packets with the aforementioned media gateway resource that is handling the call.
On occasion, it might become necessary, under certain conditions, to remove an in-service digital signal processor from service. For example, when a technician has to diagnose or physically replace the signal processor, a technician will typically need to “busy out” the processor. What makes this difficult is that the signal processor might be handling the packet streams that correspond to one or more currently active calls between a telecommunications terminal in one type of network, such as the IP network, and a terminal in another type of network, such as the switched telephone network, described earlier. Techniques in the prior art require that the technician issue a graceful busy-out command for a selected signal processor, only to have to wait for its calls to terminate before the processor can be fully removed from service. This can be a lengthy procedure, especially if some calls that are being handled by the selected signal processor are long in duration.
What is needed is a technique to accelerate the removal from service of a signal processor at a media gateway, without some of the disadvantages in the prior art.


The present inventive concept relates to a delay locked loop (DLL), and more particularly, to a DLL for generating a clock signal having a frequency obtained by multiplying the frequency of a reference clock signal, and having an accurate phase delay and a constant duty cycle by compensating for an error occurring due to process variation.
A DLL may be used to generate an internal clock signal in electronic devices. The DLL usually delays an external clock signal by a predetermined period of time using a delay line and generates an internal clock signal synchronized with the external clock signal. The DLL may be used to generate a timing signal for the operation of a semiconductor memory device, e.g., dynamic random access memory (DRAM), that is, a signal used to read data from the semiconductor memory device or write data thereto.
To increase the data transmission speed between electronic devices, it is necessary to increase the frequency of an internal clock signal of the electronic devices. To decrease errors occurring in high-speed data transmission, a data valid window needs to be accurately positioned. For instance, when an internal clock signal having a frequency obtained by multiplying the frequency of an external clock signal is used in a semiconductor memory device, the data transmission speed of the semiconductor memory device can be increased. In addition, errors in high-speed data transmission can be reduced when clock signals having an accurate phase delay and an accurate duty cycle are used.
When the frequency of the internal clock signal increases, however, harmonic locking may occur during the locking operation of the DLL. Also, the influence of process variation is increasing with the microminiaturization of manufacturing technology. Accordingly, it is increasingly difficult to generate a clock signal having an accurate phase delay and a constant duty cycle due to phase delay mismatch between delay lines of the DLL.


The invention relates to a device for providing a breathing gas, in particular to a device for conditioning a breathing gas, for managing the weight of a breathing creature, in particular for stimulating weight reduction. The invention further relates to a method and to a use of a device for conditioning a breathing gas and for providing said breathing gas to a breathing creature, for managing the weight of a breathing creature, in particular for stimulating weight reduction of the breathing creature.
In developed countries around the world, there is a tremendous interest in personal fitness, wellness and para medication. At the same time there is a disturbing trend that people, including adults and children are becoming overweight. By overweight, it is meant that the subject has exceeded the acceptable weight range and percent body fat generally considered as healthy determined by factors including, but not necessarily limited to age, height, sex, and body type.
Overweight produces a wide range of health concerns including sleep apnoea, orthopaedic complications, arterial sclerosis, diabetes, heart disease and also social and psychological problems etc. All these undesirable conditions contribute in development of an unsatisfactory quality of life and in some cases premature death.
Therefore, many people want to maintain a specific weight or even lose weight to maintain or enhance their physical condition. To lose weight the body needs to burn more energy than is provided by the food intake. Known diet methods include restriction of amounts and kinds of food, exercises and use of diet drugs to reduce or maintain body weight.
However, managing weight via known diet methods takes a long period of time, even when combined with exercises or diet drugs. Many people are not capable of maintaining a reduced food intake and/or an increased exercise level over a long period of time and therefore do not achieve the amount of weight loss aimed for or even gain weight in spite of there efforts. Also, even when the diet results in a loss of weight, for a variety of reasons, most people find it very difficult to maintain significant weight reduction over time.
Therefore only a few people are able to achieve a significant reduction of weight, and even less are able to maintain this condition.


A variety of batteries employing metallic magnesium anodes are known. Morehouse et. al., in U.S. Pat. No. 2,759,986, taught a magnesium anode cup container lined with a cathode material paste consisting of powdered sulfur, graphite, and magnesium bromide electrolyte. Roche et. al. in Argonne National Lab, ERDA Report No. 76-35, "Alternative Secondary Cell Systems", Progress Report, 1976, pp. 53 to 54, discloses a molten electrolyte, magnesium-iron sulfide cell, using FeS.sub.2 cathodes, and MgCl.sub.2 -- NaCl -- KCl electrolyte. The cathode was covered with a stainless steel screen and the anode was covered with graphite fabric. The cell operated at 450.degree. C but short circuited after four cycles due to magnesium dendrite formation.
Others in the art have substituted iron sulfide as the cathode material in combination with a lithium anode. These lithium cells provide outstanding high voltage characteristics. Vissers et. al., in U.S. Pat. No. 3,933,521, taught a molten electrolyte, rechargeable, electrochemical cell which required a LiCl -- KCl electrolyte between the anode and cathode and operated at temperatures of about 400.degree. C. The cathode contains iron, cobalt or copper sulfides in a conductive support structure, insulated with a separate boron nitride or yttria cloth separator, and disposed in the center of a housing container. The anode which lines the bottom of the container comprises a 90% porous, compacted, stainless steel or nichel felt, coated with cobalt and impregnated with molten lithium.
The use of lithium, due to its high reactivity, requires the use of expensive separator and container materials. In lithium cells, the anode and electrolyte are very expensive. The use of magnesium metal provides severe short circuit complications due to dendritic growth at the magnesium electrode during recharging. Magnesium also reacts chemically with a wide variety of separator materials, particularly oxides, to make them electrically conducting, thus causing shorting of electrodes. What is needed, is an inexpensive, secondary, electrochemical cell, which will still provide good voltage characteristics, and which will not be easily degraded over long time periods.


1. Field of the Invention
The present invention relates to a digital telecommunications system, and more particularly, to a DTV receiver and a method of processing a broadcast signal in a DTV receiver.
2. Discussion of the Related Art
The Vestigial Side Band (VSB) transmission mode, which is adopted as the standard for digital broadcasting in North America and the Republic of Korea, is a system that has been developed for the transmission of MPEG video/audio data. However, presently, the technology for processing digital signals is being developed at a vast rate, and, as a larger number of the population uses the Internet, digital electric appliances, computers, and the Internet are being integrated. Therefore, in order to meet with the various requirements of the users, a system that can transmit diverse supplemental information in addition to video/audio data through a digital television channel needs to be developed.
Some users may assume that supplemental data broadcasting would be applied by using a PC card or a portable device having a simple in-door antenna attached thereto. However, when used indoors, the intensity of the signals may decrease due to a blockage caused by the walls or disturbance caused by approaching or proximate mobile objects. Accordingly, the quality of the received digital signals may be deteriorated due to a ghost effect and noise caused by reflected waves. However, unlike the general video/audio data, when transmitting the supplemental data, the data that is to be transmitted should have a low error ratio. More specifically, in case of the video/audio data, errors that are not perceived or acknowledged through the eyes or ears of the user can be ignored, since they do not cause any or much trouble. Conversely, in case of the supplemental data (e.g., program execution file, stock information, etc.), an error even in a single bit may cause a serious problem. Therefore, a system highly resistant to ghost effects and noise is required to be developed.
The supplemental data are generally transmitted by a time-division method through the same channel as the MPEG video/audio data. However, with the advent of digital broadcasting, ATSC VSB digital television receivers that receive only MPEG video/audio data are already supplied to the market. Therefore, the supplemental data that are transmitted through the same channel as the MPEG video/audio data should not influence the conventional ATSC VSB receivers that are provided in the market. In other words, this may be defined as ATSC VSB compatibility, and the supplemental data broadcast system should be compatible with the ATSC VSB system. Herein, the supplemental data may also be referred to as enhanced data. Furthermore, in a poor channel environment, the receiving performance of the conventional ATSC VSB receiving system may be deteriorated. More specifically, resistance to changes in channels and noise is more highly required when using portable and/or mobile receivers.


Costs incurred for producing and circulating publications are often offset by revenue generated by including advertisements within the publication. Advertisements are more successful when properly targeted. Web page advertising has progressed such that advertisements can be targeted to particular viewers. This is not the case for printed publications such as newspapers where all readers of a publication run are presented with the same advertisements. Publishers do not have the tools to dynamically insert different advertising content into different copies of a given publication.


At present, freely deployed wireless access technologies, most notably the IEEE 802.11 family (a.k.a. WiFi), do not support any reliable means to determine the real achievable bit-rate over the link between a wireless terminal (STA) and an access point (AP), or between two terminal stations. This is due to fact that conventional AP beacons broadcast only their bit-rate technical capability, not real estimations of what could be achieved in the particular environment taking into account signal quality and current congestion levels. As a result, the information used by a STA to connect to an AP is inaccurate and incomplete.
This limitation in the art poses problems for WiFi users, for many end-user applications require information on the real achievable bit-rate before making a decision of which access point to associate when multiple access points are available. Conventional WiFi technology provides information regarding signal quality to assist in the determination of the estimated bit-rates; however, the conventional bandwidth (bit-rate) estimators, such as Pathcar, require build up of the full connection (i.e., a full association in the WiFi network between AP and STA and an IP connection over the created link) in order to probe by using network packets. As a result, such methods require a substantial amount of latency and overhead and, most importantly, such techniques are not applicable to a determining which AP to build up a connection to in the first place. The future 802.11k extension promises to provide some two-way signal strength information also from the AP to the STA, including history information, but not real bit-rate estimation.
In view of the needs in the art for improved bit-rate estimation prior to making WiFi connections between STAs and APs, a simple method is desired to better estimate the download bit-rate between a STA and an AP that takes into account the congestion on the corresponding AP as well as the signal quality. A system and method for achieving congestion load balancing when multiple APs are available, thus ensuring the best download bit-rate to wireless stations, is also desired. The present invention addresses these needs in the art.


The present invention relates to the treatment of dyed textiles, and more particularly to providing denim textiles which have an overdyed and stone washed appearance.


1. Field of the Invention
The present invention relates to circuitry for providing electrostatic discharge (ESD) protection. More particularly, the present invention relates to components for providing ESD protection for a circuit with components made using a 2.5 volt semiconductor process having a 5.0 volt compatible CMOS I/O.
2. Description of the Related Art
ESD can occur when a human body, or machine comes into contact with lead pins of a chip before the chip is placed in a circuit. ESD can also occur after the chip is placed in a circuit and powered up when a charged up lead pin is accidentally connected to ground. A typical circuit used to test a chip to determine if the chip offers adequate protection during an ESD event includes a series connected resistor and capacitor. To simulate the human body, a resistance of approximately 3000.OMEGA. is utilized in the test circuit along with a capacitance of approximately 10 pF. Because the instantaneous voltage from a human body can be as much as 2000 volts, the capacitor is typically charged up to as much as 3000 volts and connected through the resistor to the lead pin of a chip to assure the chip provides adequate ESD protection.
To prevent damage to circuitry on a chip during an ESD event, the output buffers are typically designed to go into avalanche breakdown to connect a lead pin receiving an electrostatic discharge directly to a ground pin without affecting other circuitry on the chip. FIG. 1 illustrates a portion of a typical output buffer of a chip which is powered down. The buffer includes an NMOS pull up transistor 102 and an NMOS pull down transistor 104. During power down, the gates of transistors 102 and 104 are connected to a ground pin through resistors. The transistors of the buffer are also connected to a pad 100 which is coupled to a lead pin of a chip.
When an ESD event occurs providing up to 3000 volts to the pad, transistor 104 goes into breakdown and then snap-back to connect the pad to ground to prevent circuit damage. To describe how snap back occurs during an ESD event to provide ESD protection, reference is made to FIGS. 2 and 3. FIG. 2 shows a cross section of a substrate containing the transistor 104 of FIG. 1. FIG. 3 graphs voltage at the pad vs. current through the source to drain of transistor 104.
In an ESD event, the voltage at the drain region 200 rises quickly. The inductance 201 will limit how quickly voltage rises on the drain region 200. Initially, with a voltage rising on the drain 200, the gate to drain overlap capacitance 208 begins to pull the gate high. The series resistance 210 of the gate initially protects the gate oxide because the voltage drop across the resistor is subtracted from the voltage that would otherwise appear across the gate oxide. As the gate is pulled up, the channel between the drain 200 and source 202 turns on.
The region of highest electric field is the pinch-off region 204 where the conducting electrons reach impact ionization energies, giving rise to electron-hole pair generation. With electroin-hole pair generation, the n+ drain region 200 will further be pulled high, to cause gate aided breakdown by creating a depletion region in the area 204 of the substrate between the gate 206 and region 200. Breakdown occurs initially in region 204 because the highest electric field occurs at this edge of the gate 206. With breakdown initially occurring, electron hole pairs are generated. Holes move away from the pad toward the p- substrate to pull the substrate high. With the p- substrate going high, forward biasing of a diode formed from the p- substrate region to the n+ source region 202 occurs with the n+ region connected to ground through an inductive line 203. With the p- to n+ diode forward biased, electrons will be injected from the region 202 into the p- substrate, which increases the carrier concentration locally. As the carrier concentration increases, the depletion width to maintain a given maximum electric field decreases thus decreasing the voltage drop--hence creating snap back.
As current increases through the transistor 104 beyond a primary breakdown point 300, which occurs at snap back, a secondary breakdown can occur at a point 302 as shown in FIG. 3. Secondary breakdown is destructive to the transistor 104 causing it to essentially melt. The size of transistor 104 is typically set to limit current below secondary breakdown when an ESD event occurs. If the size of the single transistor 104 is insufficient to limit current below secondary breakdown when an ESD event occurs, multiple transistors can be utilized as shown in FIG. 4.
In FIG. 4, three transistors 401-403 are used to connect the pad to ground. With three transistors and no resistors 411-413, when an ESD event occurs, one of the transistors 401-403 will break down first to limit the voltage potential across the source to drain of remaining transistors in 401-403, so the remaining transistors in 401-403 will not turn on. Current will then increase in the transistor which is turned on to cause secondary breakdown in the transistor turned on. To enable all transistors 401-403 to turn on during an ESD event, ballast resistors 411-413 are included in series with the source to drain path of each transistor 401-403. The ballast resistors have resistance values set so that if one of the transistors 401-403 goes into primary breakdown, the voltage applied across the remaining transistors in 401-403 will be enough to turn on those transistors so that current will not increase in one transistor enough to cause a secondary breakdown.
For an ESD event where the pad is pulled negative, referring to FIG. 2, the diode formed by region 200 and the p- substrate will be forward biased causing electron injection into the substrate. A p+ guard region 210 implanted in the substrate near the transistor 104 will complete the circuit to ground and so limits any negative voltage.
The structure for a 5.0 volt compatible output buffer made using a 2.5 volt semiconductor process makes providing ESD protection more difficult. A portion of a 5.0 volt compatible output buffer made using a 2.5 volt transistor process is shown in FIG. 5. The circuit includes two pull down transistors 501-502 with source to drain paths connected in series to connect a pad to ground. The circuit also includes two pull up transistors 503 and 504 with source to drain paths connected in series to connect the pad to a pin power supply voltage Vcc. In operation, when a 5.0 volt difference is applied from the pad to ground, or from Vcc to the pad, voltages are applied to the gates of transistors to prevent a voltage potential difference across any of transistors 501-504 from exceeding 2.7 volts. For example, when 5.0 volts is applied from the pad to ground, 3.3 volts is applied to the gate of transistor 502 to cause a 2.5 volt drop from the pad to node n2. With n2 at 2.5 volts, the gate to source, gate to drain, and source to drain voltages of transistors 501 and 502 do not exceed a maximum of 2.7 volts. Circuitry to control the gate voltage of transistors 501-504, as well as additional circuitry for a 5.0 volt compatible I/O buffer made with a 2.5 volt process, is disclosed in U.S. Patent Application Ser. No. 08/912,763, incorporated herein by reference.
FIG. 6 shows a cross section of a substrate containing either the transistors 503 and 504 of FIG. 5, or transistors 501 and 502 of FIG. 5, with a chip powered down. During an ESD event, when a high voltage is applied to the pad, with the gate of transistor 601 grounded, and the n+ region 616 of transistor 602 grounded, the n+ region 610 will be pulled high to initiate gate aided breakdown. With breakdown beginning, electron hole pairs are separated and the holes will move away from the region 610 toward the p-substrate to pull the substrate high. With the p-substrate going high, forward biasing of a diode formed from the p- substrate region to the n+ source region 616 occurs, since region 616 is grounded. With the p- to n+ (616) diode forward biased, electrons will be injected from the region 616 into the p- substrate to eventually cause snap back.
However, with transistors 501 and 502 of FIG. 5 spaced close enough to allow snap back for ESD protection, snap back can also occur during normal operation. During normal operation, the source of transistor 501 is grounded, a condition needed for snap back. When the output switches from high to low, current through the source to drain of transistor 502 can give rise to hot carrier generation creating electron-hole pairs that can charge up the p- substrate so that snap back can occur.
To prevent snap back during normal operation, the transistors 501 and 502 of FIG. 5 can be physically separated in the substrate. However, with transistors 501 and 502 physically separated to an extent needed to prevent snap back during normal operation, snap back will not occur during an ESD event. Current during an ESD event sufficient to cause breakdown at a region 611 in FIG. 6, as well as a region 615 will damage circuitry on a chip containing the buffer.
It is, therefore, desirable to provide a new ESD protection mechanism for a 5.0 volt compatible I/O buffer made using a 2.5 volt process, where two series transistors are required from a pad to ground.