An insulating-resin dam bar made of ultraviolet-curing epoxy resin with a low adhesiveness to a leadframe is applied onto an outer lead by screen printing. After the leadframe is sealed with resin, the insulating-resin dam bar is removed by wet honing such as water-jet honing or laser irradiation. Thereafter, a resin-sealed semiconductor device is finished through normal fabrication processes.

The present invention relates to a method for fabricating a semiconductor device, particularly to a method for fabricating a resin-sealed semiconductor device using a leadframe provided with a dam bar made of an electrically insulating material.
An existing leadframe used for a resin-sealed semiconductor device is provided with an island to which a semiconductor device is secured, inner leads each of which is connected to a pad of the semiconductor device by a bonding wire, outer leads formed integrally with the inner leads, a frame to which the other ends of the outer leads are connected in common, and a feed hole for moving the leadframe. In this case, the inner and outer leads are integrated to form a lead and a plurality of leads are almost-radially and separately arranged on the circumference of the island. The inner leads are sealed with resin and inner ends of the inner leads are connected with the pad of the semiconductor device to form open ends. Metal of the leadframe is removed between a plurality of arranged leads, between the island and a lead, and between a suspended lead of the island and a lead. The metal is removed by means of punching by dies or chemical etching. Some leadframes have more than 100 leads. Therefore, while a semiconductor device is secured to an island and the semiconductor device and inner leads are sealed with resin, a lead may be deformed or deviated from a predetermined position. To prevent the above trouble, a dam bar is used to connect the leads so that they are not separated from each other. The dam bar is formed by leaving a die sheet integrated with a lead or the like.
A resin-sealed semiconductor device has been provided with the dam bar connecting outer leads to each other in order to keep resin when the semiconductor device is sealed with the resin and electrically insulate outer leads from each other by cutting the dam bar with a cutting die after the device is sealed with the resin. Under the above condition, because the lead width has been decreased in recent years due to decrease of the pitch between outer leads, it has been necessary to decrease the width of a cutting punch for cutting the dam bar in accordance with the decrease of the lead width. However, when the cutting-punch width is decreased, the mechanical strength of the punch is also decreased. Therefore, as the outer-lead pitch decreases, the durability and abrasion resistance of a cutting die (punch) are greatly decreased and thereby, the punching system cannot be used when the outer-lead pitch is 0.4 or 0.3 mm.
Thus, to disuse the cutting process using the punching system, a dam bar is proposed which is made by fixing an insulating resin without forming a metallic dam bar. A resin-sealed semiconductor device using this type of the insulating-resin dam bar is roughly classified into two types in view of its configuration. The first type is a type in which dam bars are kept up to an end product without being removed even after resin sealing. In the case of a leadframe of the first type, an insulating-resin dam bar is applied onto or nearby a boundary line between an inner lead and an outer lead formed on the leadframe, that is, a mold edge line serving as a mold edge after resin sealing. Thereafter, the leadframe is sealed with resin by means of resin sealing while bonding the insulating-resin dam bar. The insulating-resin dam bar uses a polyimide-based resin or a thermosetting resin. To apply a resin to a leadframe, the dispensing method is frequently used which applies resin while dropping it. After the leadframe is sealed with resin, it is passed through normal fabrication processes to form outer leads with insulating-resin dam bars left on it and formed into an end product.
The second type is a type in which an insulating-resin dam bar is removed after resin sealing by dissolving it with chemicals including solvents. In the case of a leadframe of the second type, an insulating-resin dam bar is applied onto an outer lead of the leadframe, that is, at a position slightly outside of a mold edge line by the dispensing method or the like. Then, the leadframe is sealed with resin by means of resin sealing. In the case of this type, sealing resin protrudes between the mold edge line and the insulating-resin dam bar, that is, dam resin remains between them because the insulating-resin dam bar is set outside the mold edge line so that it is easily removed later. Therefore, it is general to decrease the distance between the mold edge line and the insulating-resin dam bar in order to decrease the amount of the dam resin. After the leadframe is sealed with resin, the insulating-resin dam bar is removed by a solvent for dissolving only the insulating-resin dam bar and thereafter passed through normal fabrication process and formed into an end product. Or, the dam bar is mechanically removed.
Therefore, by using insulating-resin dam bars, the existing dam-bar cutting process is disused, problems of the durability and abrasion of a dam-bar cutting die are solved, and a resin-sealed semiconductor device is realized which can correspond to fine outer-lead pitches of 0.4 and 0.3 mm. In the case of the first type of keeping insulating-resin dam bars up to an end product, which is one of the existing resin-sealed semiconductor devices using insulating-resin dam bars, however, it is necessary to minimize the amount of insulating-resin dam bar protruded from a mold edge line. If the protruded amount of insulating-resin dam bar is too much, this causes a trouble in later lead bending because a dam bar is caught by a bent portion of a lead when forming the lead. Therefore, a problem occurs that a predetermined lead shape or dimension cannot be obtained. Moreover, in the case of this type, because dam bars are kept up to an end product, the material of an insulating-resin dam bar requires a high reliability equivalent to that of a sealing resin. Therefore, the resin cost may increase for development and practical use of the insulating-resin dam bar. In the case of the second type, that is, the type of removing dam bars after resin sealing, chemicals including solvents are used to remove insulating-resin dam bars and these solvents are deleterious substances in general. Therefore, they cause the problem of dangerousness when an operator handles them and the problem of environmental pollution. Moreover, because solvents contact a semiconductor device, the reliability of a sealing resin may be deteriorated. Furthermore, when mechanically removing a dam bar, the airtightness of a sealing resin may be deteriorated. Furthermore, in any case, a trouble such as coating irregularity or thin spot easily occurs because an insulating-resin dam bar is coated by a dropping method such as the dispensing method which is performed by dropping resin onto a lead and moreover, a problem occurs that the coating width of an insulating-resin dam bar easily becomes inaccurate or the positional accuracy of it is easily degraded.

Method for fabricating resin-sealed semiconductor device using leadframe provided with resin dam bar


Clip-type cable management apparatus and methods are disclosed. In one embodiment, a first jaw and a second jaw having interleaved tines in a predetermined configuration are coupled by a hinge pin around which a torsion spring is disposed to urge said first jaw and said second jaw pivotally toward a close position so as to securely retain a cable being folded or coiled into a bundle of cable segments. Such cable management is further enhanced with additional features, optimized structures, and operating methods.

This invention relates to the organization and management of cables and objects of similar shapes and properties. Cables are ubiquitous in our lives, and those associated with electronic devices have exhibited unprecedented popularity nowadays due to continued and rapid growth of such devices. While people enjoy using headsets, earphones, chargers, audio/video cords, power cords, computers cables and more, we are all faced with the task and challenge of how to keep them properly managed for reasons of productivity, ergonomics, protection, safety, and so forth.
Prior to this invention, there have been various tools and devices adopted to address this common issue. Twist ties, zip ties, hook-and-loop straps, cable retractors, cable wrappers, rubber bands are among the most seen examples in this regard. Although these tools can suffice for the purpose of getting cables organized, they appear to have limitations and drawbacks, and sometimes the problems are so undesirable to users that they would rather leave cables unmanaged than use such tools. For example, headsets for mobile phones and music players are among the most commonly used accessories, and far too often an average user would find it unpleasant and cumbersome to apply cable organizers based on tying a strap around the cables or wrapping cables around an object, especially such operations become frequent and repetitive. A cable retractor, as a different example, offers much improved user interactions by coiling and uncoiling cables through a spring-loaded core. The obvious drawback, however, is that cable retractors add significant weight and volume to the cables due to inherent mechanical components. In addition, they typically require a cable to be continuously smooth, making it seldom suitable for popular items such as headsets in that their cables almost always have enlarged portions such as microphones and cable-split reinforcements. Thus, optimal cable management is still an unaddressed or under-addressed everyday issue in our lives, and there remains a strong need for a new type of device that can not only serve the basic functional purpose but offer the best user-experience such as exceptional ease of use, broad applicability, and other desirable features.


A liquid crystal display includes a first substrate having a plurality of pixel areas. At least one pair of first and second protrusions is formed at each pixel area. A pixel electrode is formed at each pixel area. The pixel electrode has an opening pattern exposing the first protrusion while covering the second protrusion. A second substrate faces the first substrate. A common electrode is formed at the second substrate. Alternatively, the opening pattern and the protrusions may be formed in parallel.

(a) Field of the Invention
The present invention relates to a liquid crystal display and, more particularly, to a vertical alignment liquid crystal display which has a structure capable of dividing a pixel area into multiple domains with different orientation directions of liquid crystal molecules.
(b) Description of the Related Art
Generally, liquid crystal displays have a structure where a liquid crystal is sandwiched between two substrates, and an electric field is applied to the liquid crystal display to control the amount of light transmission.
In the twisted nematic (TN) liquid crystal displays, the liquid crystal molecules injected into the gap between the two substrates are oriented parallel to the substrates, and spirally twisted with a predetermined pitch. The long axis (usually called the "director") of the liquid crystal molecules continuously varies in orientation direction, and the viewing angle characteristics depend upon such orientation directions of the liquid crystal molecules
However, the TN liquid crystal display, light is not completely blocked at an off state in the normally black mode so that a poor contrast ratio results. The contrast ratio is altered depending upon the viewing angle, and there is a half tone of brightness difference depending on the viewing angle so that stable picture images cannot be obtained. Furthermore, the picture qualities at side edge portions of the screen are not symmetrical to each other with respect to the middle portion. These all result in poor viewing angle characteristics.
However, the vertical alignment liquid crystal displays where the liquid crystal molecules are vertically aligned in the absence of a voltage but twisted in various directions with the voltage applied exhibit excellence in various aspects, such as contrast ratio and response speed compared to the TN liquid crystal displays. Furthermore, when a compensation film is used to divide the twisting of the liquid crystal molecules in various predetermined directions, a wide viewing angle can be effectively obtained.
Recently, a technique for forming an alignment control member such as a pyramid-shaped protrusion on the substrates, a technique for forming an opening pattern at the transparent electrodes, and a technique for forming a protrusion pattern on one of the substrates while forming an opening pattern at the other substrate have been proposed as methods to control the orientation directions of the liquid crystal molecules. The protrusion or opening pattern is designed to achieve four domain divisions in the orientation direction of the liquid crystal molecules at which the efficiency of light usage becomes highest.
FIGS. 1A and 1B are cross sectional views of a liquid crystal display according to a prior art where the orientation states of liquid crystal molecules are illustrated in the absence and presence of the voltage application.
As shown in the drawings, a transparent pixel electrode 11 is formed at a bottom substrate 10, and a first opening portion 1 is formed at the pixel electrode 11. A top substrate 20 facing the bottom substrate 10 is provided with a transparent common electrode 21. A second opening portion 2 is formed at the common electrode 21. The bottom and top substrates 10 and 20 are arranged such that the first opening portion 1 is displaced with respect to the second opening portion 2. Negative dielectric anisotropy liquid crystal molecules 30 are injected into the gap between the bottom and top substrates 10 and 20.
As shown in FIG. 1A, the liquid crystal molecules 30 are oriented perpendicular to the substrates 10 and 20 in the absence of the voltage application.
As shown in FIG. 1B, when voltage is applied to the pixel electrode 11 and the common electrode 21, most of the regions at the pixel area are under the influence of an electric field normal to the substrates 10 and 20, but the regions adjacent to the opening portions 1 and 2 are under a fringe field beginning from the edges of the opening portions 1 and 2 and focused onto the common electrode 21 and the pixel electrode 11, respectively. As the negative dielectric anisotropy liquid crystal molecules 30 are inclined to orient in a direction normal to that of the electric field, the long axes of the liquid crystal molecules adjacent to the opening portions 1 and 2 are twisted while being tilted with respect to the substrates 10 and 20. In this case, two side regions of either of the opening portions 1 and 2 where the orienting directions of the liquid crystal molecules 30 are opposite to each other are present so that the optical characteristics of the two side regions are compensated, resulting in a wide viewing angle.
FIGS. 2A and 2B are cross sectional views of a liquid crystal display according to another prior art where the orientation states of liquid crystal molecules are illustrated in the absence and presence of voltage application.
As shown in FIGS. 2A and 2B, a pixel electrode 12 based on a transparent conductive material such as indium tin oxide is formed at a bottom substrate 10, and a pyramid-shaped first protrusion 13 and a vertical alignment film (not shown) are sequentially formed on the pixel electrode 12. A transparent common electrode 22 is formed at a top substrate 20, and a second pyramid-shaped protrusion 23 and a vertical alignment film (not shown) are sequentially formed at the common electrode 22. Negative dielectric anisotropy liquid crystal molecules 30 are injected into the gap between the vertical alignment films of the bottom and top substrates 10 and 20.
As shown in FIG. 2A, in the absence of voltage application, most of the liquid crystal molecules 30 are oriented perpendicular to the vertical alignment films, but the liquid crystal molecules 30 positioned close to the protrusions 13 and 23 are tilted with respect to the vertical alignment films at predetermined angles.
As shown in FIG. 2B, when voltage is applied to the pixel and common electrodes 12 and 22, the liquid crystal molecules are twisted in a direction parallel to the substrates 10 and 20. As the liquid crystal molecules 30 positioned close to the protrusion 13 are tilted in the opposite directions with respect to the region of the protrusion 13 in the absence of the voltage application, the twisting directions thereof are also opposite to each other with the voltage applied. Therefore, two side regions of the protrusion 13 where the twisting directions of the liquid crystal molecules are opposite to each other are present so that the optical characteristics of the two regions are compensated, resulting in a wide viewing angle. In addition, disclination regions where the orientation directions of the liquid crystal molecules 30 are disorderly altered are focused at the regions of the protrusions 13 and 23 so that a black matrix for shielding the disclination regions can be formed in a predetermined manner.
However, in order to fabricate the above-described liquid crystal displays, additional processes for forming the protrusions 13 and 14 or the opening portions 1 and 2 must be performed.
On the one hand, in the case of the liquid crystal display shown in FIGS. 1A and 1B, a wet etching process for forming the opening portion 2 at the ITO-based common electrode 21 of the top substrate 20 should be provided. Furthermore, in order to prevent the color filter from being contaminated or damaged due to the etching solution, a protective layer of organic or inorganic materials should be coated onto the color filter before the ITO processing.
On the other hand, in the case of the liquid crystal display shown in FIGS. 2A and 2B, before the formation of the protrusions 13 and 23, separate organic layers should be coated onto the pixel electrode 12 and the common electrode 22, and etched.

This patent is subject to a terminal disclaimer.

Liquid crystal display having a pixel area divided into multiple domains


An outer shell for a refrigerator a cabinet formed from a plurality of vertically arranged panels each having opposed vertical edges, a top edge and a bottom edge. A plurality of dovetail-like, linear joints interlock the vertical edges of the vertically arranged panels without requiring additional fasteners or welding. A top panel is interconnected with the top edges of the vertically arranged panels and a bottom panel is interconnected with the bottom edges of the vertically arranged panels. Each of the linear joints comprise a channel having a fan shaped cross-section provided along one edge of a panel and a connecting flange formed along the edge of a second adjacent panel wherein the connecting flange is received into the channel such that the first and second panels are interconnected. The outer shell is easily assembled by joining adjacent panels via the interlocking joints. Moreover, the joints provide strength to the outer shell and are well suited for use in insulation foaming.

1. Field of the Invention
The present invention relates generally to refrigerator cabinets, and more particularly, to an outer shell or wrapper of a refrigerator cabinet having a multi-panel configuration which is adapted to be assembled using interlocking, vertical joints.
2. Description of the Related Art
Conventional refrigerator cabinets include an outer shell and an inner liner disposed within and spaced inwardly from the outer cabinet. A body of insulation is disposed between the outer shell and the liner. In certain refrigerator cabinets, it is desirable to use an outer shell of wrap-around sheet metal construction, as shown in U.S. Pat. No. 2,450,844 to Stuart. Other refrigerators use a three sided wrapper in combination with a rear panel to form the outer shell of a refrigerator, as shown in U.S. Pat. No. 4,580,852, to Smitte et al.
It is difficult to form refrigerator cabinet shells of the type shown in the '844 and '852 patents for large capacity built-in refrigerators having refrigeration components mounted on top of the cabinet. These types of wrap-around sheet metal shells are not only difficult to form in large sizes but they may not provide the cabinet strength necessary for a large built-in refrigerator. Accordingly, refrigerator cabinet shells may be fabricated from more than one panel. U.S. Pat. No. 4,714,304, for example, discloses a refrigerator cabinet including an outer shell formed from three separate panels which are either welded together or assembled using separate fasteners.
Unfortunately, refrigerator cabinet shells, such as shown in the '304 patent, are relatively costly to manufacture because of the difficulty in assembling the separate panels into a single shell structure. Welding large metallic members along a lengthy seam is relatively difficult and costly and can lead to quality problems. The use of separate fasteners, such as rivet or screws, is similarly difficult and costly.
In-plant processing is another drawback to the prior art refrigerator shell designs. Because of the difficulty in assembling multi-panel shell designs, these shells are typically fabricated into an assembled shells at a remote assembly location and then conveyed to the refrigerator assembly line. These assembled shells are large, bulky items requiring a great deal of work-in-process storage space. It would be a significant improvement to provide a shell which could be quickly assembled directly at the refrigerator assembly line from panels which could be more easily stored prior to assembly such that the work-in-process storage requirements could be reduced.
An additional concern in fabricating refrigerator cabinet shells is to provide an assembled shell which has sufficient integrity such that the interconnections between the separate panels of the shell prevent insulation from escaping when foam insulation is introduced into the cavity formed between the shell and liner. It would be an improvement in the art to provide a shell design which could be easily assembled with interlocking joints which formed adequately sealed interconnections between adjoining panels such that insulation did not escape during the cabinet foaming process.


A cell wiring module has a plurality of connection members connecting adjacent electrode terminals of a plurality of single cells having positive and negative electrode terminals, a plurality of holding portions holding the connection members, voltage detection terminals placed on the connection members and connected to terminal portions of wires, and wire insertion portions through which the wires connected to the voltage detection terminals are inserted. The wires extend from the voltage detection terminals in the direction inclined relative to a direction orthogonal to a connecting direction of the connection members. The wires extending in this direction are inserted through the wire insertion portions.

In a cell module for electric automobiles or hybrid automobiles, a plurality of single cells having positive and negative electrode terminals are aligned. The electrode terminals of the adjacent single cells are connected by bus bars (connection members), and thus the plurality of single cells are connected in series or parallel (refer to Patent Literature 1).
In a bus bar module (cell wiring module) of Patent Literature 1, a square voltage detection terminal is placed on a bus bar to detect voltage of a single cell. A wire connected to the voltage detection terminal is directed to a cell ECU.


An automated fluid transfer system and method allows a person to pour fluid, such as used motor oil, into a collection pan which automatically pumps the fluid to a bulk storage tank, without secondary containment in the collection pan. The system utilizes an air powered pump, thereby eliminating the use of electricity which creates fire and explosion hazards. A float rises and falls in response to fluid in the pan, so as to automatically turn on and turn off the pump. An alternative manual mode is provided to allow fluid to be sucked by the pump from a container directly into the bulk storage tank, while bypassing the collection pan.

Collection and disposal of waste fluids is a common issue for many businesses, particularly in view of environmental concerns and government regulations. For example, in an automotive shop, waste automotive fluids, such as used motor oil, must be handled and transported carefully to avoid spillage, and then disposed of properly. Often times, waste fluid is temporarily stored in bulk containers, which are later moved for permanent disposal. However, the bulk storage containers typically are not near the work site, thus requiring the waste fluid to be manually carried in smaller containers from the work site to the bulk storage container, which increases the risk of accidental spillage. Spills create slip hazards to workers, and increase costs associated with cleanup. Hazardous waste storage tanks also must meet certain governmental agency oversight, including OSHA standards and EPA rules and regulations. Thus, there is a need for a simpler fluid transfer system which improves transfer of waste fluids from a hand-held container to a bulk storage container.
Accordingly, a primary objective of the present invention is the provision of an automated fluid transfer system which provides quick, easy, and safe transfer of waste fluids from a small container to a larger bulk storage container.
Another objective of the present invention is the provision of a fluid transfer system which operates without electricity to avoid fire and explosion risks.
A further objective of the present invention is a provision of an automated fluid transfer system which pumps waste fluids from a small container to a bulk storage container, in a manner that avoids government agency requirements.
Still another objective of the present invention is the provision of an automated fluid transfer system which utilizes an air-powered pump to reduce fire and explosion risks.
Yet another objective of the present invention is a provision of a pneumatic fluid transfer system having a fluid collection pan to receive fluids, and then immediately pump the fluids to a bulk storage container, without storage of the fluids in the collection pan.
A further objective of the present invention is the provision of a fluid transfer system having a collection pan with a large, opened top into which fluids can be poured from an ergonomically-friendly worker position.
Still another objective of the present invention is a provision of automated fluid transfer system which is economical to manufacture, safe to use, compliant with government regulations, and environmentally safe.
These and other objections will become apparent from the following description of the invention.


The invention relates to double-stranded ribonucleic acid (dsRNA) compositions targeting one or more EGLN genes, EGLN1, EGLN2 and/or EGLN3 and methods of using such dsRNA compositions to inhibit expression of these genes.

Erythropoietin (EPO) is a hormone found in the plasma which regulates red cell production by promoting erythroid differentiation and initiating hemoglobin synthesis. The gene is in the EPO/TPO family and encodes a secreted, acidic glycosylated cytokine.
Recombinant human erythropoietin (EPO) has been used since 1986 to treat the anemia of chronic and end-stage kidney disease (Eschbach, et al., N. Engl. J. Med. 1987 Jan. 8; 316(2):73-8). However, this treatment is costly and requires parenteral administration. It has recently been linked to cardiovascular side effects (J. Bohlius et al., Lancet 373, 1532 (2009) and antibodies which form against EPO can result in Pure Red Cell Aplasia (PRCA), an uncommon condition which develops in association with a failure of the bone marrow to manufacture red blood cells, leaving patients with severe, treatment-resistant anemia (reported by Casadevall, et al, New England Journal of Medicine, Feb. 14, 2002).
In addition to its role as a kidney cytokine regulating hematopoiesis, EPO is also produced in the brain after oxidative or nitrosative stress. The transcription factor HIF1 (hypoxia inducible factor 1) is known to upregulate EPO following hypoxic stimuli (Digicaylioglu, M., Lipton, S. A. Nature 412: 641-647, 2001). This upregulation provides protection against apoptosis of erythroid progenitors in bone marrow and also apoptosis of brain neurons (Siren, A.-L., et al., Proc. Nat. Acad. Sci. 98: 4044-4049, 2001). Grimm et al. showed in the adult mouse retina that acute hypoxia dose-dependently stimulates expression of EPO, fibroblast growth factor-2, and vascular endothelial growth factor via HIF1 stabilization (Nature Med. 8: 718-724, 2002).
Further controlling the regulation of EPO production are a family of prolyl hydroxylases, the PHD proteins, which act to regulate the HIF transcription factors. PHD (prolyl hydroxylases) proteins belong to a superfamily of several 2-oxoglutarate-dependent dioxygenases (Kaelin Jr., and Ratcliffe, Mol. Cell. 30, 393 (2008). In the mouse, these genes are known as EGLN1 (PHD2, prolyl hydroxylase domain-containing protein 2 and by the synonyms hif-prolyl hydroxylase 2; hifph2; hph2; chromosome 1 open reading frame 12; c1orf12; sm20, rat, homolog of sm20; zinc finger mynd domain-containing protein 6; and zmynd6), EGLN2 (PHD1, prolyl hydroxylase domain-containing protein 1; and by the synonyms hif-prolyl hydroxylase 1; hifph1) and EGLN3 (PHD3 prolyl hydroxylase domain-containing protein 3; and by the synonyms hif-prolyl hydroxylase 3; hifph3). In an attempt to elucidate the function of PHD enzymes in hepatic EPO production, Minamishima et al., created knockout mice lacking liver expression of PHD1, PHD2, PHD3, or combinations thereof (Mol. Cell. Biol. 29, 5729 (2009)).
Subsequent studies by Minamishima and Kaelin using the knock-out model, suggested that while hepatic inactivation of PHD1, PHD2, or PHD3 alone did not increase EPO or hematocrit values, loss of all three PHDs increased both measurements (Science, 329, 407 and Supplemental Information (2010)). According to Minamishima, questions remain regarding the promoters used and the role that PHD2 plays (and at which developmental stage) independent of the other two enzymes in the activation of EPO production.
Double-stranded RNA molecules (dsRNA) have been shown to block gene expression in a highly conserved regulatory mechanism known as RNA interference (RNAi). This natural mechanism has now become the focus for the development of a new class of pharmaceutical agents for treating disorders that are caused by the aberrant or unwanted regulation of a gene.
Given the drawbacks of complete gene knockout and the inherent problems translating gene knockout to human therapy, the present invention contemplates the use of RNAi to effect gene modulation with improved outcomes in the production of erythropoietin.
During development the liver is the major source of EPO but over time eventually the liver EPO is switched off and in normal healthy adults their kidney makes the EPO to support normal red blood cell production. However, two to four million Americans with renal disease suffer from anemia due to impaired EPO production. If it is possible to turn on hepatic EPO using siRNA targeting EGLN genes the liver could now supply the EPO required to support red blood cell production to compensate for the damaged kidney function. Furthermore, using siRNA in LNPs it may be possible to activate fetally expressed genes in liver by targeting negative regulators of the pathway. This strategy could be used in the treatment of many other diseases and not just exclusively anemia.

Compositions and methods for increasing erythropoietin (EPO) production


A semiconductor device comprises a substrate comprising a major surface; a p-type Field Effect Transistor (pFET) comprising: a P-gate stack over the major surface, a P-strained region in the substrate adjacent to one side of the P-gate stack, wherein a lattice constant of the P-strained region is different from a lattice constant of the substrate, wherein the P-strained region has a first top surface higher than the major surface; and a P-silicide region on the P-strained region; and an n-type Field Effect Transistor (nFET) comprising: an N-gate stack over the major surface, an N-strained region in the substrate adjacent to one side of the N-gate stack, wherein a lattice constant of the N-strained region is different from a lattice constant of the substrate, wherein the N-strained region has a second top surface lower than the major surface and a N-silicide region on the N-strained region.

The disclosure relates to integrated circuit fabrication, and more particularly to a semiconductor device with a strained structure.
When a semiconductor device, such as a metal-oxide-semiconductor field-effect transistor (MOSFET), is scaled down through various technology nodes, a high-k gate dielectric layer and metal gate electrode layer are incorporated into the gate stack of the MOSFET to improve device performance with the decreased feature sizes. In addition, strained structures in source and drain (S/D) recess cavities of the MOSFET utilizing selectively grown silicon germanium (SiGe) may be used to enhance carrier mobility.
However, there are challenges to implement such features and processes in complementary metal-oxide-semiconductor (CMOS) fabrication. For example, it is difficult to achieve enhanced carrier mobility for a field-effect transistor (FET) because strained materials cannot deliver a given amount of strain into channel region of the FET, thereby increasing the likelihood of device instability and/or device failure. As the gate length and spacing between devices decrease, these problems are exacerbated.

Strained structure of a semiconductor device

Taiwan Semiconductor Manufacturing Company, Ltd.


This invention provides; a polyazopyrrole of the general formula (I): ##STR1## wherein n represents an integer of 5 to 10,000, and an anion-doped polyazopyrrole of the general formula (II): ##STR2## wherein X represents an anion; n represents an integer of 5 to 10,000; m represents 0.001 to 2; and a represents 1, 2, or 3.

The recent miniaturization of electronic devices calls for the development of electric batteries of reduced weight and, yet, with high performance characteristics. Conductive polymers are attracting attention as electrode active materials for such batteries and a large number of electrically conductive polymers including polyaniline, polypyrrole and polythiophene have heretofore been developed. These polymers are generally synthesized from the corresponding monomers by electrolytic or chemical oxidative polymerization. Since, up to the present time, aniline, pyrrole, thiophene and their derivatives have been chiefly used as starting monomers for such conductive polymers, the conjugated structure of the backbone chain of such polymers other than polyanilines which contain nitrogen atoms consists of carbon-carbon double bonds. Attempts have been made to improve the stability and electrical conductivity of polymers by introducing azo groups, as new structural moieties, into the backbone conjugated system consisting of carbon-carbon double bonds and, as a specific example, polyazophenylenes have been synthesized but none have proved to have characteristics surpassing the polymers in the carbon-carbon double bond series.

Polyazopyrroles and electric cells based thereon


A fingerprint detection circuit includes: a pixel region and a power grid. The pixel region includes a first pixel region and a second pixel region. The second pixel region is arranged on a periphery of the first pixel region, the first pixel region is provided with a plurality of first pixels, and the second pixel region is provided with a plurality of second pixels. The power grid is arranged below the pixel region, and configured to provide a driving electrical signal for pixel electrodes of the plurality of first pixels and pixel electrodes of the plurality of second pixels, to detect a coupling capacitance formed between the pixel electrodes of the plurality of first pixels and a biological tissue and to cause, via the plurality of second pixels, capacitances of the pixel electrodes of the plurality of first pixels to ground to be consistent.

With the development of fingerprint identification technologies, fingerprint identification chip has gained wide application in various fields. Capacitive fingerprint identification chips have good user experience, small area, low cost, high reliability and the like advantages, and are thus most commonly used fingerprint identification chips.
The capacitive fingerprint identification chip may be arranged on the front side, the rear side, the side surface or the like of a device. Due to different arrangement positions, different shapes are desired for the capacitive fingerprint identification chip. As such, the capacitive fingerprint identification chip has more and more abundant dimensions and shapes. Especially the demands on the miniaturized capacitive fingerprint identification chips are becoming urgent.
In a conventional capacitive fingerprint identification chip, a turn of power ring for supplying power is arranged on a periphery of a pixel region, and effective pixels are arranged in a region enclosed by the power ring. The effective pixels may be configured to sense fingerprint information. However, when the dimension of the capacitive fingerprint identification chip is reduced, the total area of the pixel region is also decreased whereas the area occupied by the power ring is not proportionally decreased with the pixel region. As a result, the area proportion of the effective pixels in the pixel region is decreased when the total area of the pixel region is decreased.

Fingerprint detection circuit, fingerprint identification apparatus and terminal device


A multi-stage Class AB amplifier system includes a first Class AB amplifier circuit configured to receive an input signal. A bias circuit is configured to receive an output of the first Class AB amplifier circuit. A second Class AB amplifier circuit is in communication with the bias circuit. The second Class AB amplifier circuit is configured to generate an output signal. A current mirror circuit is arranged between the first Class AB amplifier circuit and the bias circuit. A common-mode feedback circuit is configured to generate a feedback signal based on the output signal.

The background description provided herein is for the purpose of generally presenting the context of the disclosure. Work of the presently named inventors, to the extent the work is described in this background section, as well as aspects of the description that may not otherwise qualify as prior art at the time of filing, are neither expressly nor impliedly admitted as prior art against the present disclosure.
Class A amplifying devices operate over an entire cycle of an input signal. An output signal of these devices is a scaled-up replica of the input signal. These devices are not very efficient since they have a maximum efficiency of 50% with inductive output coupling and 25% with capacitive output coupling.
In Class A amplifying devices, an amplifying element such as a transistor is biased such that the device is always conducting. The amplifying element is operated over a linear portion of the transfer characteristic of the transistor. Because the amplifying element is always conducting, power is drawn from the power supply even when there is no input. If high output power is needed, power consumption (and the accompanying heat) may become significant.
Class B amplifying devices amplify during half of an input cycle. As a result, Class B amplifying devices tend to increase distortion but have higher efficiency than Class A amplifying devices. Class B amplifying devices have a maximum efficiency over 75%. This is because the amplifying element is switched off half of the time and does not dissipate power at this time.
Class B amplifying devices may use complementary transistor pairs (a "push-pull" transistor arrangement). Complementary devices amplify opposite halves of the input signal. Mismatch or crossover distortion may occur when re-joining the halves of the signal. One solution to the mismatch problem involves biasing the transistors to be just on, rather than completely off when not in use. This biasing approach is called Class AB operation. In other words, Class AB amplifying devices may include a class B output stage that is biased so that both transistors are conducting around the crossover point.

High-speed, multi-stage class AB amplifiers


Disclosed is an apparatus and method to set the speed of a clock. A computing device may include a processor and a scheduler of the processor, the scheduler may be configured to: receive a plurality of votes for requested bandwidths from a plurality of different execution environments; sum the requested bandwidths; and set the clock speed based upon the sum of the requested bandwidths.

Field
The present invention relates to an apparatus and method to set the speed of a clock.
Relevant Background
In a hardware environment that provides virtual ownership to multiple execution environments (EEs), many EEs may own a command interface (e.g., a hardware (HW) command interface). Each EE may assume that it is the sole user of the HW. If concurrent events/commands occur from various EEs, each of the EEs may experience performance degradation.
Traditional clock-voting mechanisms have been used for multiple users of HW. In this traditional clock-voting mechanism, different EE users of the HW vote to turn the HW clock on and for a particular clock speed. An aggregator of the votes selects the highest vote (i.e., the most requested speed). Traditionally, each EE manages its local voting without taking other EEs into account. Unfortunately, for some EEs the selected speed may be too low and the amount of resultant degradation may not be manageable for that particular EE.

Apparatus and method to set the speed of a clock


An elevator monitoring terminal includes a storage unit and a processing unit. The storage unit stores screen-displayed data including monitor-related screens related to an elevator monitoring operation, and the processing unit displays the monitor-related screens in the screen-displayed data read from the storage unit on a display unit.

Conventional elevator remote monitoring systems are configured to execute various processings related to an elevator monitoring operation by use of a maintenance server and various terminals (e.g., monitor station) as disclosed in JP 2003-212447 A, for example.
However, display screens for various processings related to an elevator monitoring operation are not displayed concurrently on a terminal, which leads to a problem in that the elevator monitoring operation cannot be efficiently carried out.
The present invention has been made to solve the above-described problem, and it is therefore an object of the present invention to provide an elevator monitoring terminal and elevator monitoring apparatus which enable an efficient elevator monitoring operation.

Elevator monitoring terminal and elevator monitoring apparatus with multiple display screens displaying operational data, in-car image data and communication request data


A process for making composite materials, namely reinforced Al-metal matrix composites based on either: (I) Al-W intermetallic phase and Al.sub.2 O.sub.3 ceramic whiskers, or (II) Al-Mo intermetallic phase and Al.sub.2 O.sub.3 ceramic whiskers. This process involves the oxidation of aluminum using tungsten oxide in powder form for product I, and that of aluminum and molybdenum oxide in powder form for product II. Product I contains an Al-W intermetallic phase, some sapphire whiskers, and a continuous Al-metal matrix. Product II contains an Al-Mo intermetallic phase, sapphire whiskers, and a continuous Al-metal matrix. The alumina whiskers are formed as a result of two reactions. They are: (i) the oxidation between the pre-mixed Al and the oxide, and (ii) the oxidation of Al with the atmospheric environment in the presence of the oxide, which acts as a catalytic agent for the reaction. These newly invented products are hard, strong and light. They are fabricated at above the melting point of aluminum, typically above 800.degree. C. and preferably around 1000.degree. C., and no sophisticated facility is required in the production process. Based on the above powder mixtures of I, or II, additional powders, for example, carbon (C), silicon dioxide (SO.sub.2) or other metal oxides, can be mixed to further improve the structural properties of the composites.

The present invention relates to a new type of metal matrix composite (MMC) and the process for manufacturing this new MMC. MMCs are well known structures, typically comprised of a ductile metal matrix, reinforced with ceramic fibers, whiskers, particulates, or dispersions. Most frequently, a prepared reinforcing material is mixed with molten matrix metal. Occasionally, the reinforcing structure is precipitated out of the molten phase of a melt consisting of compounds dissolved in the matrix metal.
These materials often share the best characteristics of both components of the matrix. They may combine the strength, hardness, corrosion resistance, and modulus of the reinforcement phase with the ductility, thermal and electrical conductivity, and machinability of the metal matrix phase. When aluminum is used as the matrix metal, the composite may be light, strong, and hard. This is important in many applications, specifically in machine parts, automotive and transportation parts, and electronic packaging.
Mixing a prefabricated reinforcing material with molten metal has the associated problems of inter-phase bonding, anisotropic characteristics, and non- uniform dispersion of the reinforcing structures in the matrix. Much effort has gone into solving these problems. The metal matrix does not always form a strong, cohesive bond to the reinforcing material. Methods have addressed improving both the mechanical and chemical bonding aspects, resulting in elaborately prepared starting material. For example, one technique first forms a composite of silicon carbide fibers within an alumina matrix, and then combines this composite with a metal matrix. This is done to obtain an adequate bond between the metal matrix and the silicon carbide fibers, using the alumina phase as an intermediary.
Other processes use layers or woven mats of reinforcing materials infused with molten metal. These structures have strongly anisotropic characteristics. Other fabrication techniques, such as hot or cold isostatic pressing, extrusion, and arc/drum spraying can also result in isotropic characteristics, depending on the type of reinforcing material. This results in a non-uniform material, which is undesirable in many applications.
Even without using processes that result in inherently anisotropic materials, uniform dispersion of the reinforcing phase within the matrix may result in a non-uniform material. For example, dispersed reinforcing particles may settle. One method that addresses this problem pounds the reinforcing phase into a powder of the metal, and then forms the finished part by sintering, which is a solid-phase process. Many other methods pre-form the reinforcing material into a near-finished shape and infuse it with molten matrix metal. However, obtaining a uniform infusion is difficult, as is obtaining a uniform bond between the matrix and the reinforcement phase, as discussed above.
The performance of the material is known to depend on its macroscopic mechanical properties, which must be uniform to achieve the uniform benefit of the composite. Moreover, a metal matrix that is not strongly bonded to the reinforcing phase does not gain the full value of the reinforcement. Finally, exotic, difficult, or complicated fabrication processes of either the composite or its precursor materials make the use of those composites economically unattractive, if not unfeasible. What is needed is a feasible and economically viable composite and method of fabrication.

Aluminum metal matrix composite materials reinforced by intermetallic compounds and alumina whiskers


A display method and a display device for optimizing screen brightness of a mobile terminal are provided. The display method includes: determining an external illuminance value based on a sensor signal by detecting by the sensor signal for determining a brightness value of a screen; determining the brightness value of the screen corresponding to the external illuminance value; and outputting an image signal by using the brightness value of the screen.

1. Technical Field
Aspects of the exemplary embodiments generally relate to a display method and device. More particularly, the exemplary embodiments relate to a display method and device for optimizing screen brightness according to an amount of illuminance.
2. Description of the Related Art
Currently, as various display devices such as a mobile phone, a notebook, a tablet PC and the like (hereinafter, referred to as a "mobile terminal") become common, a picture quality as well as a function thereof is considered as being important. Among various elements influencing the picture quality of the display device, proper screen brightness is a non-negligible element. If the screen brightness is automatically controlled according to external illuminance, user satisfaction may increase and power consumption may be reduced.
The display device of the related art uses fixed screen brightness or uses screen brightness controlled by the user. However, when a fixed screen brightness is used, since unnecessary power consumption is high during high external illuminance and higher screen brightness cannot be obtained in a darker environment, this results in inconvenience in using the display apparatus. For example, due to a difference of illuminance between day and night or a sunny day and a cloudy day, screen brightness of the display device becomes different from surrounding brightness, which makes a user experience great amount of eye strain.
Further, when a user manually controls the screen brightness, the user who is not skilled has difficulty in properly controlling the screen brightness. For example, the user may control the screen brightness such that the brightness is too bright or too dark compared to the surrounding illuminance.
The screen brightness suitable for the display device of the mobile terminal may vary, depending on a position or an angle of the mobile terminal held by the user. However, there is no method in the related art capable of controlling the screen brightness in consideration of an incident angle. Accordingly, even though the user controls the screen brightness, the controlled screen brightness may not be proper, depending on an angle at which the user views the corresponding display device. Therefore, there is a requirement to provide a method capable of automatically controlling the screen brightness in consideration of an incident angle of illumination of the display device in the related art.

Display method and device for optimizing screen brightness


A diamond heat sink of the present invention comprises: a support layer consisting of substantially undoped diamond; a heat sensitive layer consisting of doped diamond, disposed on the surface of the support layer; an insulation layer consisting of substantially undoped diamond, disposed on a predetermined region in the surface of the heat sensitive layer; electrodes disposed on the heat sensitive layer, wherein an exothermal device is placed on the surface of the insulation layer; and a cooling structure disposed on the backside of the support layer, the cooling structure having at least one microchannel, the microchannel being defined by a diamond, wherein an exothermal device is to be placed on the surface of the insulation layer; and wherein the heat sensitive layer and the electrodes form a thermistor, the electrical resistivity of the thermistor being capable of varying corresponding to heat generated from the exothermal device and transferred through the insulation layer to the thermistor.

1. Filed of the Invention
The present invention is directed to a diamond heat sink having an excellent heat release characteristics, which incorporates a thermistor or a cooling device with higher thermal response, and is also directed to a method of manufacturing it.
2. Related Background Art
Diamond is a suitable material for heat sink, because diamond has excellent thermal conductivity of more than 2,000W/m.cndot.K!. Further, since diamond can acquire the characteristic of semiconductor material when impurities are doped into the diamond, the resultant doped diamond can be employed as a thermistor material which has an capabilities for the use at elevated temperature and has a quick thermal response characteristics.
Japanese Patent Laid-open No. 63-184304 discloses a thermistor made with diamond. A semiconductor diamond film is formed on a substrate by vapor phase synthesis. The semiconductor diamond film of this reference serves as a heat sensitive film. Ohmic electrodes are formed on the heat sensitive film. The resistivity of the heat sensitive film are measured through these Ohmic electrodes to determine the temperature of the heat sensitive film. Examples of the available substrates on which the heat sensitive film is formed include single crystal diamond substrate, metal having a high melting point and a high thermal conductivity, semiconductor, and other compound(s) thereof.
In Japanese Patent Laid-open No. 5-67711 discloses a thermistor made of diamond to be integrated with a heat sink made of diamond, and the manufacturing method of the thermistor-integrated heat sink. According to the construction of the thermistor with this manner, the semiconductor diamond film as the heat sensitive film is formed on a predetermined region of a heat sink material by the vapor phase synthesis, and metal electrodes are then formed on the heat sensitive film. A metallized film is also formed on the surface of the heat sink material next to the thermistor. The exothermal devices such as diode and FET are seated onto the metallized film for their temperature to be measured. The exotherms from the device on the metallized film is conducted to the thermistor through the heat sink material, and the temperature of the device can be measured. Japanese Patent Laid-open No. 5-67711 also shows another thermistor-integrated heat sink. The semiconductor diamond film as the heat sensitive film is formed on the entire surface of the heat sink material and metal electrodes are formed onto the heat sensitive film. A metallized film is formed onto the surface of the heat sensitive film between the metal electrodes, and the exothermal devices are seated onto the metallized film. In both of the thermistor-integrated heat sinks of the Japanese Patent Laid-open No. 5-67711, single crystal diamond, metals having high melting point and higher thermal conductivity (or refractory metals with higher thermal conductivity), semiconductor or other compound(s) thereof are used for the heat sink material.
As mentioned above, in Japanese Patents Laid-open Nos. 63-184304 and 5-67711, the single crystal diamonds are employed as the substrate of the thermistor of the former and as the heat sink material of the thermistor-integrated heat sink of the latter, respectively. Single crystal diamonds of a consistent quality can be obtained through artificial synthetic method under extra high pressure, which are still costly.
When the vapor phase synthesis is applied to obtain the diamond heat sink, a thicker diamond would be required for the substrate and the heat sink, because of insufficient performances of the diamonds made via vapor phase synthesis. Further, since the vapor phase synthetic diamond is polycrystalline, the surface of the diamond would be considerably rough. Thus, the rough surface of the synthetic diamond needs to be polished and made flat to mount the exothermal devices. However, since diamond is an extremely hard material, the polishing process for synthetic diamond includes significant difficulties.
In the heat sink construction of Japanese Patent Laid-open No. 5-67711 where the thermistor and the exothermal device are arranged in parallel on the heat sink material, the exotherms from the exothermal device is transferred through heat sink material to the thermistor. Thus, the heat would be detected with some delay, and some of the heat would be absorbed by the heat sink material in the heat transfer process from the exothermal device to the thermistor. Therefore, the thermistor-integrated heat sinks of the above references have insufficient abilities to precisely detect and control a temperature of the mounted exothermal device.
U.S. Pat. No. 5,022,928 discloses a film-shaped thermoelectric heat pump of the Peltier device type in which Bi.sub.2 Te.sub.2 etc. are laminated onto a substrate. This patent, however, not directed to the improvement of heat transfer. In addition, the patent does not describe the point of quick response required when it is used as a heat sink.
Consequently, it is desirable to present a heat sink capable of rapidly responding.

Diamond heat sink including microchannel therein and methods for manufacturing diamond heat sinks


An emergency vehicle light bar is provided with a flexible support that can be curved to match the curvature of the top edge of a vehicle window when installing the light bar on the vehicle, giving the light bar a low profile relative to the vehicle and giving the vehicle a stealth or “unmarked” appearance.

1. Field of the Invention
The present invention pertains to a light bar for use on the exterior of emergency vehicles where the light bar is designed to have a low-profile when mounted to the vehicle. In particular, the present invention pertains to a light bar having a flexible support that can be curved to match the curvature of the top edge of the vehicle windshield when installing the light bar on the vehicle, giving the light bar a low profile relative to the vehicle and giving the vehicle a stealth or "unmarked" appearance.
2. Description of the Related Art
Light bars are typically used on emergency vehicles by being mounted to the roof or top of the vehicle with the light bar extending across substantially the entire width of the vehicle. This positioning of the light bar enhances the ability of the flashing warning lights of the light bar to be seen from in front of the vehicle and from behind the vehicle. In addition, many light bars are constructed with flashing warning lights at their opposite ends that enable the light bar to be easily seen from the sides of the vehicle. However, in many police functions, in particular traffic control, it is desirable that the police vehicle have a stealth or "unmarked" appearance of an ordinary vehicle when the warning lights are not in use, and that the vehicle become instantly recognizable as an emergency vehicle when the warning lights are energized.
For many years, the stealth or "unmarked" appearance of emergency vehicles, and in particular police vehicles, was accomplished by using a small, rotating beacon that was operated by power received from the cigar lighter outlet of the vehicle. These emergency lights typically comprised a transparent or translucent colored dome that was mounted on a magnetic base of the light. The dome covered over a rotating or flashing light assembly within the dome. This emergency light was kept inside the vehicle within access of the driver or another officer in the vehicle until needed. When needed, the emergency light was plugged into the vehicle cigar lighter outlet and the magnetic base of the light was positioned on the vehicle dashboard or on the roof or top surface of the vehicle.
Emergency lights of this type enabled the police vehicle to have a stealth or "unmarked" appearance because the emergency light was kept inside the vehicle until needed. However, as the designs of vehicles have changed over the years, use of this type of emergency light has waned because vehicles are now often constructed with dashboards and roofs of nonmetallic materials. In addition, the optical energy of this type of emergency light provides only a tiny fraction of that required by current national standards such as SAE J2498, Minimum Performance of the Warning Light System Used on Emergency Vehicles, and the requirements for small vehicles contained in NFPA 1901, Standard for Automotive Fire Apparatus.
At the present time one of the most popular approaches to installing emergency warning lights on a vehicle while maintaining a stealth or "unmarked" appearance of the vehicle is to install multiple small warning light assemblies on the inside of the vehicle. These emergency light assemblies are typically mounted on the dashboard inside the windshield of the vehicle and on the rear window deck inside the rear window of the vehicle. However, this type of emergency warning light is disadvantaged in that virtually all of the light energy is directed toward the front and rear of the vehicle. Little or none of the flashing signal provided by the light assemblies is directed to the sides or corners of the vehicle to provide protection when the emergency vehicle is entering intersections. In addition, because the highest performance lights are inside the vehicle and the signal light must pass through the angled windshield and rear window, a substantial amount of the light is lost to refraction and reflection. Even more of the light is lost if the windshield or rear window are tinted. Furthermore, unless the emergency light is sealed to the glass of the windshield and rear window, the light may be reflected back into the vehicle and into the eyes of the vehicle's driver.
Another popular approach to installing warning lights on emergency vehicles while maintaining the stealth or "unmarked" appearance of the vehicle is to install small strobe lights into the vehicles turn signal assemblies, stop taillight assemblies, and backup light assemblies. However, these new systems often do not comply with the requirements of the current national standards for emergency vehicle signal lights, and the systems are extremely expensive to install. Furthermore, when the emergency vehicle is decommissioned, these systems are also extremely expensive to remove from the vehicle before the decommissioned vehicle is sold.
To overcome the problems associated with providing a vehicle with emergency warning lights while also maintaining the stealth or "unmarked" appearance of the vehicle, what is needed is an emergency warning light system where all of the systems warning lights are mounted on the exterior of the vehicle, yet the warning lights would be virtually invisible when viewed at a distance from the vehicle. The system would also be inexpensive as well as easily installed on the vehicle, inexpensively and easily serviced, and inexpensively and easily removed from the vehicle without any significant damage to the vehicle.


A surgical sterilizing container is provided, having a bottom and a container wall. A through-opening is formed on the sterilizing container for the exchange of media. A valve device having an outlet valve is provided for opening and closing the through-opening. In order to remove fluid which has formed in the container interior while reducing the risk of germs penetrating into the container interior, the through-opening is formed in the container wall at a distance from the bottom, and the sterilizing container has a fluid lifting device for providing a fluid connection from the bottom to the outlet valve and for lifting fluid from the bottom to the outlet valve. A surgical fluid extraction device is also provided for use with a surgical sterilizing container having a container wall and a bottom.

Surgical sterilizing containers of the kind mentioned at the outset are known, in which surgical instruments can be held for sterilization. During the sterilization process, fluid, in particular, condensate forms in a container interior defined by the sterilizing container. The condensate can be evaporated, for example, during a drying phase following the sterilization process. The steam can exit from the container interior via a through-opening which is formed on the sterilizing container and is openable and closable by the outlet valve.
As condensate usually collects on the bottom of the sterilizing container, sterilizing containers have been developed in which the through-opening is formed in the bottom and the outlet valve can open and close the through-opening in the bottom. This serves to drain the condensate which has collected on the bottom from the sterilizing container to the outside. The draining of condensate, in particular, when a pressure-actuatable outlet valve is used, does, however, have the great inherent disadvantage that drained condensate exits from the sterilizing container in a gush. Where sterilizing containers are stacked one on top of the other, the condensate can flow from the higher sterilizing container over the lid of the sterilizing container below it. This results in undesired cooling of the lower sterilizing container and in undesired subsequent formation of condensate in its container interior, which has to be additionally evaporated or drained. The through-opening in the bottom also proves to be particularly disadvantageous because the sterilizing container is inadequately sealed if the outlet valve is faulty or damaged. This may lead to unsatisfactory sterilization results and facilitate penetration of germs into the container interior. Especially when the through-opening is arranged in and the outlet valve on the bottom, there is a high risk that unevenesses of a set-down surface for the sterilizing container or objects placed on the set-down surface will act from below on the outlet valve and result in damage thereto or failure thereof. An uneven set-down surface or objects on the set-down surface may also cause the valve body to be lifted off from the valve seat of the outlet valve and the through-opening to be opened, and so even if the outlet valve is as such intact, there is a great risk of germs penetrating into the container interior. A further disadvantage is that owing to the through-opening being arranged in the bottom, it is difficult for hospital staff normally handling the sterilizing container to recognize failure of or damage to the outlet valve.
A sterilizing container of the kind described hereinabove with a through-opening in the bottom and an outlet valve arranged on the bottom is described, for example, in EP 1 035 873 B1.
"Set-down surface" is a surface on which the sterilizing container can be positioned. "Set-down plane" is a contact plane which is defined by the sterilizing container and in which the sterilizing container contacts the set-down surface. The horizontally aligned set-down surface, as is usually the case, will, when the sterilizing container is used in accordance with the specifications in an operating position, result in a horizontal alignment of the set-down or contact plane. Position and orientation details such as, for example, "at the top", "at the bottom" refer, in this case, to an operating position of the sterilizing container in which it is positioned in accordance with the specifications on a set-down surface.
An object underlying the present invention is to provide a surgical sterilizing container of the kind mentioned at the outset, from which it is possible to remove fluid which has formed in the container interior while reducing the risk of germs penetrating into the container interior.

Surgical sterilizing container and surgical fluid extraction device


A collective procurement management system which permits multiple potential purchasers of a specific item or service to submit orders for the item or service on an ongoing basis. As orders enter the system, they are grouped such that potential purchasers are may “cooperate” in generating a collective bulk order so that all participants may obtain discount/volume pricing. Once a threshold level of order volume is obtained as a result of multiple orders, the grouped order is submitted to the supplier for fulfillment. The order is then fulfilled at a volume pricing level although individual portions of the collective order are routed to a plurality of purchasers. The present invention also includes a Reverse Auction Process (RAP) which, in one embodiment, operates to allow potential purchasers to select a product or service and set a maximum price that they are willing to pay for the same. Following submission of this information to the system, possibly including orders for the same item from other potential buyers, potential vendors bid to supply the item to the relevant buyers requesting the item.

Business is all about commercial transactions. These transactions result in the critical revenue streams necessary for businesses to survive. In some cases, businesses purchase goods or services which are helpful or necessary for the company to operate. Goods and services may be purchased as "overhead" (e.g. pencils and pens for employees) or for redistribution to the ultimate consumer (e.g. software to be distributed by a PC seller in connection with the sale of PCs).
While commercial transactions between parties have occurred practically since the beginning of time, the methodology by which they are conducted has evolved rapidly. This is especially true in recent years with the advent of the computer, the internet and other communications technologies.
One recent development has been so called "on-line commerce". This umbrella term generally refers to the conduct of business and the consummation of business transactions through an electronic medium available to both parties through which orders may be communicated and processed. For example, consumers may purchase various goods through on-line stores available on the internet. In this case, the age old requirement of a face to face transaction in, for example, a retail brick and mortar store is unnecessary. Instead, a consumer reviews available offerings on the internet, selects one for purchase and orders it. The consumer may pay for the purchase by credit card and receive the item in the mail a few days later.
In addition to the above described business to consumer transactions, business to business transactions which occur via computers and various communications systems have also become commonplace. For example, electronic commerce ("e-commerce") systems, services and software exist whereby companies may enter into purchase and sale transactions on an automatic or semiautomatic basis. Through the use of these e-commerce systems, purchasing entities may, for example, be set up to automatically receive re-orders of consumable supplies on a rolling basis from a predetermined supplier. In some cases, the price and quantity may be pre-negotiated or at least known ahead of time by the purchaser. In other cases, the purchasing entity may agree that it will accept a certain quantity on a rolling basis at the then current market price, whatever it may be. Communication in these systems between buyers and sellers may occur through various communication channels such as the internet, private local or wide area network or dialup access.
While these systems are extremely successful, they do suffer drawbacks. In particular, these systems generally operate under the restriction that the supplier-purchaser relationship is predefined and relatively inflexible. By way of example, existing e-commerce systems and services generally require the purchaser to preselect its supplier with respect to specific goods and/or services. After selection, these goods and services are provided exclusively by the preselected supplier regardless of price or terms. As mentioned above, in many cases where rolling orders are used, the purchasing entity is required to accept goods/services at a future price which is likely unknown at the time of the initial order or when the relationship is set up. This can be disadvantageous to the purchaser not only in terms of pricing but also in terms of product/service quality and fitness for purpose. In other words, the purchaser may, due to a prior commitment made to a supplier, be stuck with an inferior product/service or one that does not meet its needs as well as another product/service which would otherwise be available to the purchaser.

Collective procurement management system


A device includes an audio capture device for receiving an audio signal in an ultrasonic frequency range. The device includes a processor to determine whether the received audio signal corresponds to an ultrasonic message. The processor extracts a content of the ultrasonic message, when it is determined that the received audio signal corresponds to an ultrasonic message, automatically handles the ultrasonic message based on the extracted content, stores at least a portion of the content of the ultrasonic message, and displays the portion of the content of the ultrasonic message to a user of the mobile device at a time subsequent to a time of the receipt of the audio signal.

As mobile consumer electronic devices, such as mobile phones, tablet computers, personal digital assistants (PDAs), portable gaming devices, etc., have become increasingly ubiquitous, the public's general reliance on these devices for storing and managing events and details in their lives has also risen. Unfortunately, despite the large number of services, features, and applications now available on such devices, usage is often limited by the difficulty in accessing or activating the service, feature, or application. In some instances, it has been determined that adding a single user action (e.g., a click, button press, swipe, etc.) to a process required to access a feature or perform a function, decreases usage of the feature by up to 50%.

Method and system for transmitting information using ultrasonic messages


An economy running system having: a function of stopping an internal combustion engine of a vehicle when the vehicle stops and all of stop conditions are satisfied; and a function of restarting the internal combustion engine of the vehicle. The economy running system includes: a control unit that judges whether the vehicle stops or not, and judges whether each of the stop conditions is satisfied or not; and a notification unit. When the control unit judges that the vehicle stops and that at least one of the stop conditions is not satisfied, the control unit causes the notification unit to notify to a user first notification information concerned with the at least one of the stop conditions.

1. Field of the Invention
The present invention relates to an economy running system, an economy running controller and a navigation apparatus. More particularly, it relates to an economy running system having a function of stopping and restarting an engine in accordance with a state of a vehicle, an economy running controller and a navigation apparatus cooperated with the economy running controller.
2. Description of the Related Art
An economy running system by which an engine is stopped automatically when the engine need not be operated (while a vehicle stops, for example, to wait for a signal to change, to wait for a train to pass or to wait for a person) and by which the engine is restarted automatically when the engine needs to be operated has been recently developed and put into practice in order to reduce fuel expenses and reduce exhaust gas.
The vehicle having such an economy running system is provided with an indicator for indicating execution of automatic stopping and restarting of the engine, that is, execution of economy running to a user (driver etc.) when such economy running is executed, and the indicator for indicating non-execution of economy running to the user when such economy running is not executed. The user can confirm whether economy running is executed or not, by referring to these indicators (e.g. see JP-A-2001-88580).
In the present circumstances, the mechanism of the economy running system has been not correctly recognized yet because the economy running system has been not common to family cars. Generally, the economy running system is recognized as such a system that the engine is stopped automatically when the vehicle is stopped.
When, for example, the engine is to be stopped automatically by actual economy running control while the shift lever is in a D range, the engine can be stopped automatically when all stop conditions including the stopped state of the vehicle (the vehicle speed of 0 km/h), the accelerator off state (the released state of an accelerator pedal), the brake on state (the stepped state of a brake pedal), the non-panic braking (non-sudden braking) state, the state in which electricity stored in a battery used at the time of automatic stopping of the engine is not lower than a predetermined level, and other states are satisfied.
Accordingly, when any one of the stop conditions is unsatisfied in spite of the stopped state of the vehicle (i.e. the vehicle speed of 0 km/h), there arises a phenomenon that the engine cannot be stopped automatically. In the background art, when such a phenomenon occurs, non-execution of economy running is only indicated by the indicator. Accordingly, if the user falsely recognizes that the system should stop the engine automatically when the vehicle is stopped, the user will doubt the reason why the engine is not stopped automatically in spite of the stopped state of the vehicle. Moreover, a fear that the economy running control does not work normally is given to the user. There is a problem that the user may mistake this state for an accident.
There is assumed the case where the user performs a predetermined operation to lead the unsatisfied stop condition into a satisfied condition to stop the engine automatically when such a phenomenon occurs. For example, in the system in which stopping of the engine by sudden braking is recognized as a "panic braking state", the engine is not stopped automatically even in the case where the vehicle is stopped by sudden braking. In this case, when the shift lever is shifted to a P range and the brake is turned off (the brake pedal is released), the "panic braking state" can be cancelled. By this operation, the engine can be stopped automatically.
It is however impossible to stop the engine automatically by the economy running control if the user does not correctly understand a cause of unsatisfaction of stopping the engine automatically (i.e. the unsatisfied stop condition) and a way to cope with the cause. It is not easy for the general user to correctly understand the plurality of stop conditions and the way to cope with the unsatisfaction of automatic stopping the engine in advance. For this reason, there is a problem that it is difficult for the user to use the functions of the economy running system efficiently.

Economy running system, economy running controller and navigation apparatus


The present invention provides human, humanized and/or chimeric antibodies as well as fragments, derivatives/conjugates and compositions thereof with a specific binding affinity for interleukin-18. The invention includes the use of these antibodies for diagnosing and treating diseases associated with increased IL-18 activity, the latter in the form of a pharmaceutical composition.

Interleukin-18 (IL-18) is a potent cytokine that plays a role in both innate and acquired immune responses. IL-18 was first identified for its ability to induce the production of IFN-γ, one of the primary effector molecules of a T helper (Th) 1-type immune response (Okamura et al (1995) Nature 378:88-91). It was shown subsequently that, in certain settings, IL-18 can also contribute to the development of additional responses such as Th2 (Nakanishi et al (2001) Annu Rev Immunol. 19:423-74). In addition to its stimulatory effect on cluster of differentiation (CD) 4+ and CD8+ T cells, IL-18 has been shown to have a broad spectrum of inflammation-related effects on various cells types including neutrophils, monocytes/macrophages, natural killer (NK) cells, epithelial and endothelial cells.
IL-18 belongs to the interleukin-1 (IL-1) superfamily, and like IL-1 beta (IL-1β) it is first synthesised as an inactive intracellular polypeptide, pro-IL-18 (24 kDa). Enzymatic cleavage of the pro-peptide releases the biologically active mature form of IL-18 (18 kDa). IL-18 is produced by macrophages and other cells involved in the immune response. Apart from its physiological role, IL-18 also contributes to severe inflammatory reactions, providing indication of its role in certain inflammatory disorders such as autoimmune diseases. IL-18 is regulated in part by endogenous IL-18 binding protein (IL-18BP) which binds to IL-18 and blocks its binding to the IL-18 receptor (IL-18R), thereby quenching the IL-18 activity. However, in certain circumstances, this negative feedback loop is insufficient to adequately quench the biological effects of IL-18 whilst still providing enough IL-18 biological activity to initiate innate immune responses.
The biological activity of IL-18 is generated when IL-18 binds to cell-bound IL-18R, initiating cell signaling which leads to expression of other cytokines. The IL-18R is a heterodimer comprising two IgG like polypeptide chains that form a functional complex in which the β chain contains the IL-18 binding motif and the α chain contains an intracellular signalling domain (TIR) (Torigoe et al (1997) J Biol Chem 272:25737). IL-18 appears to first bind IL-18Rα and the β chain is then recruited to form the functional heterodimer. The binding of IL-18 to the α/β complex results in activation of the intracellular signalling cascade. Thus, blocking the binding of IL-18 to IL-18Rα may be useful in quenching unwanted IL-18.
IL-18 has been implicated in a number of human diseases, primarily autoimmune or inflammatory diseases and cancer. Psoriasis patients have increased IL-18 both in the skin lesions and in the circulation (Flisiak et al. (2006) 11:194). Elevated plasma IL-18 levels have been observed in cerebrospinal fluid and plasma of patients with multiple sclerosis (Fassbender et al. (1999) Neurology 53:1104; Nicoletti et al. (2001) Neurology 57:342). Patients with inflammatory bowel diseases (e.g. Crohn's disease, ulcerative colitis) have elevated IL-18 levels in the circulation (Ludwiczek et al (2005) Eur. Cytokine Netw. 16:27; Wiercinska-Drapalo et al (2005) World J Gastroenterol. 11:605). Patients with rheumatoid arthritis (RA) have elevated IL-18 levels in the synovial fluid (Gracie et al (1999) J Clin Invest 104:1393). IL-18 has also been shown to be increased in the serum of patients with other arthritic diseases with systemic manifestations such as Still's disease (Kawashima et al (2001) Arthritis Rheum. 44(3):550-60) and systemic juvenile idyopathic arthritis (sJIA) (Maeno et al (2002) Arthritis Rheum. 46(9):2539-41; Shimizu et al (2010) Rheumatology 49(9):1645-53) and has been proposed as a marker of disease severity (Kawagushi et al (2001) Arthritis Rheum. 44(7):1716-7; Lotito et al (2007) J Rheumatol. 34(4):823-30). In these autoinflammatory disorders, circulating IL-18 was shown to be further increased during the active phase of the disease and in a subset of patients developing complications such as macrophage activation syndrome (Shimizu et al (2010) Rheumatology 49(9):1645-53). IL-18 levels were also shown to be increased both systemically and in the pulmonary tissues of Chronic Obstructive Pulmonary Disease (COPD) patients, where IL-18 is associated with alveolar macrophages, CD8+ T cells and airway epithelial cells (Imaoka et al (2009) Eur Respir J. 31:287-97; Kang et al. (2007) J. Immunol. 178(3):1948-59; Petersen et al. (2007) Lung 185:161-71; Rovina et al (2009) Respir Med. 103:1056-62). IL-18 may also contribute to COPD co-morbidities (Petersen et al (2007) Lung 185:161; Larsen et al (2008) Cardiovasc Res 80:47).
In cardiovascular diseases, elevated plasma or serum levels of circulatory IL-18 were measured in acute coronary syndrome, myocardial infarction, coronary atherosclerosis, and unstable angina (Mallat et al (2002) Heart 88:467; Hulthe et al (2006) Atherosclerosis 188:450; Mallat et al (2001) Circulation 104:1598). Serum IL-18 levels are also associated with intima-media thickness of the carotid arteries (Yamagami et al (2004) Arterioscler Thromb Vasc Biol 25:1458).
Several types of cancers are also associated with elevated IL-18 expression levels. However the role of IL-18 may be dual in malignant diseases (Dinarello (2008) Cancer & Metastasis Rev 25:307). On one hand, IL-18 may be pro-angiogenic and thereby may promote tumor development, on the other hand it may stimulate cellular immune responses, e.g. NK cell mediated cytotoxicity and thereby act as an anti-tumorigenic agent (Kim et al. (2007) Oncogene 26:1468.).
Many of these clinical observations have also been corroborated in animal models of human disease. These studies have addressed both disease mechanisms dependent on IL-18 and IL-18 as a potential target for intervention. Development of CNS lesions in experimental autoimmune encephalitis (EAE), the most widely used animal model for multiple sclerosis, was shown to be dependent on IL-18Rα engagement (Gutcher et al. (2006) Nat Immunol 7:946.). The administration of IL-18 to animals was shown to enhance disease in the collagen induced arthritis model of RA (Gracie et al. (1999) J Clin Invest 104:1393), while lack of IL-18 or IL-18 neutralising therapies attenuated the severity of the disease (Banda et al. (2003) J Immunol 170:2100). IL-18 knockout mice are resistant to experimentally induced colitis (Hovet et al (2001) Gastroenterol 121:1372), whereas transgenic animals overexpressing IL-18 are more susceptible (Ishikura et al. (2003) J Gastroenterol Hepatol 18:960). IL-18 neutralising treatment attenuates intestinal inflammation (Lochner and Foster (2002) Pathobiol 70:164).
In an animal model developed for COPD, cigarette smoke was shown to increase IL-18 expression locally in the lung tissue (Kang et al (2008) Clin Invest 118:2771, Kang et al (2007) J Immunol 178:1948). In this model, impairment of IL-18 signaling via disruption of IL-18Rα gene resulted in a decreased lung inflammation, cell apoptosis and emphysema (Kang et al (2007) J Immunol 178:1948). Conversely, over-expression of IL-18 in the lung of mice was associated with pulmonary inflammation characterized by the recruitment of CD8+ T cells, macrophages, neutrophils and eosinophils as well as lung with an emphysematous phenotype (Hoshino et al (2007) Am J Respir Crit Care Med 176:49). In addition to chronic lung inflammation, IL-18 may be associated with virally or bacterially-triggered exacerbations. In a cigarette smoke mouse model, IL-18 levels were shown to be further enhanced by treatment of mice with poly(I:C) or infection with influenza and to contribute to the inflammation, alveolar remodeling and apoptosis (Kang et al (2008) supra).
A number of experimental animal models have addressed the role of IL-18 in cardiovascular diseases, especially the development of atherosclerosis. Administering recombinant IL-18 to ApoE−/− mice resulted in increased atherosclerotic lesion size and elevated plasma IFNγ levels (Tenger et al. (2005) Arterioscler Thromb Vasc Biol 25: 791). Overexpressing the naturally occurring IL-18 inhibitor, IL-18BP, in ApoE−/− mice resulted in reduced atherosclerosis and major changes in plaque phenotype, indicating more "stable" lesions (Mallat et al. (2001) Circ Res 89:E41). The phenotype of the double knockout ApoE−/− x IL-18−/− mice is similar to the IL-18BP overexpressing ApoE−/− mice in that the lesions are smaller and their phenotype is more "stable" (Elhage et al. (2003) Cardiovasc Res 59:234). Administering a neutralising anti-IL-18 antibody in a rat vascular injury model significantly reduced neointima formation, corresponding to reduced intra-intimal cell proliferation, and IFNγ and IL-6 gene expression (Maffia et al (2006) Circulation 114:430). Additionally, IL-18−/− mice are susceptible to hyperphagia, obesity and insulin resistance (Netea et al (2006) Nat. Med. 12:650).
As described above, IL-18 may be considered a proinflammatory cytokine which mediates disease, as well as an immunostimulatory cytokine that is important for host defense against infection and cancer.
The high-affinity, constitutively expressed, and circulating IL-18 binding protein (IL-18BP), which competes with cell surface receptors for IL-18 and neutralizes IL-18 activity, may act as a natural anti-inflammatory as well as immunosuppressive molecule. In humans, four different isoforms (a, b, c and d) of IL-18BP have been identified resulting from alternative splicing. Only IL-18BPa and IL-18BPc have been shown to bind and neutralise the biological activity of human IL-18, isoform a having a 10-fold higher affinity than isoform c (Kim et al (2000) PNAS 97 1190-1195). Computer modeling of human IL-18 identified two charged residues, Glu-42 and Lys-89, which interact with oppositely charged amino acid residues buried in a large hydrophobic pocket of IL-18BP. The cell surface IL-18 receptor alpha chain competes with IL-18BP for IL-18 binding, although the IL-18 receptor alpha chain does not share significant homology to IL-18BP.
The structure of soluble IL-18 has been determined by NMR spectroscopy and consists of 12 strands forming a β-trefoil (Kato et al (2003) Nat. Struct. Biol. 10:966). Three specific surface areas have been identified. Site I is formed by five residues (Arg13, Asp17, Met33, Asp 35 and Asp 132) located on one side of the core barrel and is responsible for binding to IL-18Rα. Site II is formed by six residues (Lys4, Leu5, Lys8, Arg 58, Met60 and Arg104) located at the top of the β-barrel and is also important for IL-18Rα binding. Site III (Lys 79, Lys 89, asp98) located opposite to site II at the bottom of the β-barrel is binding to IL-18Rβ (Kato et al. (2003) supra).
Antibodies that bind IL-18 are known in the art (see for example U.S. Pat. No. 6,706,487, WO 2001/058956, EP 1621616, US 2005/0147610; EP 0 974 600; and WO 0158956). However, there is still a need for anti-IL-18 antibodies that reduce the biological activity of IL-18 in a therapeutic context.


This invention relates to the isolation and cloning of the promoter and other control regions of human PPARγ gene. It provides a method for identifying and screening for agents useful for the treatment of diseases and pathological conditions affected by the level of expression of the PPARγ gene. These agents interact directly or indirectly with the promoter or other control regions of the PPARγ gene.

Peroxisome proliferator activated receptors (PPARs) constitute a subfamily of the nuclear hormone receptors. Three distinct PPARs, termed α, δ (also called β, NUC-1 or FAAR) and γ, each encoded by a separate gene and showing a distinct tissue distribution pattern, have been described [Reviews: Desvergne, B. and Wahli, W., Birkhauser. 1: 142–176 (1994); Green, S., Mutation Res. 333: 101–109 (1995); Schoonjans, K. et al., Biochem. Biophys. Acta. 1302: 93–109 (1996); Schoonjans, K. et al., J. Lipid Res. 37: 907–925 (1996)]. Although it was known that PPARs are activated by a wide variety of chemicals including fibrates, phthalates and fatty acids, PPARs were initially considered orphan receptors, since no direct binding of these compounds to the receptors could be demonstrated.
Activated PPARs heterodimerize with retinoid X receptors (RXRs), another subfamily of nuclear hormone receptors, and alter the transcription of target genes after binding to PPAR response elements (PPREs). A PPRE typically contains a direct repeat of the nuclear receptor hexameric DNA core recognition motif, an arrangement termed DR-1 when recognition motifs are spaced by 1 nucleotide [Schoonjans, K. et al., J. Lipid Res. 37: 907–925 (1996)].
Recently, ligands that induce the transcriptional activity of PPARα (fibrates and leukotriene B4) and γ (prostaglandin J derivatives and thiazolidinediones) have been identified [Devchand, P. R. et al., Nature 384: 39–43 (1996); Kliewer, S. A. et al., Cell 83: 813–819 (1995); Forman, B. M. et al., Cell 83: 803–812 (1995); Lehmann, J. M. et al., J. Biol. Chem. 270: 12953–12956 (1995)].
Numerous PPAR target genes have been identified so far [Review: Schoonjans, K. et al., Biochem. Biophys. Acta. 1302: 93–109 (1996)], and additional target genes continue to be identified [Hertz, R. et al., Biochem. J. 319: 241–248 (1996); Ren, B. et al., J. Biol. Chem. 271: 17167–17173 (1996)]. Because they are activated by various fatty acid metabolites as well as several drugs used in the treatment of metabolic disorders, PPARs are key messengers responsible for the translation of nutritional, pharmacological and metabolic stimuli into changes in gene expression.
PPARγ was the first PPAR for which ligands were identified. In rodents, PPARγ was thought to be confined to adipose tissue. However, low levels of PPARγ expression were detected in other tissues. This led to the suggestion that PPARγ is a key factor triggering adipocyte differentiation, a hypothesis later confirmed [Spiegelman, B. M. and Flier, J. S., Cell 87: 377–389 (1996)]. It is now known that several transcription factors including the nuclear receptor PPARγ (6, 7), the family of CCAATT enhancer binding proteins (C/EBP)1 (8–13) and the basic helix-loop-helix leucine zipper transcription factor ADD1/SREBP1 (14, 15) orchestrate the adipocyte differentiation process (for reviews, see Refs. 1, 3, 16–18).
Two isoforms of PPARγ (PPARγ1 and PPARγ2 that differ by an extra 30 amino acids at the N-terminus) have been identified in mice (Tontonoz, et al. Genes & Development 8:1224–1234 (1994)). Two forms of human PPARγ, γ1 and γ2, have been identified; PPARγ1 has been shown to be the most common form in humans [Mukherjee, R. et al., J. Biol. Chem. 272: 8071–8076 (1997)]. PPARγ2 is expressed at high levels specifically in adipose tissue and is induced early in the course of differentiation of 3T3-L1 preadipocytes to adipocytes. Overexpression and activation of PPARγ protein stimulates adipose conversion in cultured fibroblasts (Tontonoz, et al. Cell 79:1147–1156 (1994)). In addition, PPARγ together with C/EBPα can induce transdifferentiation of myoblasts into adipocytes (19). Activation of PPARγ is sufficient to turn on the entire program of adipocyte differentiation (Lehmann, et al. J. Biol. Chemistry 270:12953–12956 (1995)).
PPREs have been identified in several genes that play crucial roles in adipocyte differentiation, most of them affecting lipid storage and control of metabolism. Examples are fatty acid binding protein (aP2) [Tontonoz, P. et al., Genes Dev. 8: 1224–1234 (1994)], phosphoenolpyruvate carboxykinase (PEPCK) [Tontonoz, P. et al., Mol. Cell. Biol; 15: 351–357 (1995)], Acyl CoA Synthase (ACS) [Schoonjans, K. et al., Eur. J. Biochem. 216: 615–622 (1993); Schoonjans, K. et al., J. Biol. Chem. 270: 19269–19276 (1995)], and lipoprotein lipase (LPL) [Schoonjans, K. et al., EMBO J. 15: 5336–5348 (1996)], all of which are regulated by PPARγ.
Recently, prostaglandin J2 (PGJ2) was shown to be a naturally occurring ligand [Forman, B. M. et al., Cell 83: 803–812 (1995); Kliewer, S. A. et al., Cell 83: 813–819 (1995)] and the anti-diabetic thiazolidinediones (TZDs) [Forman, B. M. et al., Cell 83: 803–812 (1995); Lehmann, J. M. et al., J. Biol. Chem. 270: 12953–12956 (1995)] were shown to be synthetic ligands for PPARγ. The identification of PGJ2 and TZDs as PPARγ ligands corroborates the earlier observation that both prostanoids and TZDs are potent inducers of adipose differentiation programs [Gaillard, D. et al., Biochem. J. 257: 389–397 (1989); Negrel, R. et al., Biochem. J. 257: 399–405 (1989); Forman, B. M. et al., Cell 83: 803–812 (1995); Kliewer, S. A. et al., Cell 83: 813–819 (1995); Aubert, J. et al., FEBS Lett. 397: 117–121 (1996)]. TZDs are currently being developed as insulin sensitizers for the treatment of non-insulin dependent diabetes mellitus (NIDDM) [Reviews: Hulin, B. et al., Current Pharm. Design 2: 85–102 (1996); Saltiel, A. R. and Olefsky, J. M., Diabetes 45: 1661–1669 (1996)]. Interestingly, their relative potency to activate PPARγ in vitro correlates well with their anti-diabetic potency in vivo, suggesting that PPARγ mediates their anti-diabetic effect [Berger, J. et al., Endocrinology 137: 4189–4195 (1996); Willson, T. M. et al., J. Med. Chem. 39: 665–668 (1996)]. These observations define the role of PPARγ in adipose differentiation and a role in glucose and lipid metabolism.
Although many PPARs have been isolated and their cDNAs have been cloned from various species (International Patent publication nos. WO 96/23884, WO96/01430, WO95/11974, Elbrecht, A. et al., Biochem. Biophys. Res. Comm. 224: 431–437 (1996), Greene, M. E. et al., Gene Expression 4: 281–299 (1995), Aperlo, C. et al., Gene 162: 297–302 (1995), Sher, T. et al., Biochemistry 32: 5598–5604 (1993), Isseman, et al. Nature 347:645–650 (1990); Dreyer, et al., Cell 68:879–887 (1992); Gottlicher, et al Proc. Natl. Acad. Sci. USA. 89:4653–4657 (1992); Sher, et al. Biochemistry 32:5598–5604 (1993); and Schmidt, et al. Mol. EndocrinoL 6:1634–16414–8 (1992); Tontonoz, et al. Genes & Development 8:1224–1234 (1994); Kliewer, et al. Proc. Nail. Acad. Sci. 91:7355–7359 (1994); Chen, et al. Biochem. and Biophy. Res. Com. 196:671–677 (1993)), information regarding the regulation of PPAR expression is very limited (see, e.g. Wu, Z. et al., Mol. Cell. Biol. 16(8): 4128–4136 (1996), Zhu, Y. et al., Proc. Natl. Acad. Sci. USA 92: 7921–7925 (1995), Mukherjee, R. et al., J. Steroid Biochem. 51(3/4): 157–166 (1994)). In particular, the regulatory regions controlling the expression of the human PPARγ genes have not yet been disclosed.

Human peroxisome proliferator activated receptor gamma (pparγ) gene regulatory sequences and uses therefor