A system including a setback and racking system and a set of wellbay accesses, at least a portion of the setback and racking system positioned at an elevation lower than the elevation of the wellbay accesses. A system including a centrally located setback and racking system, a set of wellbay accesses, and at least one peripheral skidding system, wherein the setback and racking system is positioned at least partially below the elevation of the peripheral skidding system. A system including at least one peripheral skidding system and a set of wellbay accesses positioned along a wellbay access perimeter surrounding a central focus that is not an integral part of the peripheral skidding system. A method of drilling by aligning each of at least two drilling modules with a respective wellbay access via a peripheral skidding system and operating at least two drilling modules at least partially simultaneously.

1. Field of the Invention
The present disclosure relates generally to a multi-operational system for use in petroleum exploration and development. More particularly, the present disclosure relates to a drilling system comprising a peripheral skidding system and/or a removed, lowered, and centrally located setback and racking system to enable a plurality of operations, such as, but not limited to, offline stand building and racking of tubulars, workover, and drilling operations, to be performed concurrently.
2. Background of the Invention
Offshore production of oil and gas requires the use of offshore drilling, completion, and workover rigs. These drilling, completion, and workover rigs are used in different phases of operation for the exploration and production of oil and gas. Offshore rig operations require a vast amount of manpower and the cost of operating these rigs is substantial. The rigs comprise systems for, among other operations, lifting and handling of loads, rotating of tubulars, power generation, circulation of fluids, monitoring of down hole activity, and maintenance of well control and safety.
Conventional systems comprise drilling equipment used in offshore activity for lifting and moving loads, rotating and handling of tubulars (e.g., drill pipe, drill collars, logging tools, casing, etc.), and assembling of tubulars (e.g., connecting multiple pieces of pipe in an end-to-end manner, etc.) prior to lowering the multi-piece unit into the well bore), assembling pipe and equipment, disassembling pipe and equipment, lowering pipe and equipment to the sea floor, and inserting components into the wellbore, and are also used in recovery operations. The systems are also used in drilling, completion, and workover operations.
When drilling operations are conducted in deep water, greater costs and logistical challenges can be confronted relative to operations in shallower waters. A major cost associated with drilling and producing a well is the cost of leasing the platform and associated equipment. Each day of rig time can cost hundreds of thousands of dollars. Accordingly, it is desirable to plan and design drilling operations to operate as efficiently as possible. The increased costs are compounded, for example, by the additional time required to deal with the challenges of operating in deep waters, and the make-up and break-out of tubulars during a drilling operation.
Operations for lifting and moving loads, for rotating and handling tubulars, and for drilling generally occur in the rig floor area. The rig floor area is positioned over the wellbays. Since the standard wellbay design is established in a matrix or grid format (e.g., a 4×4 layout), access to the wellbays below the rig floor is restricted by such designs. Therefore, due to the limited access to the wellbays, such a matrix format typically allows for only a single rig function (e.g., an active drilling derrick/mast, a workover operation, a wireline operation, a coiled tubing operation, etc.) to take place at a time. For example, the running of a drilling riser generally precludes the building of stands on a rig of standard design, thus relegating the first trip into the well bore to utilizing singles for tubulars.
Additionally, to assist the efficient handling thereof, tubulars are typically assembled and stacked vertically in an area within the rig floor known as the setback.
The racking of tubulars in the derrick or mast of the rig may undesirably act as a sail, imparting excessive wind loading forces onto the rig during inclement weather. In gusting wind conditions, for example, so-designed prior art rigs can thus be adversely affected by the resulting dangerous motions and dynamics caused by the impact of the wind on the setback within the derrick or mast. The mass, wind resistance, etc., imparted to the rig by the positioning of tubulars in an elevated setback normally mandates the removal and dismantling of such tubulars during high wind (e.g., hurricane) conditions.
The current industry standard of locating the setback and the derrick or mast within/on the rig floor requires a high level of complexity and automation, and undesirably provides that numerous activities take place overhead of the drilling crew. A serious cause of injury to, or even fatality of, offshore drilling rig workers is the falling of objects dropped from above the rig floor.
Traditionally, offshore wellbores are formed (e.g., drilled and completed) using a single load path (e.g., derrick, rig, drilling assembly), thus mandating that all wellbore tasks (e.g., drilling, completion, stimulations, workovers, etc.) be performed from a single drilling assembly. Recently, efforts have been made to decrease the time required to drill offshore wells by performing some tasks simultaneously. For example, U.S. Pat. Nos. 6,085,851 and 6,056,071 to Scott et al. disclose a multi-activity apparatus and method for conducting drilling operations. In general, Scott et al. disclose a drilling platform having dual drilling assemblies (e.g., separate load paths and/or derricks). In the method disclosed in Scott et al., some activities during the top hole drilling phase and the post drilling phase are performed substantially simultaneously by a main derrick and an auxiliary derrick.
U.S. patent application Ser. No. 12/840,658 describes a method for drilling an offshore wellbore into the seabed from a platform positioned proximate the water surface. The disclosed method comprises making up a first tubular string with a first conveyance assembly and running the first tubular string into the wellbore with the first conveyance assembly, and, while performing a wellbore task with the first tubular string, making-up a second tubular string from a second conveyance assembly, withdrawing the first tubular string from the wellbore with the first conveyance assembly once the wellbore task is completed, and running the second tubular string with the second conveyance assembly into the wellbore. Such a system enhances the speed at which wellbore tasks can be completed, but does not enable multiple wellbays to be serviced simultaneously and limits operations to two activities.
U.S. Pat. No. 4,444,275 to Beynet et al. discloses a carousel for a vertically moored platform. The disclosed carousel rotates about a central support post such that a drilling apparatus can be guided thereby from an anchored drilling vessel or tethered platform above a drilling template placed on the sea floor. Beynet et al. do not address the issues created by positioning a setback on the drilling floor in a drilling rig with regards to safety, wind loading and dynamics associated with the high CG (center of gravity) of the setback.
Accordingly, there remains a need for a drilling system that addresses the significant problems associated with the limitations of a matrix drilling format, the excessive wind loading forces that must be dealt with as a result of conventional racking of tubulars within a drilling rig, and/or improves the safety of workers on a rig by limiting the quantity and types of objects that are elevated and handled above the rig floor. Desirably, such a system provides for improvements in drilling performance, safety, and/or hurricane evacuation response. Improvements in drilling performance can include a reduction in the time required to drill and/or complete a wellbore, for example, by more efficient utilization of the rig floor of a platform rig assembly to enable multiple activities or operations, including exploration and/or production operations as well as completion, testing, workover, and maintenance operations to be performed more efficiently. Improvements in safety and/or hurricane evacuation response can be provided by eliminating the use of or the need for some physical equipment (e.g., a setback located on the rig floor and elevated within a drilling rig) traditionally required to conduct offshore drilling operations. Such an improved drilling system is also desirably more efficient than conventional drilling systems, providing for reduced costs associated with leasing capital drilling equipment, and/or lowered design costs for new drilling rigs.


A semiconductor device with a transistor region has a first conductor pattern formed within a multilayer interconnect structure positioned under a signal line and above the transistor region. The first conductor pattern is coupled to ground or a power supply and overlaps the transistor region. The signal line overlaps the first conductor pattern.

The present invention relates to semiconductor devices having a transmission line which uses a multilayer interconnect structure.
In recent years, as the processing speeds of semiconductor devices increase, the signals which flow in semiconductor devices tend to have higher frequencies. For transmission of signals at high frequencies, a transmission line must be used.
Japanese Patent Application Publication No. 2007-535825, which corresponds to WO2005/112105, discloses a method for forming a transmission line at the back end of line in the manufacture of semiconductor devices. According to this document, a ground shield for a transmission line is formed in an interconnect layer just under a signal line.
Japanese Patent Publication No. 2008-141474 describes that a silicon substrate and a multilayer interconnect structure above it are used to form a transmission line not for a semiconductor device but as a component for interconnection. According to this document, a ground shield for the transmission line is formed by the silicon substrate.
Japanese Patent Publication No. 2000-269429 discloses that ground planes and transmission lines are formed through a CMOS process. It also discloses that a digital IC is created through a CMOS process and a matching circuit for RFIC is independently formed and these are integrated on a chip.
The present inventors have realized that these techniques have the following problem. When transistors and a transmission line are formed on a chip through a CMOS process, the transistors and transmission line are coupled by interconnect wiring. With the progress in microfabrication, there is a tendency that the resistance of the interconnect wiring is larger, resulting in an increase of loss in the transmission line. It has been thus found that even when loss in the transmission line for coupling between elements such as transistors is decreased, deterioration in characteristics occurs.


Photosensitive cardiac rhythm modulation structures and systems are described. A genetically-engineered tissue comprising a population of pacing cells expressing a photosensitive membrane transport mechanism that is responsive to light of a particular wavelength(s) combined with one or more of a light source, a power generator, and a sensor provides pacemaker and/or defibrillator function to a subject. The systems further provide in vitro model systems for electrophysiological studies.

Pacemaker and defibrillator devices use electrical impulses to regulate beating of the heart. Current implantable artificial pacemakers and defibrillators rely on a programmable electronic device and wired electrodes to electrically stimulate and synchronize beating of the myocardium (pacemaker) or to correct cardiac arrhythmia (defibrillator). However, these implantable devices are unresponsive to autonomic heart rate modulation, require invasive surgical implantation and replacement every 5-10 years, are susceptible to temporary malfunction in the presence of magnets, e.g., metal detectors or MRI machines, or environmental noise, and increase the patient's inflammatory response and risk of infection. They have a limited battery life and their long-term use has been associated with permanent cardiac tissue damage. In addition, these electronic devices are often unsuitable for pediatric patients (see, e.g., emedicine.medscape.com/article/780825-overview).
Furthermore, implantable electrical cardiac defibrillators function by delivering a large, brief electric shock to reset a tachycardic/fibrillating heart and restore normal beating. Like pacemakers, the defibrillators must be implanted surgically and are prone to mechanical failure. A major complaint of patients with implanted defibrillators is the extreme pain from the electric shock produced by the devices.
Biological pacemakers are one alternative to artificial electrical pacing therapy. Biological pacemakers are responsive to autonomic modulation, require no external power source or replacement, present minimal inflammatory response, can be permanent, and can be autologous. Attempts at restoring cardiac automaticity with biologics have recently focused on two main approaches: gene therapy and cell transplantation (reviewed in M R Rosen et al., Anat. Rec. Part A 280A: 1046-1052, 2004). Gene therapy approaches introduce genes, such as the pacemaker gene, HCN2, directly into myocardial cells to restore or enhance automaticity. For example, adenovirus carrying an HCN2 construct has been injected into the left ventricular bundle branch system of canine hearts. Upon vagal stimulation, transgenic hearts demonstrated a more rapid heart rate than control hearts. Cell transplantation approaches involve transplanting isolated spontaneously active or genetically-engineered cells directly into the myocardium. For example, adult mesenchymal stem cells have been transformed with HCN2. The transformed stem cells were injected into the left ventricular anterior wall of a canine heart and were capable of stimulating heart rhythms (M R Rosen et al., Anat. Rec. Part A 280A: 1046-1052, 2004).
These short-term studies demonstrate the potential of biological pacemakers. Biological defibrillators have not, as yet, been explored. However, for both technologies, miniaturized systems and a minimally invasive means to access and regulate the cellular devices would facilitate and optimize control and repair of cardiac function in patients. Thus, there is a need in the art for biological pacemakers and/or defibrillators which are less invasive and more effective in regulating beating of the heart.

Photosensitive cardiac rhythm modulation systems

President and Fellows of Harvard College


To efficiently control channel quality indicators CQIs in response to a plurality of downlink component frequency bands in a wireless communication system using a plurality of component frequency bands, and enable a mobile station apparatus to suitably transmit signals including the channel quality indicators CQIs, the mobile station apparatus is provided with an uplink control data generation part 407 that generates a channel quality indicator in response to each of the downlink component frequency bands, an uplink control channel selection part 409 that selects a particular radio resource when a plurality of radio resources, which are beforehand allocated from the base station apparatus to transmit the channel quality indicator for each of the downlink component frequency bands, occurs in the same time frame, and a transmission processing part 405 that arranges the channel quality indicator generated in the uplink control data generation part 407 in the radio resource selected in the uplink control channel selection part 409 to transmit to the base station apparatus.

<Channel Quality Indicator (CQI)>
Described below is the channel quality indicator CQI in EUTRA (Evolved Universal Terrestrial Radio Access; hereinafter, referred to as "EUTRA"). The channel quality indicator CQI is a measurement result of channel quality measured by a mobile station apparatus using a downlink reference signal of a downlink pilot channel received from a base station apparatus, and is information indicative of channel quality of a downlink system band for each mobile station apparatus. For example, information, which is indicative of modulation scheme-coding rate considered suitable for the downlink shared channel based on the measured quality information, is configured as the channel quality indicator CQI. More specifically, on the condition that the error rate of information data arranged on the downlink shared channel does not exceed 0.1, information indicative of a combination of modulation scheme and coding rate with the highest communication efficiency is configured as the channel quality indicator CQI.
The mobile station apparatus periodically transmits the channel quality indictor CQI to the base station apparatus, using an uplink control channel beforehand assigned from the base station apparatus. In addition, in starting communication connection with a mobile station apparatus, the base station apparatus allocates periodical radio resources (hereinafter, CQI arrangement-capable control channels) for the mobile station apparatus to arrange the channel quality indicator CQI. In addition, herein, the radio resources indicate radio resources comprised of a predetermined frequency band and time band. In addition, code multiplexing is also applied to the uplink control channel for arranging the channel quality indicator CQI in EUTRA, but is omitted herein, for convenience in description.
Using the channel quality indicator CQI received from the mobile station apparatus, the base station apparatus performs radio resource allocation (frequency scheduling) of a downlink shared channel to the mobile station apparatus, and selection of the modulation scheme and coding rate (adaptive modulation and coding) of the downlink shared channel. For example, the base station apparatus assigns the downlink shared channel to a downlink resource block of good channel quality indicator CQI for the mobile station apparatus. Further, the base station apparatus sets the modulation scheme of the downlink shared channel from among QPSK (Quadrature Phase Shift Keying), 16 QAM (16 Quadrature Amplitude Modulation), and 64 QAM (64 Quadrature Amplitude Modulation), corresponding to the channel quality indicator CQI.
<Component Frequency Band>
Meanwhile, 3GPP (3rd Generation Partnership Project) has started studies of the 4th Generation (hereinafter, referred to as "4G") radio access scheme (Advanced EUTRA; hereinafter, referred to as "A-EUTRA") and 4G network (Advanced EUTRAN) of cellular mobile communications.
In A-EUTRA, it is studied supporting wider frequency bands than EUTRA, and ensuring compatibility with EUTRA. Therefore, in A-EUTRA, studied are techniques (referred to as Spectrum aggregation or Carrier aggregation) that the base station apparatus performs communications using a system band comprised of a plurality of component frequency bands with a frequency band of EUTRA regarded as a single unit (component frequency band) (in addition, the component frequency band is sometimes referred to as a carrier component or component carrier.) (Non-patent Document 1) In the techniques, the base station apparatus performs communications with a mobile station apparatus supporting EUTRA using any one of component frequency bands in each of uplink and downlink, while performing communications with a mobile station apparatus supporting A-EUTRA using one or more component frequency bands in each of uplink and downlink.

Wireless communication system, mobile station apparatus, base station apparatus, communication control method and integrated circuit


A PTO switch for the attachment drive of a lawn and garden tractor includes a solenoid activated detent to retain the normally off switch in an on position. The switch includes an interlock override position for permitting a function such as mow in reverse. An interlock circuit interrupts drive to the attachment under certain conditions. Once drive is interrupted for any reason, the solenoid deactivates and the switch is moved to the off position so that PTO switch position corresponds to attachment drive condition, even when the drive is interrupted by means other than movement of the switch.

The present invention relates generally to lawn and garden tractors or similar vehicles, and more specifically to an interlock circuit and detent switch for such a vehicle.
Vehicles such as some lawn and garden tractors with PTO driven attachments include an interlock circuit with several functions including the prevention of PTO operation when the vehicle is placed in reverse and stopping of the engine when the operator leaves the seat. Under certain conditions, operation of the PTO while the vehicle is in reverse is necessary. Various override systems have been proposed for this purpose. For example, one type of available override system on a mower allows PTO operation when the vehicle is backing up, but only after the PTO is automatically disconnected during the shift into reverse. Another type requires the operator to continuously push a switch during reverse operation. Further types are shown in U.S. Pat. Nos. 6,316,891 and 5,994,857 of common ownership with the present application.
Problems with some of the previously available systems is that the PTO switch can remain in the on position under certain conditions when relays have been deactivated by the interlock system and the engine stops or the PTO is disengaged. In the engine kill situation, the operator must first return the PTO switch to the off position to restart the engine, but often the operator initially fails to notice that the PTO switch is on and tries other options first. When PTO operation is interrupted, the operator must reactivate the PTO by moving the switch back to the on position. Although such systems have provided the necessary interlock and override functions, they are not as intuitive and user-friendly as systems wherein the position of the PTO switch actually corresponds to the operational state of the PTO.
It is therefore an object of the present invention to provide an improved interlock system for a vehicle such as a lawn and garden tractor. It is another object to provide such a system which overcomes most or all of the aforementioned problems.
It is a further object of the present invention to provide an improved interlock system for a vehicle such as a lawn and garden tractor with a PTO or similar attachment drive switch wherein the on and off positions of the switch correspond directly to the on and off conditions of the driven attachment, even if the attachment drive is disabled or the engine is stopped by action of an interlock system.
It is yet another object of the present invention to provide an improved interlock system for a vehicle such as a lawn and garden tractor with a bypass circuit allowing operation in reverse under certain conditions. It is a further object to provide such a circuit with an improved PTO or attachment drive switch wherein switch position corresponds directly to the PTO or attachment drive condition. It is another object to provide such a circuit having a switch that moves to the off position if the vehicle engine is shut down or if the interlock circuit is operated to disable drive to the attachment.
It is another object of the present invention to provide an improved switch for controlling drive to an attachment on a lawn and garden tractor or similar vehicle. It is still another object to provide such a switch which is particularly useful for interlock circuits with a bypass system to allow operation of an attachment in reverse under certain conditions.
It is yet another object to provide such an improved switch for controlling drive to an attachment on a lawn and garden tractor or similar vehicle, the switch including an actuation device to move the switch handle to an off position in response to an interlock circuit on the vehicle interrupting drive to the attachment so that switch position corresponds to the actual attachment on or off condition. It is a further object to provide such a switch which returns to the off position when the engine is killed.
A PTO switch for the attachment drive of a lawn and garden tractor includes a solenoid activated detent to retain the normally off switch in an on position. The switch includes an interlock override position for permitting a function such as mow in reverse. An interlock circuit interrupts drive to the attachment under certain conditions. Once drive is interrupted for any reason, the solenoid deactivates and the switch is moved to the off position so that PTO switch position corresponds to attachment drive condition, even when the drive is interrupted by means other than movement of the switch. Since the switch is returned to the off position, the problems associated with the operator failing to notice that the PTO switch is on are reduced or eliminated. Machine disruption and operator frustration are minimized, and the time necessary for the operator to get the machine back up and running after an engine kill or PTO interruption is reduced.

Interlock system and a detent switch therefor


A control system is provided for an actuating member including a controller, a solenoid valve electrically coupled to the controller, a fluid driven actuator operatively coupled to the solenoid valve, an actuating member operatively coupled to the fluid driven actuator, a potentiometer operatively coupled to the actuating member for converting a rotational position of the actuating member into a proportional electrical resistance, signal converting means for converting the electrical resistance to a proportional electrical current, and means for conducting the current to the controller. The controller includes means for comparing the current to a control signal indicative of a desired position of the actuating member, and means for generating a voltage pulse to the solenoid valve to displace the fluid driven actuator and move the actuating member to the desired position. A method utilizing the above system is also provided.

1. Field of the Invention
This invention relates to a feedback control system, and more particularly, to a feedback system for controlling the position of tilting burners of a coal-fired furnace.
2. Description of Related Art
In the operation of present-day steam generating units, it is common to physically raise or lower the burners over a considerable distance to make use of more or less heat absorption surface in the furnace and thereby effect a wide range control of the temperature of the combustion gases leaving the furnace. Thus, burner tilt-drive devices have been developed to facilitate movement of the burners at each corner of the furnace. Conventionally, such devices include pneumatic cylinders which manipulate rotary actuators to control the position of the burners. The pneumatic cylinders include a piston which divides a cylindrical housing into first and second chambers on opposite sides of the piston. To adjust the burner, pneumatic fluid is supplied to or vented from the first and second chambers.
The Clean Air Act Amendment places an emphasis on low NOx emission, thus necessitating tighter control of burner tilt to improve combustion. Conventionally, control of the burner tilt corners had been done collectively, to reduce cost. However, with the need for tighter burner control, it has been proposed to isolate each burner corner and provide individual control thereof. Further, to ensure optimum combustion, feedback position for each burner tilt device at each burner corner has been proposed. However, to establish such feedback, the rotational position of the final control element must be monitored, requiring that the feedback device be exposed to the excessive heat of the furnace. Such devices may thus be exposed to temperatures exceeding 240.degree. F. consequently, feedback devices tend to degrade with excessive heat and ultimately induce errors in the positioning of the burners tilt devices. In addition, conventional control systems have included linkages which may induce further errors. Even further, individual control of burner corners utilizing conventional feedback control systems generally requires high cost modifications to existing systems.

c/o Virginia Power, Innsbrook Technical Center, 5000 Dominion Blvd.


Thiazolopyridin-2-yloxy-phenyl and thiazolopyrazin-2-yloxy-phenyl amine compounds are described, which are useful as LTA4 hydrolase (LTA4H) modulators. Such compounds may be used in pharmaceutical compositions and methods for modulation of LTA4H and for the treatment of disease states, disorders, and conditions mediated by LTA4 hydrolase activity.

Inflammation is normally an acute response by the immune system to invasion by microbial pathogens, chemicals or physical injury. In some cases, however, the inflammatory response can progress to a chronic state, and be the cause of inflammatory disease. Therapeutic control of this chronic inflammation in diverse diseases is a major medical need.
Leukotrienes (LT) are biologically active metabolites of arachidonic acid (B. Samuelsson, Science 1983, 220(4597): 568-575) that have been implicated in inflammatory diseases, including asthma (D. A. Munafo et al., J. Clin. Invest. 1994, 93(3): 1042-1050; N. Miyahara, et al., Allergol Int., 2006, 55(2): 91-7; E. W. Gelfand, et al., J. Allergy Clin. Immunol. 2006, 117(3): 577-82; K. Terawaki, et al., J. Immunol. 2005, 175(7): 4217-25), inflammatory bowel disease (IBD) (P. Sharon and W. F. Stenson, Gastroenterology 1984, 86(3): 453-460), chronic obstructive pulmonary disease (COPD) (P. J. Barnes, Respiration 2001, 68(5): 441-448), arthritis (R. J. Griffiths et al., Proc. Natl. Acad. Sci. U.S.A. 1995, 92(2): 517-521; F. Tsuji et al., Life Sci. 1998, 64(3): L51-L56), psoriasis (K. Ikai, J. Dermatol. Sci. 1999, 21(3): 135-146; Y. I. Zhu and M. J. Stiller, Skin Pharmacol. Appl. Skin Physiol. 2000, 13(5): 235-245) and atherosclerosis (Friedrich, E. B. et al. Arterioscler Thromb Vasc Biol 23, 1761-7 (2003); Subbarao, K. et al. Arterioscler Thromb Vasc Biol 24, 369-75 (2004); Helgadottir, A. et al. Nat Genet 36, 233-9 (2004); Jala, V. R. et al Trends in Immun. 25, 315-322 (2004)). The synthesis of leukotrienes is initiated by the conversion of arachidonic acid to an unstable epoxide intermediate, leukotriene A4 (LTA4), by 5-lipoxygenase (5-LO) (A. W. Ford-Hutchinson et al., Annu. Rev. Biochem. 1994, 63: 383-347). This enzyme is expressed predominantly by cells of myeloid origin, particularly neutrophils, eosinophils, monocytes/macrophages and mast cells (G. K. Reid et al., J. Biol. Chem. 1990, 265(32): 19818-19823). LTA4 can either be conjugated with glutathione by leukotriene C4 (LTC4) synthase to produce the cysteinyl leukotriene, LTC4, or hydrolyzed to the diol, leukotriene B4 (LTB4) (B. Samuelsson, Science 1983, 220(4597): 568-575). LTC4 and its metabolites, LTD4 and LTE4, induce smooth muscle contraction, broncho-constriction and vascular permeability, while LTB4 is a potent chemo-attractant and activator of neutrophils, eosinophils, monocytes/macrophages, T cells and mast cells.
The stereospecific hydrolysis of LTA4 to LTB4 is catalyzed by leukotriene A4 hydrolase (LTA4H), a zinc-containing, cytosolic enzyme. This enzyme is ubiquitously expressed, with high levels in small intestinal epithelial cells, lung, and aorta (B. Samuelsson and C. D. Funk, J. Biol. Chem. 1989, 264(33): 19469-19472). Moderate expression of LTA4H is observed in leukocytes, particularly neutrophils (T. Yokomizo et al., J. Lipid Mediators Cell Signalling 1995, 12(2, 3): 321-332).
Leukotriene B4 is a key pro-inflammatory lipid mediator, able to recruit and activate inflammatory cells, such as neutrophils, eosinophils, monocytes/macrophages, T cells and mast cells (F. A. Fitzpatrick et al., Ann. N. Y. Acad. Sci. 1994, 714: 64-74; S. W. Crooks and R. A. Stockley, Int. J. Biochem. Cell Biol. 1998, 30(2): 173-178; A. Klein et al., J. Immunol. 2000, 164: 4271-4276). LTB4 mediates its pro-inflammatory effects by binding to G protein-coupled receptors, leukotriene B4 receptor 1 (BLT1) and leukotriene B4 receptor 2 (BLT2) (T. Yokomizo et al., Arch. Biochem. Biophys. 2001, 385(2): 231-241). The receptor first identified, BLT1, binds LTB4 with high affinity, leading to intracellular signaling and chemotaxis. BLT1 is expressed mainly in peripheral leukocytes, particularly neutrophils, eosinophils, macrophages (Huang, W. W. et al. J Exp Med 188, 1063-74 (1998)) and monocytes (Yokomizo, T., Izumi, T. & Shimizu, T. Life Sci 68, 2207-12 (2001)). The murine receptor is also expressed on effector T cells and was recently shown to mediate LTB4-dependent migration of effector CD8+ T cells (Goodarzi, K., Goodarzi, M., Tager, A. M., Luster, A. D. & von Andrian, U. H. Nat Immunol 4, 965-73 (2003); Ott, V. L., Cambier, J. C., Kappler, J., Marrack, P. & Swanson, B. J. Nat Immunol 4, 974-81 (2003)), early effector CD4+ T helper type 1 (TH1) and TH2 chemotaxis and adhesion to endothelial cells, as well as early effector CD4+ and CD8+ T cell recruitment in an asthma animal model (Tager, A. M. et al., Nat Immunol 4, 982-90 (2003)). LTB4 receptor BLT2 (S. Wang et al., J. Biol. Chem. 2000, 275(52): 40686-40694; T. Yokomizo et al., J. Exp. Med. 2000, 192(3): 421-431) shares 42% amino acid homology with BLT1, but is more broadly expressed, including in peripheral tissues such as the spleen, ovary and liver, as well as in leukocytes. BLT2 binds LTB4 with lower affinity than BLT1 does, mediates chemotaxis at higher concentrations of LTB4, and differs from BLT1 in its affinity for certain antagonists. While LTB4 receptor antagonists may differ in their affinity for BLT1 versus BLT2, blocking the production of LTB4 using LTA4H inhibitors would be expected to inhibit the downstream events mediated through both BLT1 and BLT2.
Studies have shown that introduction of exogenous LTB4 into normal tissues can induce inflammatory symptoms (R. D. R. Camp et al., Br. J. Pharmacol. 1983, 80(3): 497-502; R. Camp et al., J. Invest. Dermatol. 1984, 82(2): 202-204). Increased production of LTB4 is considered important for the inflammatory component in a number of diseases, including atopic dermatitis (O. Koro et al. J. Allergy Clin. Immunol. 1999, 103, 663-670), asthma (M. Frieri et al., Ann. Allergy Asthma Immunol. 1998, 81, 331-336), inflammatory bowel disease, chronic obstructive pulmonary disease (W. A. Biernacki et al. Thorax 2003, 58, 294-298; J. S. Seggev et al., Chest 1991, 99, 289-291), atherosclerosis and cardiovascular disease, multiple sclerosis (I. S. Neu et al., Acta Neurol. Scand. 2002, 105, 63-66), psoriasis (D. M. Reilly, Acta Derm. Venereol. 2000, 80, 171-174), cystic fibrosis (J. T. Zakrzewski, et al., Br J Clin Pharmacol 1987, 23:19-27), and rheumatoid arthritis (N. Ahmadzadeh, Inflammation 1991, 15, 497-503). Therefore, inhibitors of LTB4 production should have therapeutic value as anti-inflammatory agents for these conditions. Thus, reduction of LTB4 production by an inhibitor of LTA4H activity would be predicted to have therapeutic potential in a wide range of diseases.
This idea is supported by a study of LTA4H-deficient mice that, while otherwise healthy, exhibited markedly decreased neutrophil influx in arachidonic acid-induced ear inflammation and zymosan-induced peritonitis models (R. S. Byrum et al., J. Immunol. 1999, 163(12): 6810-6819). LTA4H inhibitors have been shown to be effective anti-inflammatory agents in pre-clinical studies. For example, oral administration of LTA4H inhibitor SC57461 caused inhibition of ionophore-induced LTB4 production in mouse blood ex vivo, and in rat peritoneum in vivo (J. K. Kachur et al., J. Pharm. Exp. Ther. 2002, 300(2), 583-587). Eight weeks of treatment with the same inhibitor compound significantly improved colitis symptoms in cotton top tamarins (T. D. Penning, Curr. Pharm. Des. 2001, 7(3): 163-179). The spontaneous colitis that develops in these animals is very similar to human IBD. The results therefore indicate that LTA4H inhibitors would have therapeutic utility in this and other human inflammatory diseases.
Events that elicit the inflammatory response include the formation of the pro-inflammatory mediator leukotriene B4. Hydrolase LTA4H catalyzes the formation of this mediator, and LTA4H inhibitors block the production of the pro-inflammatory mediator LTB4, thus providing the ability to prevent and/or treat leukotriene-mediated conditions, such as inflammation. The inflammatory response is characterized by pain, increased temperature, redness, swelling, or reduced function, or by a combination of two or more of these symptoms. Regarding the onset and evolution of inflammation, inflammatory diseases or inflammation-mediated diseases or conditions include, but are not limited to, acute inflammation, allergic inflammation, and chronic inflammation.
Compounds of the present invention were shown to inhibit LTA4H in in vitro assays. Inhibition was shown in a recombinant enzymatic assay and in a cellular assay using murine (diluted 1 in 15) or human whole blood (diluted 1:1). Embodiments of the invention were also shown to inhibit murine ex vivo LTB4 production in whole blood (diluted 1:1), as well as arachidonic acid-induced neutrophil influx in murine ear tissue.
Atopic dermatitis (AD) is a chronic inflammatory skin disease that usually occurs in individuals with a personal or family history of atopy. The major features are pruritus and chronic or relapsing eczematous lesions. Complications include bacterial, fungal and viral infections as well as ocular disease. Atopic dermatitis is the most common inflammatory skin disease in children and affects more than 15% of children in the US (Laughter, D., et al., J. Am. Acad. Dermatol. 2000, 43, 649-655). Atopic dermatitis may persist in 60% of adults who were affected as children (Sidbury, R., et al., Dermatol. Clin. 2000, 18(1), 1-11).
Atopic dermatitis has significant societal impact. The family stress related to caring for children with moderate to severe AD may be comparable to the stress seen in families of children with type I diabetes mellitus (Su, J. C., et al., Arch. Dis. Child 1997, 76, 159-162). In the US, the annual cost of medical services and prescription drugs for the treatment of AD/eczema is similar to those for emphysema, psoriasis and epilepsy (Ellis, C. N., et al., J. Am. Acad. Dermatol. 2002, 46, 361-370).
Several lines of evidence support the role of LTB4 in AD. LTB4 levels are elevated in skin lesions (K. Fogh et al., J. Allergy Clin. Immunol. 1989, 83, 450-455; T. Ruzicka et al., J. Invest. Dermatol. 1986, 86, 105-108) and plasma in AD, and contribute to the inflammation through chemotactic effects on inflammatory cells (Wedi and Kapp. BioDrugs. 2001; 15, 729-743. Reported in vivo and in vitro studies have shown that leukotrienes, especially LTB4, contribute to the inflammation of the skin in AD through their chemotactic effect on inflammatory cells. LTB4 receptors are expressed on mast cells, T cells, eosinophils, dendritic cells and macrophages, all of which accumulate in AD lesions. LTB4 itself is a pruritic agent, and has also been shown to mediate substance P-induced pruritus (T. Andoh et al., J. Invest. Dermatol. 2001, 117, 1621-1626), a key component of the itching in AD (T. Ohmura et al., Eur. J. Pharmacol. 2004, 491, 191-194). LTB4 induces proliferation of keratinocytes, an effect that is further potentiated by substance P (M. J. Rabier et al., J. Invest. Dermatol. 1993, 110, 132-136). Recent reports indicate a role for LTB4 in development of a Th2 immune response and IgE production. The role of LTB4 in AD is supported by beneficial effects of the 5-lipoxygenase inhibitor, zileuton, in a small, open-label clinical trials of AD (Woodmansee, D. P., et al., Ann. Allergy Asthma Immunol. 1999, 83, 548-552) and in relieving the pruritus in Sjogren-Larsson syndrome patients who have elevated LTB4 due to an impairment in its degradation (Willemsen, M. A., et al., Eur. J. Pediatr. 2001, 160, 711-717).
While AD that is mild to moderate in severity generally responds to topical therapy, correct use of these therapies and compliance remain a major issue in the clinic (T. Agner, Acta Derm. Verereol. Suppl. (Stockh) 2005, 213, 33-35). Topical corticosteroids and emollients are the standard of care in the treatment of AD. However, systemic immunomodulatory therapies and potent topical corticosteroids used to treat severe AD are associated with significant cutaneous side effects, such as striae, atrophy and telangeictasia that limit the long-term use of these agents (Hanifin, J. M., et al., J. Am. Acad. Dermatol. 2004, 50, 391-404).
Emollients have a steroid-sparing effect and are useful for both prevention and maintenance therapy. Crude coal tar and preparations containing coal tar derivatives have also been used for many years in the treatment of AD and have significant cosmetic disadvantages that influence compliance (Hanifin, et al., 2004). Topical doxepin may be a useful short-term adjunctive therapy for the relief of pruritus but sedation and contact dermatitis may complicate its use (Hanifin, et al., 2004).
The topical calcineurin inhibitors tacrolimus (Protopic®) and pimecrolimus (Elide)®) have been shown to reduce the extent, severity and symptoms of AD in adults and children and are approved for use as second-line therapy of AD. However, the recent addition of boxed warnings to the product labels regarding rare cases of malignancy reported in patients treated with topical calcineurin inhibitors limits long term use of these agents in the treatment of AD (Food and Drug Administration [FDA]/Center for Drug Evaluation and Research [CDER] resources page).
Antibiotics are used in the treatment of Staphylococcus aureus infections in patients with AD but have a minimal effect on the dermatitis (Hanifin, et al., 2004). Although sedating antihistamines may be useful if sleep disruption is present, oral antihistamines are generally not effective in treating AD-associated pruritus (Hanifin, et al., 2004). Ultraviolet (UV) phototherapy, including photochemotherapy with psoralen is well established in the treatment of AD but relapse upon cessation of therapy frequently occurs (Hanifin, et al., 2004).
Systemic immunomodulatory therapy with cyclosporine and corticosteroids is effective but can be associated with severe side effects and is generally reserved for patients with severe disease. Systemic corticosteroids are associated with growth retardation in children, avascular necrosis of bone, osteopenia, increased risk of infection, poor wound healing, cataracts, hyperglycemia and hypertension. Cyclosporine is nephrotoxic in a majority of patients and is associated with tremor, hirsutism, hypertension, hyperlipidemia and gum hyperplasia.
While AD that is mild to moderate in severity generally responds to topical therapy, correct use of these therapies and compliance remain a major issue in the clinic. An oral or topical agent lacking the risks associated with corticosteroids and the calcineurin inhibitors would be a welcome addition to the armamentarium of treatments for AD that is mild to moderate in severity. An effective oral or topical therapy with fewer side effects than systemic immunomodulatory therapies and potent topical corticosteroids would fill an unmet medical need in the treatment of AD.
Sjogren-Larsson syndrome is an autosomal recessive neurocutaneous disorder with severe ichthyosis. It is caused by mutation of the gene encoding microsomal fatty aldehyde dehydrogenase (FALDH) leading to a defect in fatty alcohol metabolism. FALDH catalyzes the oxidation of medium- to long-chain fatty aldehydes to their corresponding carboxylic acids. LTB4, a pro-inflammatory mediator synthesized from arachidonic acid, is inactivated by microsomal omega-oxidation, successively yielding 20-OH-LTB4, 20-CHO-LTB4 and 20-COOH-LTB4. The urine of Sjogren-Larsson syndrome patients contains highly elevated levels of LTB4 and 20-OH-LTB4. Defective LTB4 degradation in Sjogren-Larsson syndrome patients is now considered to be shown with "unambiguous evidence". (Willemsen, M. A., et al., J. Neurol. Sci. 2001, 183(1), 61-7). Sjogren syndrome is an autoimmune disease that features inflammation in some glands. Sjogren syndrome may feature also extraglandular manifestations. When the gland inflammation is not associated with another connective tissue disease, then the syndrome is referred to as primary Sjogren syndrome. When it is associated with a connective tissue disease, such as rheumatoid arthritis, systemic lupus erythematosus or scleroderma, then it is referred to as secondary Sjogren syndrome. The term "Sjogren syndrome" herein refers to any one of the primary and secondary Sjogren syndromes. No cure is currently known for this syndrome. The current treatments usually focus on the specific area of the body that is affected and also in the treatment of associated complications. Immuno-suppressants such as cortisones, azathioprine and cyclophosphamide are sometimes used to threat some serious complications, and antibiotics are also used to treat associated infections.
Embodiments of this invention have shown dose-dependent inhibition of dermal inflammation in the arachidonic acid-induced murine ear inflammation model. Oral administration of embodiments of this invention dose-dependently inhibited neutrophil influx and edema, and were shown to inhibit the ex vivo ionophore-stimulated LTB4 production at doses between 0.3 and 30 mg/kg.
LTA4H inhibitors are hypothesized to specifically block the production of LTB4 from LTA4, without affecting the biosynthesis of lipoxins, which are also produced from LTA4. Increasing or maintaining lipoxin A4 (LXA4) production may have beneficial therapeutic effects in dermal inflammation as it has been reported that topical application of a stable lipoxin analogue inhibits edema, granulocyte infiltration and epidermal hyperproliferation in murine skin inflammation models. 5-LO inhibitors block the pathway upstream of LTA4. This would be expected to lead to a block in not only synthesis of LTA4, LTB4 and cysteinyl leukotrienes (CysLT), but also LXA4.
Embodiments of this invention have been studied in in vivo inflammation models including arachidonic acid-induced ear inflammation and allergic lung inflammation, including an ovalbumin (OVA) sensitization and airway challenge model and a rat ionophore-induced lung inflammation model. For example, embodiments of the invention show dose-dependent inhibition of the accumulation of inflammatory cells in the lungs in an ovalbumin-induced allergic airway inflammation model, a common animal model for human allergic inflammation.
Asthma is a chronic disease characterized by a variable degree of airflow obstruction, bronchial hyperresponsiveness and airway inflammation (Busse & Lemanske, 2001). Immunohistopathologic features include denudation of airway epithelium, collagen deposition beneath basement membrane, edema, mast cell activation, and inflammatory cell infiltration by neutrophils (especially in sudden-onset, fatal asthma exacerbations), eosinophils, and Th2 lymphocytes (W. W. Busse et al., N. Engl. J. Med. 2001, 344, 350-362). Airway inflammation contributes to the airway hyperresponsiveness, airflow limitation (acute bronchoconstriction, airway edema, mucus plug formation and airway wall remodeling, leading to bronchial obstruction), respiratory symptoms and disease chronicity (NIH Guidelines for the Diagnosis and Management of Asthma 1997).
Current therapy for asthma is directed at controlling acute bronchoconstrictive symptoms with beta2-adrenergic receptor agonists and managing underlying airway inflammation with inhaled corticosteroids, chromates such as cromolyn sodium and nedocromil, and antileukotriene agents, such as the cysteinyl leukotriene receptor antagonists montelukast and zafirlukast and the 5-lipoxygenase inhibitor zileuton. Systemic steroids are used in severe disease and acute exacerbations of asthma. The humanized monoclonal anti-IgE antibody omalizumab was approved for the treatment of patients with moderate-to-severe persistent asthma who have a positive skin test or in vitro reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with inhaled corticosteroids (XOLAIR® [omalizumab] July 2007).
The inflammatory component of mild persistent and moderate asthma can generally be controlled with inhaled corticosteroids, but patient compliance remains a major issue in disease management (H. Milgrom et al., J. Allergy Clin. Immunol. 1996, 98, 1051-1057). Despite optimum therapy, including long-acting beta-agonists and inhaled corticosteroids, many patients have poorly controlled asthma (J. M. Fitzgerald et al., Can. Respir. J. 2006, 13, 253-259; D. Bellamy et al., Prim. Care Respir. J. 2005, 14, 252-258). Severe asthma requires treatment with high-dose inhaled steroids or the frequent use of oral corticosteroids (W. Moore et al., J. Allergy Clin. Immunol. 2006, 117, 487-494), both of which can be associated with negative side effects such as osteopenia and growth retardation in children (D. Allen et al., Suppl. J. Allergy Clin. Immunol. 2003, 112, 51; P. Schimmer et al., Adrenocorticotropic Hormone; Adrenocortical Steroids and Their Synthetic Analogs; Inhibitors of the Synthesis and Action of Adrenocortical Hormones in Hardman J G, Limbird L E; eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics, 10th ed. New York: McGraw-Hill; 2001; 1666-1668). An oral therapy that could effectively treat moderate-to-severe asthma and reduce corticosteroid requirements would address unmet medical needs.
Leukotrienes are important mediators in asthma pathogenesis and comprise two classes—the cysteinyl leukotrienes (LTC4, LTD4 and LTE4) and LTB4. Leukotriene receptor antagonists, such as montelukast or zafirlukast, target only the cysteinyl leukotrienes, while 5-lipoxygenase inhibitors, such as zileuton, inhibit the pathway upstream of both classes, and thus decrease formation of both the cysteinyl leukotrienes and LTB4. LTA4H inhibitors selectively inhibit LTB4 synthesis and do not impact cysteinyl leukotriene (CysLT) synthesis. Both classes of leukotrienes are elevated in asthma, and LTB4 is more significantly increased in severe asthma, which is associated with increased neutrophilic inflammation.
Several preclinical and clinical findings suggest that inhibition of LTB4 synthesis by LTA4H inhibitors will have therapeutic benefit in asthma. Studies in mice lacking LTB4 receptors have shown that LTB4 plays a role in eosinophil and effector T cell recruitment, IL-13 production, goblet cell hyperplasia and mucus secretion, IgE production and airway hyperreactivity (Miyahara et al., Allergy Intl. 2006, 55, 91-97). The importance of LTB4 in development in airway hyperreactivity is supported by data with the LTB4 receptor antagonist (CP-105,696), which reduced airway hyperresponsiveness induced by multiple antigen challenges in a primate model (C. R. Turner et al., J. Clin. Invest. 1996, 97, 381-387). Furthermore, the reduction of bronchial hyperresponsiveness in human asthma by the 5-LO inhibitor, zileuton, has been attributed to its inhibition of LTB4 synthesis (S. E. Dahlen et al., Eur. J. Pharmacol. 2006, 533(1-3), 40-56). Inhibition of LTB4 may also be beneficial in severe asthma (S. E. Wenzel et al., Am. J. Respir. Crit. Care Med. 1997, 156, 737-743) and viral exacerbations of asthma (S. D. Message, Eur. Respir. J. 2001, 18, 1013-1025), where neutrophilic inflammation is more prominent. CysLT antagonists and steroids have limited efficacy in severe asthmatics, while zileuton has been shown to significantly improve quality of life in these patients (R. Menendez et al., American Thoracic Society Meeting, San Diego, 2006).
An allergy is an abnormal reaction to an allergen (an ordinarily harmless substance) that triggers an abnormal response in a sensitized individual. Allergic rhinitis is an inflammation of the mucus membranes of the nose that occurs in response to an airborne antigen (allergen). Allergic rhinitis, also called allergic rhinoconjunctivitis, is characterized by frequent or repetitive sneezing, runny or congested nose, and pruritus of the nose, eyes and throat. It may also be associated with other symptoms such as headache, impaired smell, postnasal drip, conjunctival symptoms (e.g., itchy watery eyes), sinusitis and other complicating respiratory symptoms. Depending upon the time of exposure, allergic rhinitis can be classified as perennial, seasonal or occupational.
Embodiments of this invention have shown dose-dependent inhibition of lung inflammation in pre-clinical models, Based upon the well-described leukotriene biosynthesis pathway, LTA4H inhibitors are hypothesized to specifically block the production of LTB4 from LTA4, without affecting the biosynthesis of lipoxins, which are also produced from LTA4. Lipoxins, such as LXA4, have been the focus of intense study and are known to play a key role as natural anti-inflammatory agents and key mediators of the natural process of resolving an inflammatory response. Furthermore, production of endogenous LXA4 has been described in a variety of inflammatory diseases and lower levels of LXA4 have been found in patients with severe versus moderate asthma. These data are consistent with the proposition that LXA4 plays an important role in resolution of acute inflammation. Unlike LTA4H inhibitors, 5-LO inhibitors block this pathway upstream of LTA4. This would lead to a block in not only synthesis of LTA4, LTB4 and cysteinyl leukotrienes, but also LXA4. Furthermore, there is a possibility that LTA4H inhibitors result in a buildup of LTA4, and pathway shunting to pro-inflammatory cysteinyl leukotrienes, although to date there is no known data to support this possibility.
Neutrophil infiltration is a prominent feature of severe asthma. Zileuton (Zyflo®), which targets both LTB4 and cysteinyl leukotrienes, has been suggested to be efficacious in severe asthma patients, while CysLT antagonists (for example, Montelukast/Singulair®), which target only cysteinyl leukotrienes, show limited efficacy. Combination of an LTA4H inhibitor and at least one of a CysLT receptor antagonist and LTC4 synthase inhibitor would target both LTB4 and cysteinyl leukotrienes, while leaving production of the anti-inflammatory lipoxins intact. Embodiments of this invention reduced inflammatory responses to airway allergen challenge in sensitized mice, leading to dose-dependent decreases airway recruitment of inflammatory cells.
Embodiments of this invention are expected to find utility in treating inflammatory bowel disease. In trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats, LTA4H inhibition had significant inhibitory effects on colonic inflammation, including macroscopic colonic injury, inflammatory cell content, and levels of tumor necrosis factor alpha (TNF-α), LTB4, and IL-6. Whittle et al. (Br J Pharmacol. 2008, 153, 983-991). LTA4H inhibition also significantly attenuated the joint inflammation and swelling associated with the destruction of collagen in murine models of arthritis. Mice deficient in receptors for LTB4 or lacking LTA4H do not develop arthritis in murine models (Mathis, S., et al. Role of leukotriene B4 receptors in rheumatoid arthritis, Autoimmun. Rev. 2007 November, 7(1):12-7). Embodiments of this invention are thus expected to find utility in treating arthritis, including, but not limited to, rheumatoid arthritis.
Abdominal aortic aneurysm (AAA) is a localized dilatation of the abdominal aorta that exceeds the normal diameter (2 cm) by more than 50%. It is caused by a degenerative process of the aortic wall. An aortic aneurysm may also occur in the thorax. Surgery is eventually required to prevent the progression to AAA rupture, which is most often a fatal event. Thus therapeutics which delay or prevent the need for surgery are an unmet medical need.
Recent genetic studies in humans as well as studies in mice and rabbits have implicated the leukotriene synthesis pathway in cardiovascular disease (reviewed in Whatling et al., Expert Opin Investig Drugs 2007, 16(12), 1879-93). In a well-established murine abdominal aortic aneurysm (AAA) model, mice that lack the receptor for LTB4 exhibit a reduced incidence of AAA formation (Ahluwalia et al., J Immunol. 2007, 179(1), 691-7). Diminished AAA formation in LTB4-receptor-deficient mice was associated with significant reductions in mononuclear cell chemoattractants and leukocyte accumulation in the vessel wall, as well as striking reductions in the production of matrix metalloproteinases-2 and -9. Thus, it has been shown that signaling by LTB4 through its receptor contributes to the frequency and size of abdominal aortic aneurysms in mice, and prevention of LTB4 signaling by deletion of the gene coding for the LTB4 receptor in turn inhibits proinflammatory circuits and enzymes that modulate vessel wall integrity. Thus LTB4 signaling is a target for intervention in modulating development of aortic aneurysms. Inhibitors of LTA4H in the context of this invention are expected to have utility in inhibition of aortic aneurysms.
Embodiments of this invention are expected to find utility in treating also any one or a combination of atopic dermatitis, contact dermatitis, acne (T. Alestas, et al., J. Mol. Med. 2006, 84(1): 75-87; Ch. C. Zouboulis, et al., Dermatology, 2005, 210(1): 36-8; Arch. Dermatol. 2003, 139(5): 668-70), myocardial infarction (A. Helgadottir, et al., Nat. Genet. 2006, 38(1): 68-74; Nat. Genet. 2004, 36(3): 233-9; H. Hakonarson, et al., JAMA 2005, 293(18): 2245-56), stroke (A. Helgadottir, et al., Nat. Genet. 2004, 36(3): 233-9; F. C. Barone, et al., Mol. Chem. Neuropathol. 1995, 24(1): 13-30), pain (J. M. Cunha, et al., Br. J. Pharmacol. 2003, 139(6): 1135-45; S. W. Hwang, et al., Proc. Natl. Acad. Sci. USA 2000, 97(11): 6155-60), itch (T. Andoh, et al., Eur. J. Pharmacol. 2006, 547(1-3): 59-64, 2000, 406(1): 149-152, 1998, 353(1): 93-96); J. Investigativ. Dermatol. 2004, 123(1): 196-201, 2001, 117(6): 1621-26; gingivitis (G. Emingil, et al., J. Periodontol. 2001, 72(8): 1025-31), uveitis (T. Liao, et al., Invest. Ophthalmol. Vis. Sci. 2006, 47(4): 1543-9), bronchitis (S. Gompertz, et al., Eur. Respir. J. 2001, 17(6): 1112-9), allergic rhinitis, cystic fibrosis (G. E. Carpagnano, et al., Am. J. Respir. Crit. Care Med. 2003, 167(8): 1109-12), upper grastrointestinal cancer (X. Chen, et al., Curr. Cancer Drug Targets 2004, 4(3): 267-83; J. Natl. Cancer Inst. 2003, 95(14): 1053-61), and sepsis (H. Nakae, et al., Res. Commun. Chem. Pathol. Pharmacol. 1994, 83(2): 151-6, and 84(3): 271-81), Sjogren Larsson syndrome, Sjogren syndrome, and skin burns, such as those due to sunburn or some other agent.
Examples of textbooks on the subject of inflammation include: 1) Gallin, J. I.; Snyderman, R., Inflammation: Basic Principles and Clinical Correlates, 3rd ed.; Lippincott Williams & Wilkins: Philadelphia, 1999; 2) Stvrtinova, V., et al., Inflammation and Fever. Pathophysiology Principles of Diseases (Textbook for Medical Students); Academic Press: New York, 1995; 3) Cecil; et al. Textbook Of Medicine, 18th ed.; W.B. Saunders Co., 1988; and 4) Stedman's Medical Dictionary.
Background and review material on inflammation and conditions related with inflammation can be found in articles such as the following: C. Nathan, Points of control in inflammation, Nature 2002, 420: 846-852; K. J. Tracey, The inflammatory reflex, Nature 2002, 420: 853-859; L. M. Coussens and Z. Werb, Inflammation and cancer, Nature 2002, 420: 860-867; P. Libby, Inflammation in atherosclerosis, Nature 2002, 420: 868-874; C. Benoist and D. Mathis, Mast cells in autoimmune disease, Nature 2002, 420: 875-878; H. L. Weiner and D. J. Selkoe, Inflammation and therapeutic vaccination in CNS diseases, Nature 2002, 420: 879-884; J. Cohen, The immunopathogenesis of sepsis, Nature 2002, 420: 885-891; D. Steinberg, Atherogenesis in perspective: Hypercholesterolemia and inflammation as partners in crime, Nature Medicine 2002, 8(11): 1211-1217.
Inflammation is due to or associated with any one of a plurality of conditions, such as asthma, chronic obstructed pulmonary disease (COPD), atherosclerosis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases (including Crohn's disease and ulcerative colitis), psoriasis, atopic dermatitis, contact dermatitis, acne, myocardial infarction, stroke, pain, itch (pruritus), gingivitis, uveitis, bronchitis, allergic rhinitis, cystic fibrosis, upper gastrointestinal cancer, sepsis, Sjogren syndrome, Sjogren-Larssen syndrome, and skin burns, which are each characterized by excessive or prolonged inflammation at some stage of the disease.
Organ transplant rejection and autoimmune disease treatment with a cyclooxygenase-2 inhibitor and an LTA4H inhibitor are disclosed in WO1997/29774, U.S. Patent Appl. Publ. Nos. US2003/004191 and US2005/043355, and in U.S. Pat. Nos. 5,700,816, 6,407,140. LTA4H inhibitors are disclosed in U.S. Pat. Nos. 5,719,306, 6,506,876, 5,723,492, 5,585,492, and publication WO1996/11192. Cyclic and bicyclic diamino histamine-3 receptor antagonists are disclosed in U.S. Pat. No. 6,559,140. Benzothiazole and benzoxazole LTA4H modulators have been described in U.S. Patent Appl. Publ. Nos. US2005/0043378 and US2005/0043379, and by Grice et al. (Abstracts of Papers, 234th ACS National Meeting, Boston, Mass., United States, Aug. 19-23, 2007), Rao et al. (J. Pharmacol. Exp. Ther. 2007, 321(3), 1154-1160) and Whittle et al. (Br J Pharmacol. 2008, 153, 983-991). In addition, diamine derivatives are described as LTA4H inhibitors in U.S. Patent Appl. Publ. No. 2007/0155726 and Intl. Patent Appl. Publ. No. WO2007/079078. Aryl-substituted bridged diamines are disclosed as LTA4H modulators in U.S. Provisional Pat. Appl. No. 60/984,126. Combinations of a cyclooxygenase-2 inhibitor and an LTA4H inhibitor for the treatment of inflammation and inflammation-related disorders are disclosed in U.S. Pat. No. 5,990,148 and in publication WO1996/41625. Nitrogeneous derivatives have been disclosed in patent-related as well as in nonpatent-related publications, such as WO2008/016811; US2008/0057074; WO2006/002133; U.S. Pat. No. 6,316,490; U.S. Pat. No. 6,632,823; U.S. Pat. No. 6,432,976; WO2006/133802; WO2003/037904; EP 623621; EP 416521; S. Collin, J. Pharmacie de Belgique, 1991, 46(1) 55-66; P. Dostert, et al., European. J. Med. Chem., 1984, 19(2) 105-110; FR 2446823; U.S. Pat. No. 4,410,535; U.S. Pat. No. 4,352,802; U.S. Pat. No. 4,471,120; U.S. Pat. No. 4,424,358; U.S. Pat. No. 4,321,378; U.S. Pat. No. 4,329,466; U.S. Pat. No. 4,536,580; U.S. Pat. No. 4,273,778; U.S. Pat. No. 4,336,259; U.S. Pat. No. 4,544,660; U.S. Pat. No. 4,599,420; and U.S. Pat. No. 4,705,858. However, there remains a need for potent LTA4H modulators with desirable pharmaceutical properties.
Certain thiazolopyridin-2-yloxy-phenyl and thiazolopyrazin-2-yloxy-phenyl amine derivatives have been found in the context of this invention to have LTA4H-modulating activity. References cited throughout the written description are incorporated herein by reference.

This patent is subject to a terminal disclaimer.

Thyazolopyridin-2-yloxy-phenyl and thiazolopyrazin-2-yloxy-phenyl amines as modulators of leukotriene A4 hydrolase


A vehicle interior member with an air bag includes an air bag door portion that can be made to be invisible and of improved construction. The vehicle member includes a skin molded to a substrate. The skin includes a tear line formed by a diagonal cut portion. In the vicinity of a lateral tear line of the skin side tear line, a projecting portion is provided on a lower mold to form a groove portion of the substrate along the diagonal cut portion so as to intercept a flow of a resin from the cutting direction of the diagonal cut portion. Therefore, as the resin flows in a reverse direction to the cutting direction of the diagonal cut portion at an opening portion thereof, a flow of the resin into a PP foam layer of a three-layer skin through the opening portion of the diagonal cut portion can be suppressed. This prevents the PP foam layer from being melted and damaged.

1. Field of Invention
The present invention relates to a vehicle interior member having an air bag door portion, and more particularly to a door portion of an air bag system formed in the vehicle interior member, such as an instrument panel. The present invention further relates to a method for molding the same.
2. Description of the Related Art
Conventionally a vehicle interior member having an air bag door portion such as the instrument panel is known and disclosed, for example, in Japanese Patent Application Laid-open No. HEI 9-156443.
In this instrument panel having the air bag door portion, a three-layer skin including a foam layer as an intermediate layer is disposed on a surface (design face) of a resin substrate constituting a body portion and the air bag door portion of the instrument panel.
However, in order to mold the product having the air bag door portion of the instrument panel invisible (designed to have a relief such as a tear line invisible), the following process is required. A three-layer skin 72 having a cut portion 70 for a tear line at a skin side formed on a back surface thereof is set in an upper mold 74 of molds 74 and 76. Then, a resin 78 is injected into the mold as shown in FIG. 9. In this case, when the resin 78 moves along an injection direction (a direction shown by the arrow X in FIG. 9), a foam layer 72A of the three-layer skin 72 is compressed by the resin 78 toward the upper mold 74 (a direction shown by the arrow Y in FIG. 9). As a result, each thickness of two sections of the three-layer skin 72 separated by the cut portion 70 becomes different. Thus, the resin 78 in a molten state flows through the cut portion 70 into the foam layer 72A that is not compressed. As a result, the foam layer 72A is damaged to form, for example, an undesirable recess on the design face of the product, which degrades the quality of the appearance. For this reason, the conventional technology has never achieved an air bag door portion that is invisible.
In view of these problems, it is an object of the invention to provide a vehicle interior member having an air bag door portion that prevents a foam layer from being melted and damaged, has an invisible air bag door portion, and improves design even after setting a three-layer skin formed with a cut portion forming a skin side tear line in a mold and injection insert molding a substrate.
To achieve the above and other objects, according to a first aspect of the present invention, there is provided a vehicle interior member having an air bag door portion including a three-layer skin, a body portion substrate formed of a hard resin material and injection molded together with the three-layer skin, and an air bag door portion substrate formed of the same hard resin material as the body portion and injection molded integrally with the body portion substrate. The air bag door portion substrate has a groove portion forming a substrate side tear line that is formed during the injection molding to define a shape of a projecting portion formed on a mold and torn upon deployment of an air bag. The three-layer skin has a diagonal cut portion forming a skin side tear line that is formed to extend from a face of the three-layer skin, the face being close to the air bag door portion substrate, at a predetermined inclination angle such that an opening portion of the diagonal cut portion is directed substantially toward the groove portion forming the substrate side tear line.
Therefore, if the three-layer skin is set in the mold and then the three-layer skin and the substrate of the body portion and the air bag door portion are integrally molded by injection molding, a resin flow from a cutting direction of the diagonal cut portion is suppressed by a projecting portion formed on the mold to form the groove portion forming the tear line at the substrate side. Accordingly, the resin flows in a reverse direction to the cutting direction of the diagonal cut portion at the opening portion of the diagonal cut portion of the three-layer skin. As a result, even if the three-layer skin is compressed by the resin, each section separated by the diagonal cut portion may not become a different thickness. Also, the resin flow into a foam layer of the three-layer skin through the opening of the diagonal cut portion can be suppressed, thus preventing the foam layer from being melted and damaged. Therefore, the air bag door portion can be made invisible and the design can be improved. Also, the present invention can be easily achieved by adjusting the incline angle of the diagonal cut portion of the three-layer skin and a thickness of the substrate at the groove portion forming the tear line at the substrate side.
According to a second aspect of the present invention, there is provided a vehicle interior member having an air bag door portion including an air bag door portion having a three-layer skin and a substrate formed of a hard resin and injection molded together with the three-layer skin, and a body portion to which the air bag door portion is fixed. The air bag door portion substrate has a groove portion forming a substrate side tear line that is formed during the injection molding to define a shape of a projecting portion formed on a mold and is torn upon deployment of an air. The three-layer skin has a diagonal cut portion forming a skin side tear line which is formed to extend from a face of the three-layer skin, the face being close to the air bag door portion substrate, at a predetermined inclination angle such that an opening portion of the diagonal cut portion is directed toward the groove portion forming the substrate side tear line.
Therefore, in addition to substantially the same advantages as achieved by the first aspect of the invention, the second aspect of the invention achieves the following advantages. Materials for the skins and substrates of the air bag door portion and the body portion can be separately and freely selected. Considering the design face, the skin of the air bag door portion skin and the skin of the air bag door portion may be formed from the same material in order to make the air bag door portion inconspicuous. The substrate of the air bag door portion and the substrate of the body portion substrate may be formed from different kinds of hard resins in accordance with their performance requirements.
According to a third aspect of the present invention, there is provided a vehicle interior member based on the first or second aspect, in which the diagonal cut portion and the groove portion are positioned such that an edge of the substrate of a passenger side portion which has been torn and deployed upon deployment of the air bag door is hidden by the skin.
Therefore, the edge of the substrate of a passenger side portion which has been torn and deployed upon deployment of the air bag door is hidden by an end portion of the skin of the passenger side door portion that has been torn and deployed upon deployment of the air bag door so that the edge is not exposed.
According to a fourth aspect of the invention, there is provided a vehicle interior member having an air bag door portion including a three-layer skin, a body portion substrate formed of a hard resin material and injection molded together with the three-layer skin, and an air bag door portion substrate formed of the same hard resin material as the body portion substrate and injection molded integrally therewith. The three-layer skin has a diagonal cut portion forming a skin side tear line that has a cutting direction inclined in a direction substantially reverse to a flow direction of the hard resin during injection molding of the body portion substrate and the air bag door portion substrate and is torn upon deployment of an air bag.
According to a fifth aspect of the invention, there is provided a vehicle interior member based on the fourth aspect of the invention, wherein the skin side tear line and a substrate side tear line extend in a direction substantially parallel to the flow direction of the hard resin, and wherein the air bag door portion substrate has a thin portion that is formed adjacent to the groove, the thin portion being positioned at a site facing an opening portion of the diagonal cut portion and extending along the opening portion of the diagonal cut portion in a direction substantially parallel to the flow direction of the hard resin.
Therefore, as the thin portion formed in the substrate substantially prevents the resin from flowing toward the opening portion of the diagonal cut portion, the direction of the resin flowing at the opening portion of the diagonal cut portion is in the reverse direction to the cutting direction of the diagonal cut portion. As a result, the resin flow into the foam layer of the three-layer skin through the opening portion of the diagonal cut portion can be suppressed, thus effectively preventing the foam layer from being melted and damaged.
According to a sixth aspect of the invention, there is provided a vehicle interior member having an air bag door portion including an air bag door portion having a three-layer skin and a substrate formed of a hard resin and injection molded together with the three-layer skin, and a body portion to which the air bag door portion is fixed, wherein the three-layer skin has a diagonal cut portion forming a skin side tear line that has a cutting direction inclined in a direction substantially reverse to a flow direction of the hard resin during injection molding of the air bag door portion substrate and is torn upon deployment of an air bag.
According to a seventh aspect of the present invention, there is provided a method for molding a vehicle interior member having an air bag door portion including the steps of: setting a three-layer skin having a diagonal cut portion with a cutting direction inclined relative to a surface in a first mold; assembling the first mold and a second mold; injecting a hard resin into a cavity defined by the three-layer skin and the second mold to form a substrate of an interior member integrally with the three-layer skin while controlling injection of the hard resin such that a flow direction of the hard resin is substantially opposite to the cutting direction of the diagonal cut portion; and cooling an integral molding of the three-layer skin and the substrate after injecting the hard resin.

Method for molding a vehicle interior member having air bag door portion


Some embodiments may be associated with a cloud-based computing environment. A multi-tenant master process platform, associated with a RDBMS, may create a logical database for a tenant on a physical instance of the cloud-based computing environment. A connection to the logical database may be received from a client user associated with the tenant, and a process for the connection may be created. A process identification number created for the process may then be captured along with the database identifier for the tenant using an in-kernel virtual machine program. The system may send the process identification number and the database identifier to a user space program. The user space program creates a control group with the name of the database identifier and places the process identification number into the control group. The control group can then be limited with respect to a maximum amount of resources (memory, CPU etc.).

An enterprise may utilize applications or services executing in a cloud-based computing environment. For example, a business might utilize applications that access a database at a data center to process purchase orders, human resources tasks, payroll functions, etc. Note that cloud-based computing environment might want to support multiple tenants (e.g., associated with different enterprises). Creating a separate database instance for each tenant, however, can be an expensive approach that consumes substantial resources. As a result, a single instance may be shared among multiple tenants. With some multi-tenant implementations, however, one tenant might execute a complex query (e.g., consuming substantial memory resources, computing power, etc.) which could degrade performance for other tenants resulting in a "noisy neighbor" scenario. It would therefore be desirable to provide multi-tenant support for a cloud-based computing environment in a fair, automatic, and accurate manner.

Multi-tenant resource allocation using control groups in cloud-based computing environment


In an excessive burn detection method for detecting an excessive burn during a regeneration process, in which particulates accumulated in a particulate filter arranged in an exhaust passage of a diesel engine are burned and removed for regenerating the particulate filter, an oxygen concentration in exhaust gas in the exhaust passage downstream of the particulate filter is measured in predetermined time intervals after the regeneration process starts and it is determined whether the excessive burn occurs by determining whether the measured oxygen concentration decreases with a predetermined tendency.

1. Field of the Invention
The present invention relates to a method for detecting excessive burn (excessive burning state) during a regeneration process of a particulate filter disposed at an exhaust passage of a diesel engine.
2. Description of Related Art
Exhaust gas of a diesel engine includes particulates, which are exhaust particles of mainly carbon. The particulates cause black smoke in the exhaust gas. Thus, there is provided an exhaust gas purifying apparatus, in which a honeycomb ceramic particulate filter is provided in an exhaust passage of the diesel engine to collect the particulates with the filter.
The filter of the exhaust gas purifying apparatus is clogged with the particulates attached thereto with the passing of time. As a result, pressure in the exhaust passage increases thereby degrading an engine output and a fuel economy.
Therefore, there is proposed a method for automatically sensing the clog of the filter to regenerate the filter by burning the collected particulates.
A method for providing a burning state (method for burning the particulates) includes, for example, providing an intake air throttle valve upstream of the engine. In this method, the intake air is reduced to increase exhaust gas temperature of the engine, thereby the particulates are burned. Also, another method for providing the burning state includes mixing the exhaust gas with unburned gases such that the hydrocarbon (HC) in the unburned gases reacts with an oxidation catalyst to increase the exhaust gas temperature. Thus, the particulates are burned. (see Japanese Unexamined Patent Publication No. 2001-207830).
When the collected particulates are burned and removed, the temperature in the filter increases due to the burning. At this time, the filter may be melted and damaged when, for example, the particulates are partially accumulated in the filter to cause excessive burn. Therefore, to limit the filter from breaking due to the excessive burn, there has been utilized a method for determining whether excessive burn (excessive burning state) occurs by monitoring the exhaust gas temperature downstream of the filter.
However, the temperature features in having a relatively large time constant so that there is a delay before the exhaust gas temperature notifies a change of the burning state of the particulates. In other words, even when the excessive burn occurs due to the regeneration process, it may take a certain amount of time before the change of the exhaust gas temperature is detected. Thus, the regeneration process may be excessively continued for more than a necessary period and a risk for melting and damaging the filter due to the excessive burn may be enhanced.


A heating appliance including a metal substrate, at least a part of which is covered with a self-cleaning coating including at least one oxidation catalyst selected from the platinoid oxides, and at least one dopant of said oxidation catalyst selected from the rare-earth oxides. The self-cleaning coating is a bilayer coating including: an inner layer at least partially covering the metal substrate and including the dopant; and an outer layer in contact with the ambient air and including the oxidation catalyst. Also provided is a method for producing such a heating appliance.

1. Field of the Invention
The present invention relates generally to heating appliances or appliances intended to be heated during the use thereof and comprising a self-cleaning coating.
2. Description of Related Art
The term "heating appliance" is understood to mean, within the meaning of the present patent application, any appliance, article or utensil, which, during the functioning thereof, reaches a temperature at least equal to 65° C. (which is the minimum reheating temperature) and preferably at least equal to 90° C. The appliance can reach this operating temperature by means which are specific to it, such as, for example, a heating base incorporated in the appliance and equipped with heating elements, or by external means. It concerns in particular sole plates of irons, cooking appliances, ovens, grills and cooking utensils. Among these heating appliances, some, such as sole plates of irons or cooking appliances, exhibit qualities of ease of use and effectiveness which depend, inter alia, on the state and the nature of the surface of the coating thereof. As regards sole plates of irons, the latter have been able to be improved by virtue of the care contributed to the glide qualities of the ironing surface, in combination with those which make possible easier spreading of the laundry. One way of obtaining these qualities is to resort to sole plates enameled with an enamel having a smooth appearance, optionally with lines of excessive thickness for promoting the spreading of the fabric during the movement of the iron. It is also known to use metal sole plates which are treated mechanically and/or which are or are not covered with a deposit for facilitating the gliding.
However, with use, the sole plate can become tarnished by carbonizing in a more or less diffuse fashion over its ironing surface, and, in a more or less incomplete fashion, various contaminants of organic origin (in particular in a particulate form) which are captured by the sole plate by rubbing over the ironed fabrics. The tarnishing of the sole plate, even in a not very visible way, results in an at least partial loss of its glide qualities. In addition, with the fouling, ironing becomes more difficult. Finally, the user dreads using a tarnished iron, fearing that it may detrimentally affect her laundry.
Iron sole plate coatings, comprising a hard and resistant layer covered by a layer which improves the surface properties, are known, such as taught by the U.S. Pat. No. 4,862,609. However, this patent does not indicate a solution for combating fouling.
This problem of fouling may also be encountered for other types of heating appliances, such as, for example, the walls of cooking appliances. It is known to cover them with an enameled layer having a smooth appearance, in order to prevent possible spat fat or food from adhering to the surface of these walls. In particular, enameled self-cleaning surfaces, which may in particular be encountered in ovens and cooking utensils, are known, such as taught, for example, by U.S. Pat. No. 4,029,603 or French patent FR 2 400 876. However, these surfaces are not entirely satisfactory as regards their self-cleaning properties.
In order to improve these properties, the Applicant Company has previously developed a self-cleaning coating intended to coat a metal surface of a heating appliance which is more effective in terms of catalytic activity. This coating forms the subject matter of the French patent FR 2 848 290, which describes a heating appliance comprising a metal support, at least a portion of which is covered with a self-cleaning coating, which comprises an external layer in contact with the ambient air and comprising at least one oxidation catalyst chosen from platinum group metal oxides, and at least one internal layer, located between the metal support and the external layer, comprising at least one oxidation catalyst chosen from oxides of the transition elements of Group Ib. However, this self-cleaning coating exhibits the disadvantage of requiring a large amount of platinum group metal oxides in the external layer in order to achieve correctly satisfactory levels of catalytic activity, the consequence of which is in particular a significant increase in the coating cost and thus, in the end, in that of the heating appliance.

Heating appliance covered with a self-cleaning coating and production method thereof


Disclosed is a method for configuring a ranging channel in various frame structures and using the same in a communication system. A ranging channel is effectively configured according to a data structure, namely, frame structure, transmitted and received between a mobile station (MS) and a base station (BS) in a wireless communication system, and ranging information is transmitted therethrough to thereby improve performance of a communication channel and resource efficiency. In the wireless communication system, a ranging channel is configured by using a time interval, such as an idle time, an idle symbol, an RTG, a TTG, and the like, not actually used for transmission of data or a signal in a data structure, namely, in a frame structure, transmitted and received between an MS and a BS, to transmit ranging information, so the channel performance and resource efficiency can be improved.

IEEE (Institute of Electrical and Electronics Engineers) 802.16 standard provides techniques and protocols to support a broadband wireless access. Standardization started from 1999 and IEEE 802.16-2001 was approved in 2001. It is based on a single carrier physical layer called 'WirelessMAN-SC'. Later, besides the 'WirelessMAN-SC', 'WirelessMAN-OFDM' and 'WirelessMAN-OFDMA' were added to a physical layer in IEEE 802.16a standard approved in 2003. After the IEEE 802.16a standard was completed, a revised IEEE 802.16-2004 standard was approved in 2004. IEEE 802.16-2004/Cor1 (referred to as 'IEEE 802.16e', hereinafter) was finalized in the form of 'corrigendum' in 2005 in order to resolve and correct bugs and errors of the IEEE 802.16-2004 standard.
In order to receive and demodulate data of a wireless communication system, synchronization needs to be matched between a receiver and a transmitter. In particular, for a successful data transmission and reception in a mobile communication system in which a channel environment between a base station (BS) and a mobile station (MS) continuously changes, the synchronization between the BS and the MS should be matched through close signaling.
A communication channel between the BS and the MS includes a downlink (DL) channel proceeding from the BS to the MS and an uplink (UL) channel proceeding from the MS to the BS. In downlink, a plurality of MSs match downlink synchronization with data frames transmitted from the BS. In order for the MSs to match the synchronization, the BS may insert a preamble for synchronization into a portion of a frame. The MSs match synchronization for the downlink channels through the preamble. Alternatively, the BS may use a synchronization channel.
In uplink, each MS must transmit data through a time and/or frequency domain allocated to each MS in order to avoid an interference between the MSs and allow the BS to receive data. Thus, for the uplink synchronization, each MS needs to adjust synchronization through signaling between the BS and the MSs in consideration of the channel environment.
A signal exchanged between the MSs and the BS to match uplink synchronization in the IEEE 802.16 standard is called a ranging signal. A ranging process is a sequential process of adjusting transmission power through the process of exchanging the ranging signal between the MS and the BS and matching time/frequency synchronization. That is, the sequential process for obtaining uplink synchronization may be called the ranging process.
In an initial ranging, an accurate timing offset is obtained between the MS and the BS and transmission power is adjusted at the early stage. When power is turned on, the MS obtains downlink synchronization from a received downlink preamble signal. Subsequently, the MS performs initial ranging in order to adjust the uplink timing offset and the transmission power. Unlike the initial ranging, a periodic changing is a process of periodically tracking an uplink timing offset and a reception signal strength following the initial ranging.
In attempting a ranging process, a pre-set ranging code is used as a ranging signal.
Configuration of ranging channels in various frame structures will be described. First, technical terms will now be described.
In the description of the present invention, TCP is an OFDMA cyclic prefix duration, Tu is an available OFDMA symbol duration, and Ts (=TCP+Tu) is an OFDMA symbol duration including a CP (cyclic prefix).
A TTG, an RTG, an SSTTG, and an SSRTG are defined for a time division duplex (TDD) frame structure in 802.16e of IEEE P802.16 Rev2 standard.
1) RTG (Base Station (BS) Receive/Transmit Transition Gap)
The RTG is a gap between the last sample of an uplink burst and a first sample of a subsequent downlink burst at an antenna port of the BS having TDD transceiver. The RTG, namely, the gap, is an allowable time for the BS to switch from a reception mode to a transmission mode. During this gap, the BS simply ramps up a BS transmitter carrier and allows a transmission/reception antenna switch to actuate, without transmitting modulated data. The RTG is not applicable for frequency division duplex (FDD) systems.
2) TTG (Base Station (BS) Transmit/Receive Transition Gap)
The TTG is a gap between the last sample of the downlink (DL) burst and the first sample of the subsequent uplink (UL) burst at the antenna port of the BS having a time division duplex (TDD) transceiver. The TTG, namely, the gap, is an allowable time for the BS to switch from the transmission mode to the reception mode. During this gap, the BS simply ramps down a BS transmitter carrier and allows a transmission/reception antenna switch to actuate and a BS receiver to operate, without transmitting modulated data. The TTG is not applicable for frequency division duplex (FDD) systems.
3) SSRTG: (Subscriber Station Receive/Transmit Gap)
The SSRTG is a minimum receive-to-transmit turnaround gap. The SSRTG is the gap measured from the time of the last sample of the received burst to the first sample of the transmitted burst at the antenna port of the SS.
4) SSTTG (Subscriber Station Transmit/Receive Gap)
The SSTTG is a minimum transmit-to-receive turnaround gap. The STTG is the gap measured from the time of the last sample of the transmitted burst to the first sample of the received burst at the antenna port of the SS).
Meanwhile, the length of the TTG and the RTG is defined to be at least 5 μs in the 802.16e standard, and the BS informs the MSs about that through DCD channel encoding. Here, the DCD channel encoding is as shown in Table 1.
TABLE 1TypeName(1 byte)LengthValue(variable length)PHY scopeDownlink_Burst_Profile1—May appear more thanAllonce(see 18.104.22.168.1). Thelength is the number of bytesin the overall object,including embedded TLVitems.BS EIRP22Signed in units of 1 dBmAllFrame34The number of PSs containedSCdurationin a Burst FDD or TDDframe. Required only forframed DLs.PHY Type41The PHY Type to be used.SCPower adjustment510 = Preserve PeakSCrulePower1 = Preserve Mean PowerDescribes the power adjustmentrule whenperforming a transition fromone burst profile to another.Channel Nr61DL channel number asOFDM,defined in 8.5. Used forOFDMAlicense-exempt operationonly.TTG72 for TDD, 4TTG (in PSs). Note: for H-OFDMAFOR H-FDDFDD, the first set of 2 bytescorresponds to H-FDD Group1, While the second set of 2bytes corresponds to H-FDDGroup 2RTG81 for TDD, 2RTG (in PSs). Note: for H-OFDMAFOR H-FDDFDD, the first byte correspondsto H-FDD Group1, While the second byte correspondsto H-FDD Group 2.
Also, the length of the SSTTG and the SSRTG may be transmitted between the BS and the MS through SBC-REQ/RSP management message encoding in the 802.16e standard. However, the message is generated between the BS and the MS for a capability negotiation during an initial network entry procedure, and the length cannot be known in the state that the MS initially transmits a ranging code to the BS.
TABLE 2TypeLengthValueScope22Bits: 0-7: SSTTG(μs) Bits: 8-15:SBC-REQSSRTG(μs)Allowed(see 6, 3, 2, 3, 23)values: OFDM mode: TDDSBC-RSPand H-FDD 0 . . . 100. Other(see 6, 3, 2, 3, 24)modes: TDD: 0 . . . 50; H-FDD: 0 . . . 100.
In order to guarantee a minimum performance of the MS from a WiMAX Forum Mobile System Profile Release 1.0 (Revision 1.4.0), the SSRTG and the SSTTG may have a time length of 50 μs, while the TTG and the RTG may have different values according to system bandwidth as shown in Table 3 below:
TABLE 3TTGRTGBW [MHz]nFs [MHz]PS [us][PS][us][PS][us]101.1211.20.357143296105.7143168608.751.142857100.421887.218674.471.14285780.53761881206051.125.60.714286148105.714384603.51.142857411881886060
In Table 3, the BW indicates a system bandwidth, 'n' is a sampling factor and 8/7 or 28/25 is used depending on a BW. Fs is a sampling frequency, which is defined as Fs=floor(n·BW/8000)?8000. A PS is a physical slot, which is defined as PS=4/Fs. The values of TTG and RTG are indicated by PS and us.
FIG. 1 illustrates a type-1 frame structure in the TDD duplex mode. In FIG. 1, TCP in the 802.16m standard is TCP=1/8·Tu. In FIG. 1, a superframe having a 20 ms duration includes four frames. Each frame has 5 ms and includes eight subframes. The subframes are divided into a type-1 subframe (or a regular subframe) and a type-1 short subframe (or an irregular subframe). The type-1 subframe includes six OFDMA symbols of 0.617 ms. The type-1 short subframe occupies the same time as that of the type-1 subframe, but is different from the type-1 subframe in that the last OFDMA symbol of the type-1 short subframe is an idle symbol. The idle symbol is not used for a transmission. While changing from DL to UL, there is an idle time of 102.857 us, and an idle time of 62.86 us exists at a switching point at which US is changed to DL.
FIG. 2 illustrates the type-1 frame structure in the FDD duplex mode. In FIG. 2, TCP in the 802.16m standard is TCP=1/8·Tu. In FIG. 2, a superframe having a 20 ms duration includes four frames. Each frame has 5 ms and includes eight subframes, and there exists an idle time of 62.86 us. A subframe includes six OFDM symbols of 0.617 ms.
FIG. 3 illustrates a frame structure in a TDD and FDD duplex mode having a TCP=1/8·Tu in the 802.16m standard. In FIG. 3, each frame has 5 ms and includes eight subframes. The subframes are divided into a type-1 subframe and a type-2 subframe. Namely, the type-1 subframe includes six OFDM symbols of 0.583 ms, and the type-2 subframe includes seven OFDM symbols of 0.680 ms. In case of the TDD duplex mode, there exists a transmitter transition gap (TTG) while DL is changed to UL and there exists a receiver transition gap (RTG) while UL is changed to DL. In case of the FDD duplex mode, there exists an idle time at the end of each frame.

Method for transmitting ranging information in wireless communication system and terminal thereof