This invention relates to a phenylene derivative represented by the following formula (1) or a salt thereof and also to a medicine containing it as an effective ingredient. ##STR1## wherein R.sup.1 represents H or halogen; A represents --CH.dbd.CH--, --CH.dbd.N--, --N(R.sup.2)--, --O-- or --S--; W represents --CH.dbd.CH-- or --CH.sub.2 O--; X represents --CH.sub.2 O--, --CH.sub.2 S--, --CH.sub.2 N(R.sup.3)--, --CH.dbd.N--, --COO-- or --CONH--; Y represents ##STR2## B.sup.1 represents --C(R.sup.7)(R.sup.8)(CH.sub.2).sub.l, --S(O).sub.m (CH.sub.2).sub.n -- or --CH.dbd.C(R.sup.9)--; B.sup.2 represents --CH.sub.2 CH.sub.2 -- or --CH.sub.2 CH.sub.2 CH.sub.2 --; Z.sup.1 and Z.sup.2 each represents O or S; etc. The phenylene derivative or salt thereof has antileukotrienic action and antihistaminic action and is useful as a medicine such as an asthma preventive or curative.

a). Field of the Invention
This invention relates to phenylene derivatives or salts thereof, which are useful as medicines.
b). Description of the Related Art
Leukotrienes (LT) are associated with causes for most inflammatory diseases, especially asthma, psoriasis, rheumatism and inflammatory colitis, and are considered to play an important role in inflammatory processes through cytopathy. Leukotrienes are principal mediators of allergy and inflammation, and therefore many substances which inhibit the action and/or syntheses of leukotrienes are useful for the treatment of these diseases.
Leukotrienes are arachidonate metabolites synthesized by 5-lipoxygenase (5-LO), and consist of two groups. One of the groups is LTB.sub.4 and has strong chemotaxis towards leukocytes. The other group is collectively called cysteine leukotrienes (CysLT) and includes LTC.sub.4, LTD.sub.4 and LTE.sub.4. As biologically active substances, they have been called "slow-reacting substances of anaphylaxis (SRS-A)" for many years. CysLT binds to their receptors in human tissues to exert its action. A selective LTD.sub.4 receptor inhibitor has been found to inhibit contracting actions of both LTC.sub.4 and LTD.sub.4 in human lung tissues, so that LTC.sub.4 is suggested to bind to the same site of a receptor as LTD.sub.4 (Buckner C. K. et al: Ann. NY Acad. Sci., 524, 181-6, 1988; Aharony D. et al.: New Trends in Lipid Mediators Research, Basel: Karger 67-71, 1989). LTE.sub.4 is also considered to act via the same receptor as LTD.sub.4, but is called a partially active substance for its lower potency.
On the other hand, histamine exhibits bronchial smooth muscle constricting action and capillaropenetration accelerating action as a result of its binding to the H.sub.1, receptor in cell membranes, and is an important mediator in allergic diseases. Histamine is believed to cause aggravation of asthmatic symptoms by its bronchoconstricting action and also to increase transudation of blood components into intercellular spacings due to accelerated capillaropenetration and hence to take part in the formation of edema seen in allergic rhinitis and conjunctivitis. For the treatment of these allergic diseases, antihistaminic agents are therefore used. These antihistaminic agents are however not considered to be significantly effective for severe allergic diseases such as asthma. Especially in a late asthmatic response of asthma, the symptom of airway constriction which is typical to asthma is observed due to infiltration of inflammatory cells on the bronchial mucosa, oversecretion of mucus and the like. Pharmaceuticals of a new type are therefore desired for its treatment.
Described specifically, a severe allergic disease such as asthma is considered to develop, as successive morbid conditions, an immediate asthmatic response such as bronchial constriction and edematous formation, in which a mediator such as histamine takes principal part, and a late asthmatic response such as airway constriction due to cell infiltration and mucus secretion in which a leukotriene or the like takes part.
For the prevention or curation of a variety of allergic diseases, especially asthma, a compound having antagonism against both an LTD.sub.4 receptor and a histamine H.sub.1, receptor is considered to become an effective pharmaceutical.
In addition to such marked peripheral action, leukotrienes have also been reported to have certain relevance to causes for cerebropathy such as cerebral ischemia and cerebral apoplexy (Masamune H. and Melvin L. S.: Ann. Rep. Med. Chem., 24, 71-79, 1989). It has also been reported that upon occurrence of procepharic ischemia, the concentration of LTC.sub.4 produced in neurocytes arises in the hippocampus (13.37.+-.0.24 pmol/g-tissue) and the cerebral cortex (3.29.+-.1.09 pmol/g) (Ohtsuki T. et al.: Am. J. Physiol., 37, H1249-57, 1995). Further, it has also been reported that intravenous administration of FPL55712, an LTD.sub.4 antagonist, after occurrence of ischemia significantly inhibited increase and aggravation of cortical edema (Watanabe T. et al.: J. Pharmacol. Exp. Ther., 271, 1624-29, 1994).
Accordingly, leukotriene receptor antagonistic compounds are considered to become effective pharmaceuticals for such cerebropathy.
It is however the current circumstances that no compound has been found with fully satisfactory antagonism against both an LTD.sub.4 receptor and a histamine H.sub.1, receptor. Further, all the LTD.sub.4 antagonists which have been developed so far contain at least one acidic group, so that these LTD.sub.4 antagonists are hydrophilic compounds having high polarity. They are thus unavoidably insufficient in absorption and brain penetration upon inhalative administration or oral administration. This is believed to have led to the increased doses of these pharmaceuticals and hence, to the development of side effects.


An elastic composite article and methods of manufacturing the same are disclosed. The elastic composite article includes a pair of coverwebs, a plurality of elastic filaments located between the pair of coverwebs. One or both of the pair of coverwebs is a nonwoven fibrous coverweb with a tear pattern of weakened areas formed therein. The tear patterns are formed before the coverwebs are attached to each other to form the elastic composite article.

Elastic sheet articles may find a variety of uses as, e.g., backings for tapes, mechanical fasteners, etc. Some elastic sheet articles are provided as composites of two coverwebs with elastic filaments located between the coverwebs. When the two coverwebs are attached to each other while the elastic filaments are stretched, the finished composite exhibits elasticity if, e.g., the elastic filaments are allowed to relax after the coverwebs are attached to each other.
Some elastic composite articles are provided with cohesive materials to form cohesive elastic composite articles such as those described in U.S. Pat. No. 3,575,782 (Hansen) and U.S. Pat. No. 4,984,584 (Hansen et al.), and those marketed under the tradenames COBAN and VETRAP by 3M (St. Paul, Minn.). Cohesive elastic composite articles are commonly used to provide compressive support for injuries or to hold compresses, medicated pads and the like in place on a human or an animal. The cohesive elastic composite articles preferably do not stick to skin or a variety of other materials (e.g., compresses, medicated pads, etc.) but will cohesively bond to other layers of the cohesive elastic composite article with sufficient force to hold the contacting layers together against reasonably high shearing forces.
To use the cohesive elastic composite article, a portion of the desired length may be unrolled and separated from the remainder of the composite remaining on the roll. Separation of the elastic composite article can occur before or after the elastic composite article is applied to an individual. Although the elastic composite articles may exhibit relatively straight tear characteristics in the down-web or machine direction, the elastic composite articles exhibit much less desirable tear characteristics in the cross-web or cross-machine direction.
Attempts to tear the elastic composite articles in the cross-web direction can result in jagged or uneven tear lines that extend over a significant distance in the down-web direction as well as in the cross-web direction. Such tear properties are undesirable. As a result, users typically resort to scissors or other cutting tools when separating lengths of elastic composite article from a roll of the elastic composite article. The use of a tool may require the user to let go of the unrolled elastic composite article and/or the roll of elastic composite article.
One attempt to provide desirable cross-web tear characteristics in cohesive elastic composite article materials involves the use of woven or knitted coverwebs. The woven or knitted coverwebs are, however, more expensive than nonwoven coverwebs. As a result, a cohesive elastic composite article including one or more woven or knitted coverwebs is more expensive than a comparable elastic composite article using only nonwoven coverwebs. Another potential disadvantage is that the woven or knitted coverweb may undesirably increase the force required to tear the elastic composite article in the cross-web direction and/or undesirable stiffen the elastic composite article.
Another attempt to provide desirable cross-web tear characteristics in a cohesive elastic composite article involves the addition of a scrim layer (e.g., woven or knitted scrim) that includes fibers or filaments extending in the cross-web direction. The addition of a scrim layer, however, can increase the cost of the elastic composite article and may adversely affect the flexibility or conformability of the elastic composite article, as well as its breathability. Another potential disadvantage is that the scrim may undesirably increase the force required to tear the elastic composite article in the cross-web direction.
Another attempt at providing cross-web tear characteristics to an elastic composite article involves the use of cross-web lines of perforations, with the cross-web lines of perforations located at intervals along the down-web length of the elastic composite article as described in, e.g., International Publication WO 95/06449. The lines of perforations are formed through the entire elastic composite article after it has been assembled.

Tearable elastic composite article and method of manufacture


A method of user-defined key setting in a portable electronic communication device. Corresponding relationships between keys and functions is recorded in a first mapping table and the portable electronic communication device executes the functions accordingly. When a user-defined key is to be set, a first key input and a function input are first received. The corresponding relationship between the first key input and the function input is then recorded in a second mapping table. The portable electronic communication device executes the functions according to the second mapping table.

The invention relates to methods of setting keys for electronic device, and in particular to user-defined key settings thereof.
Currently, function keys of electronic communication devices, such as a mobile phone or PDA (personal digital assistant), are set by the manufacturer through function key definition, such as a mapping table, coordinating with hardware for specific functions. For example, a mobile phone may provide a menu key, a dial key, and an off key on the keypad to display menus, dial, and turn off. The function keys generally cannot be changed, including the key arrangement or their corresponding functions.
FIG. 1 is a diagram of a keypad of an exemplary portable electronic communication device, where "b" is a menu key, "g" is a dial key, and "d" is an off key. When a key on the keypad is pushed, the hardware produces an interrupt to notify a function execution module. The function execution module then acquires the function corresponding to the key according to a mapping table stored in the portable electronic communication device. An application program corresponding to the acquired function is activated accordingly.
The mapping table is predefined by the manufacturer and coordinated with hardware. Thus, function keys generally cannot be modified or redefined by users. Whenever a user adopts a new portable electronic communication device, different key arrangements and operation must be assimilated, causing inconvenience.


A method for determining quality of service (QoS) description information includes receiving at least one piece of QoS description information of a service. Each piece of the at least one piece of QoS description information includes parameter type information and a parameter requirement. The method also includes sending to a second core network element or an application function network element corresponding to the service, parameter type information and a parameter requirement in the at least one piece of QoS description information. The method further includes receiving from the second core network element or the application function network element, feedback information of the parameter type information and the parameter requirement. The method additionally includes determining at least one piece of target QoS description information in the at least one piece of QoS description information based on the feedback information.

Currently, a communications network may use a preset quality of service (QoS) mechanism to resolve problems such as network latency and congestion, to meet a communication quality requirement of a user. The preset QoS mechanism usually uses a subjective assumption or fixed QoS information to perform different control and management on different types of services. However, the subjective assumption or fixed QoS information may be inaccurate or not applicable to a network element. For example, when the fixed QoS information includes a packet loss rate or latency, a base station cannot determine, by using the packet loss rate or the latency, whether a quality of service requirement of a service is satisfied, and therefore cannot ensure quality of service of the service.

Method for determining QoS description information and apparatus


A tap assembly includes a body with a chamber having an inlet and an outlet, and a seat therebetween. A clapper is disposed for movement relative to the seat between a first position engaged upon the seat for resisting flow of fluid toward the outlet, and a second position of for permitting flow. The tap assembly also includes a reciprocal positioning assembly with a rod mounted for axial movement between a first position for allowing the clapper to engage upon the seat and a second position for precluding the clapper from engaging upon the seat; a cylindrical housing; and an elastically deformable elongated element which forms a split ring positioning unit for the rod. The positioning unit has an inner ring and an outer ring.

The invention relates to tap assemblies, and more specifically to a reciprocal positioning assembly for a tap assembly.
Tap assemblies typically include a body which defines a fluid flow chamber into which at least two sleeves lead, one which is connected with an inlet and the other which is connected with an outlet, for flow of fluid. A third sleeve houses a pressure limiting means and clapper driving means. To control flow of fluid through the chamber, from the inlet toward the outlet, a clapper moves very nearly perpendicularly to a seat which is supported by the body at the lower end of a corresponding sleeve.
For the control of a tap or cock by a thermostatic feeler, the reciprocal positioning assembly is usually shaped like a rod, the end part of which penetrates into the body, and specifically into the sleeve, until, according to the temperature which has been detected, the feeler or rod has taken a position which allows the clapper to be closed, or which precludes the tap or cock from being shut.
The section of the feeler or rod is sufficiently large to resist any warping due to the force which it must exert on the clapper, without undergoing any buckling. However, the section must also be sufficiently reduced to provide an adequate passage within the sleeve through which the fluid can flow. Because of the difference between the inner diameter of the sleeve and the outer diameter of the end part of the feeler, the end part, when moved and translated, cannot be guided directly by the sleeve. The feeler, because of its length, requires a positioning means which operates with precision.
A rod positioning assembly located in a bore is well known in the art. An "elastic ring" or a "circlips" can only provide a thrust stop in an axial direction. The only positioning function it can ensure is along the axis. These "positioners" are inadequate when, in relation to the axis, a precise positioning is required on a radial plane. Neither can the positioners provide any effective guidance during a translation or transfer of the rod assembly.
The elastic ring is shaped like a radially split washer. Its outer or inner edge is then placed in the groove of a rod or a shaft. After the washer has been put into place, only one of its radial faces is operational. The other one, an inner or outer edge, is generally an irregular shape and remains free. Elastic rings shaped like wide washers are also known in the art. Because of their width, they adequately obstruct the space between the sleeve and the rod, but are insufficient to solve the guidance problem in any tap or cock assembly. This is because the washer, although it is split, would then substantially inhibit and prevent the flow. Instead of wide elastic rings in the shape of split washers, elastic positioners are known, made up with a short length of steel wire, the middle part of which is shaped like an open ring. This ring follows the outer edge of an elastic organ or part. From the edges of the ring opening, the extreme parts of the ring are pressed and folded down towards the inner zone of the ring on its level. The rings thus constitute inner branches, the ends of which are connected with the open ring, thus providing an interval or space between one and the other. Their other ends lean and are shored up, one against the other.
In addition to the lack of stability of the ring, misshaping, or material deformation, is also a problem. As a result, the ring cannot be used to position the rod in the sleeve or provide guidance during translations and transfers in a precise manner.
Accordingly, it is an object of the invention to provide a precise positioning operation. Another object of the invention is to ensure guidance when the rod is being translated.

Tap assembly reciprocal positioning assembly


The present invention aims to provide an electrolyte solution for electrochemical devices, which has excellent thermal stability and high decomposition voltage and produces a small amount of evaporation at high temperatures. The present invention also aims to provide an aluminum electrolytic capacitor and an electric double layer capacitor, both of which include the electrolyte solution for electrochemical devices. The present invention relates to an electrolyte solution for electrochemical devices, the electrolyte solution including a solvent and an electrolyte, the solvent containing a sulfone compound represented by the formula (1):

As electrolyte solutions used for electrochemical devices such as electric double layer capacitors, aqueous electrolyte solutions and non-aqueous electrolyte solutions are known. Non-aqueous electrolyte solutions have more advantages in having a decomposition voltage of 2 to 3 V while aqueous electrolyte solutions have a decomposition voltage of about 1.2 V. In other words, non-aqueous electrolyte solutions have advantages in having a higher withstand voltage than aqueous electrolyte solutions and thus have been rapidly spreading.
Sulfone compounds are generally used as extract solvents and solvents for various reactions. Particularly, sulfone compounds having a high dielectric constant are also used as aprotic polar solvents for non-aqueous electrolyte solutions. Among sulfone compounds, sulfolane, which has a high decomposition voltage, has been widely used as aprotic polar solvents for non-aqueous electrolyte solutions that are used as electrolyte solutions for electrochemical devices and the like.
The following are disclosed examples of electrochemical devices each containing a sulfone compound (e.g. sulfolane) as an aprotic polar solvent for an electrolyte solution: an electric double layer capacitor and an aluminum electrolytic capacitor, both of which include a mixture containing sulfolane or a sulfolane derivative such as 3-methyl sulfolane (Patent Literature 1, Patent Literature 2); an electric double layer capacitor that contains a solvent mixture of sulfolane or a sulfolane derivative (e.g. 3-methyl sulfolane) and propylene carbonate or the like (Patent Literature 3); and an aluminum electrolytic capacitor that contains a solvent mixture of sulfolane and a benzyl alcohol or a derivative thereof (Patent Literature 4).

Electrolyte solution for electrochemical devices, aluminum electrolytic capacitor, and electric double layer capacitor

Abstract: wherein R represents a C1-6 alkyl group.


The present invention relates to an ink for ink-jet recording containing carbon black particles having a specific surface active hydrogen content, water, and polyethyleneimine or alkylene oxide adduct of acetylene glycol.

1. Field of the Invention
The present invention relates to an aqueous pigment ink suitable for ink-jet recording methods.
2. Description of the Related Art
Among the various current recording methods, ink-jet recording methods are nearly noiseless during recording and are capable of recording at high speed, and are particularly noteworthy because recording is accomplished on plain paper without a special fixing process.
In general, aqueous dye inks comprising a water-soluble dye dissolved in an aqueous medium are used as ink-jet recording inks. When such aqueous dye inks are used in ink-jet recording, the recorded image is influenced by the physical properties of the aqueous dye ink and may disadvantageously show deterioration in respect to moisture resistance and light fastness. In the case of black inks in particular, a plurality of dyes are mixed for use as black ink because there are few water soluble dyes which have excellent black color reproducibility; however, a disadvantage arises insofar as black color tone changes when some dyes fade or discolor. This type of ink containing aqueous dye does not have high storage stability.
In recent years, aqueous inks using pigments such as carbon black and the like have been experimentally adapted to ink-jet recording methods in place of the aforesaid inks using dyes. Images formed by the ink including carbon black has excellent moisture resistance compared to that formed by the ink including water-soluble dyes because it is insoluble in water, and further provides excellent light fastness.
A disadvantage arises, however, insofar as the insolubility of carbon black in water, i.e., the ink medium, makes it difficult to assure the stability of carbon black finely dispersed in an aqueous medium. Further disadvantages arise when dispersion agent such as water-soluble resin or the like is added to improve the dispersion stability of the carbon black due unstable continuous discharge resulting from clogging of the discharge nozzle due to the viscosity of the medium.
In order to eliminate the aforesaid disadvantages, U.S. Pat. No. 5,609,671 discloses an ink having excellent dispersibility in water without adding dispersion agent such as water-soluble resin or the like by using a carbon black having a specific amount of surface active hydrogen.
A further disadvantage arises, however, in this aqueous ink containing a dispersion of carbon black provides inadequate glossiness of obtained images. This disadvantage produces a sense of unease in images as the black color fades when color images are reproduced with color inks. Further disadvantages arise such as the detachment of the carbon black from the surface of the print sheet when the image is immersed in water. This detachment is thought to be due to the low bonding strength of the carbon black to the print sheet compared to dyes, because the carbon black particles are simply bonded to the surface of the print sheet whereas dyes bond to the print sheet on the molecular level.
New disadvantages arise when the aforesaid aqueous ink containing a dispersion of carbon black is used for printing in an ink-jet printer, insofar as fluctuation environment temperature produces variation in the quality of the printed image.


A package tray for arthroscopic H-fastener needles. The tray has a flexible base member having a central opening, and proximal and distal needle mounting members extending form the base member having slots and undercut engagement members for receiving and retaining the needles. The proximal needle mounting end slot contains a proximal guide member adjacent to the proximal end of the slot.

The use of H-type fasteners to repair tissue is known in the art. A device and H-fastener for repairing tissue are disclosed in U.S. Pat. No. 5,470,337. A method of repairing a meniscus in a knee using an H-fastener is disclosed in U.S. Pat. No. 5,320,633. A method of repairing tissue using H-fasteners is disclosed in U.S. Pat. No. 4,006,747.
In order to apply an H-fastener to a tissue site, a specially designed applicator is typically used. The applicator typically has a handle, a trigger mechanism connected to an actuation mechanism and a needle mounted to the distal end of the applicator. The needles typically have a hollow passage and a longitudinal slot for receiving H-fasteners. The needles may be straight or curved, and come in various sizes, depending upon the type of tissue which it is desired to approximate. One leg of the H-fastener is typically loaded into the slotted needle, and after penetration through tissue, the leg is ejected from the needle by the actuation mechanism after engaging the trigger.
There is a need in this art for a simple package for meniscal repair needles useful with H-fasteners which would accommodate a wide variety of needle shapes and sizes. There is also a need in this art for a package for such a needle which would assist the health care professional in mounting the needle to the applicator.


One embodiment disclosed relates to a method of providing CPU functional testing. Operations are executed on multiple functional units of a same type in the CPU. The outputs of the multiple functional units are automatically compared. The results of the comparison are checked only for redundant operations. Another embodiment disclosed relates to a microprocessor with built-in functional testing capability. The microprocessor includes multiple functional units of a same type and registers that receive outputs from the multiple functional units. In addition, comparator circuitry is built-in that also receives the outputs from the multiple functional units and compares the outputs to provide functional testing.

1. Field of the Invention
The present invention relates generally to computer systems. More particularly, the present invention relates to compilers.
2. Description of the Background Art
One conventional solution for providing fault tolerance in digital processing by central processing units (CPUs) involves a computer system with multiple CPUs. For example, the multiple CPUs may be operated in full lock-step to achieve a level of fault-tolerance in their computations. Such a solution is expensive in that it disadvantageously requires additional system hardware and support infrastructure.
Another conventional solution for providing fault tolerance in digital processing by central processing units (CPUs) involves the use of software verification. The software verification may be performed either by executing the program multiple times on the same computer or on different computers. However, this solution is expensive in that it disadvantageously requires a longer run-time or requires multiple computers.
The above-discussed conventional solutions are expensive in terms of cost and/or system performance. Hence, improvements in systems and methods for providing fault tolerant digital processing by CPUs are highly desirable.

Opportunistic CPU functional testing with hardware compare

Hewlett-Packard Development Company, L.P.


The invention relates to a method for the automatic analysis of microscope images of biological objects such as, for example, fluorescence images of cells, comprising: a) at least two microscope images are taken from a sample; b) a positive training set is determined from image excerpts; c) a negative training set is determined from a sequence of image excerpts; d) characteristic features of a training set are assigned to classification values; e) classification values of a sequence of images are automatically determined by means of the assignment determined in d); f) the position of biological objects is recognized by comparing the classification value with a threshold value.

In numerous experiments in the field of modern biomedical research, fluorescence techniques, amongst others, are used for marking in order to make biologically significant objects visible under the microscope. Such objects may be cells of a certain type or of a certain state, for example. In recent years, the progress made in automating such experiments has made it possible for biomedical laboratories to perform large numbers of such image-producing experiments fully automatically.
DE 197 09 348 C1, for example, describes a fluorescence microscope technique which produces a set of n images of a single sample by preparing said lymphocyte sample with n different fluorochrome markers. In each image, different lymphocyte subsets will be fluorescent and appear to have shining outlines. Each lymphocyte in the sample will have its specific fluorescent behavior in the image set. It will appear fluorescent in one subset of images, otherwise remaining invisible in the other images of the set.
For extracting the fluorescence patterns from the image set, the fluorescent lymphocytes will first of all have to be detected in the n images. The fluorochrome marked lymphocytes differ in number, location and intensity. Since such vast numbers of images and image data will result, from which the information will first of all have to be extracted for biological interpretation later on, there will be a so-called bottleneck in the evaluation of the experiments. Image interpretation by human employees is impractical since it is too time-consuming and the results are often not reliable. This is due to the visual evaluation work which is tiring and will lead to concentration losses already after a short time only. Moreover, the objects to be detected differ in number, location and intensity. Consequently, image parameters such as contrast and noise will differ from image to image. Furthermore, the objects, for example cells in tissue samples, vary considerably as regards their shape and size.
Consequently, there is a need for automatic evaluation methods which are capable of locating the objects to be detected in one image.
Earlier work on the automation of cell detection essentially focused on model-based approaches. Numbering amongst these is also the idea to adapt a geometric model to a gradient ensemble (Mardia et al., 1997, In: IEEE Transactions of Pattern Analysis and Machine Intelligence, 19: 1035-1042). This also includes the exploitation of wave propagation (Hanahara and Hiyane, 1990, In: Machine Visions and Applications, 3: 97-111) or a Hough transformation for detecting circular objects (Gerig and Klein, 1986, In: Proc. Int. Conf. on Pattern Recognition, 8: 498-500). These approaches, however, have the disadvantage that they are frequently susceptible to changes in the shape of the object, and they may not be readily adapted by persons not skilled in the art. Furthermore, the images will not infrequently contain noise, owing to heterogeneous lighting conditions, and the cells will be partly obscure, which makes detection by boundary scanning unsuitable (Galbraith et al.; 1991, In: Cytometry, 12: 579-596).

Method for the automatic analysis of microscope images

MPB MelTec Patent-und Beteiligungsgesellschaft mbH


A process for forming interconnection lines on a printed circuit board is described. The surface of a circuit board substrate is covered with a photoresist layer, and the photoresist layer in turn is covered with a halide emulsion layer. The emulsion layer is then exposed to a predetermined pattern of white light, and the image developed. The board is then exposed to UV light through the imaged emulsion layer which acts as a pattern masking selected portions of the photoresist mask. The emulsion layer is then stripped and the photoresist processed in conventional manner.

The ongoing integration and miniaturization of components for electronic circuitry has become a growing challenge to the limits of printed wiring board technology over the last twenty years. Printed circuit boards or printed wiring boards (PWB) as they are more commonly termed, play several key roles. First, the electrical components, such as specially packaged integrated circuits, resistors, etc., are mounted or carried on the surface of the flat usually sturdy card-like board. Thus, the PWB serves as a support for the components. Secondly, using chemically etched or plated conductor patterns on the surface of the board, the PWB forms the desired electrical interconnections between the components. In addition, the PWB can include a metal area serving as a heat sink.
Conductor patterns typically are formed by photoetching a copper foil clad epoxy fiberglass substrate. A photoresist layer is applied to the copper foil and patterned by exposure to ultraviolet (UV) light projected through a mask, often referred to as "artwork", e.g., to a positive art work image of the circuit pathways and contacts. Those areas exposed to the light are altered and are removed by treatment with a solvent for the resist, leaving areas of copper, e.g., in the desired conductor pattern, underneath the protective barrier of the remaining photoresist. The exposed copper is etched away and the remaining photoresist is then chemically removed to expose the resulting conductor pattern. Alternatively, the photoresist can be patterned to form channels for electroless plating of conductor patterns. There are, of course, many variations on this procedure, but all of them require photo-patterning of the resist layer.
Increased use of integrated circuits, and surface mount technology (SMT) has accelerated the densification of electronic circuitry. Surface mount devices (SMD) are applied directly to the surface of the PWB and soldered using vapor phase, infra-red (IR) or other mass soldering techniques. SMT is revolutionizing the electronic manufacturing industry by reducing assembly cost by about 50%, increasing component density by over 40% and enhancing reliability. The array of terminals on SMD's has a higher density or finer pitch then those on conventional components. As each terminal still has to be properly electrically connected to the respective conductor on the board, registration of SMD's requires high resolution for the PWB conductor lines. Indeed, SMD circuitry has become so dense that double-sided boards cannot accommodate all of the needed electrical connections. Thus, multilayer PWB's have become the focus of attention and several competing technologies are evolving. Those techniques which rely on stacks or layers of conductor patterns have interlayer registration requirements in additional to the exacting line width and spacing of a conductor pattern in a given layer. Manufacturing very fine lines on the order of 3 to 5 mils in registration over four or more layers deep is very difficult.
To take fullest possible advantage of the benefits offered by the emerging SMT, new fabrication processes must be developed in the manufacture of substrates and boards. In the past, one of the problem areas in fabrication of PWB's has been the generation and use of artwork masters for patterning the photoresist layers. Using photographic film or glass plates poses inherent difficulties in stability, registration, transport and storage.
In order to eliminate artwork masters the industry has fostered the development of UV laser plotters. These machines pattern the UV sensitive resist directly without artwork. Conductor patterns are designed using computer-assisted design (CAD) which digitizes the coordinates and dimensions of all of the paths and converts them to control signals for a UV laser x-y plotter. However UV laser plotters have a number of limitations, particularly when used for fine line, high density work. Principal among these is the fact that UV sensitive resists are relatively insensitive materials, requiring high levels of exposure energy. As a result, line edge resolution is limited. In order to achieve high plot speeds, these systems operate in a raster scan mode. Raster scanning produces considerable edge irregularities which are particularly apparent in plotting angled lines. Limitations in accuracy and minimum line width are characteristic of existing raster plotting systems. Another problem of current raster plotting systems is the short life expectancy of the laser source. A further problem with direct-from-CAD UV plotting of the photoprocessible layer is that such systems do not permit inspection before polymerization. If an error is made in the plot, the mistake is indelibly embedded in the UV sensitive layer. In the case of a resist, the board may be salvaged only by removing the entire resist layer and starting over after cleaning and baking the board free of moisture a second time. In the case of a UV plotted solder mask, a glitch in the pattern may result in the entire panel being discarded. Also, UV laser plotters are very expensive, and are relatively slow.
The foregoing discussion of the prior art is taken largely from Lake et al, U.S. Pat. No. 4,666,818 who propose a method for fabricating a printed circuit board utilizing two photo-reactive coatings. According to Lake et al a photo-processable ultraviolet sensitive layer is overlayed with a thin, unexposed, and undeveloped (silver halide) photographic film. A CAD system, containing within it the desired pattern layout for the interconnection lines, drives a white light x-y plotter to expose the silver halide film on the board in the desired pattern, without effecting the underlying ultraviolet sensitive layer. The film is then developed and used as an in-situ mask for patterning the ultraviolet layer during an exposure of the board to ultraviolet light. The silver halide photographic film is not further affected by the exposure of the board to ultraviolet light. After the ultraviolet exposure, the silver halide photographic film is peeled off, to expose the resist, and the resist-coated board is processed further according to conventional methods.
Although capable of producing somewhat respectable interconnection line resolution and definition, the teachings of this patent result in serious drawbacks. First, even though Lake et al. teaches use of a white light x-y plotter and not a UV laser, all of the drawbacks associated with the use of a UV laser, e.g. speed, cost, etc., are presented by Lake et al. Moreover, the presence of the photographic film substrate introduces optical problems which results in reduced interconnection line definition and resolution due to white light diffusion through the film.

Circuit board substrate for use in fabricating a circuit board on which is formed a light sensitive emulsion layer covering and in direct contact with photoresist


The calibration of time-depending measurement uncertainties of gyros and inertial systems by the differences of angular and/or velocity and/or positional measurements which are carried out and repetitiously executed with a view to undetermined reference directions and/or fixed locations varying with time. The differentiation allows to forego precise reference data. Measurement uncertainties can be corrected through calibration subsequently to the measurement process. For the measurement of spatial angles a three-axis gyro measurement package comprising a computer and the possibility of feeding or automaticly reading-in of reference data characterizing the reference directions. The reference data can be a number, a marker of the measurement point or in the case of positional measurements a terrestrial aiming point. When measuring angular characteristics, i.e. the interdependence of angles and external forces or moments, the latter are considered as references. For the measurement of contours the distance has to be fed in or read in, or computed by accelerometers within an integrated inertial system, respectively. By such a system and through the application of the invention the measurement accuracy of movements and gravity anomalies can be increased while refraining from external references otherwise necessary under the present state of the art.

Measuring spatial angles, trajectories, contours and movements as well as gravity anomalies signifies a difficult problem in the technical field, as can be seen from the following examples.
In structural engineering inclinations as a function of curved radii have to be measured for the construction of roads or railroads; similar problems exist in civil engineering in connection with the measurement and construction of tunnels, wells and pipes. For boring into the interior of the earth the course of the drill stems has to be defined and controlled. Elastic deformation characteristics, i.e. angular and positional changes as a function of exterior strain have to be considered in automotive engineering and aircraft construction. In wind tunnel techniques aerodynamic forces and moments have to be included as regards their dependence upon the angle of attack. In tests with aircraft and vehicles movements have to be traced with regard to position, velocity, attitude and heading as a function of time. In geodesy a tract of land is determined by measurements and plotted into maps starting from an astronomicly determined point of reference. Finally in connection with these measurements gravity anomalies are often of interest, as the direction of gravity and its anomalies affect astronomical measurements. Gravity anomalies can supply information on possible mineral resources.
Nowadays gyros and complete inertial systems (INS) are already being used for the resolution of the above mentioned problems. Because of the integration with time of the gyro and accelerometer signals (a*) for the computation of the angle or position, system deviations build up which increase with time and are due to the sensor's measurement deviations. In order to keep these deviations small, either high- capacity and therefore expensive systems are being used and/or calibration or aiding procedures.
Calibration procedures are implemented either before or after the measuring procedure itself, as known external references are then available. When using gyros or complete inertial systems, the calibration procedures are insofar disadvantageous, as they require a large amount of time. The computation of the parameters of an error model is implemented through integration with time, and the calibration accuracy increases with increasing time. Calibration procedures of that kind are, for example, known for the gyros of a three-axis stabilized satellite [German Specification DE 37 34941 C2] or for the initiation and/or recalibration of a subsidiary inertial navigation system [German Specification DE 3445463 A1]. A further disadvantage of the calibration procedure lies in the fact that the accuracy of the subsequent measurement series will be limited, if sensors are being used whose error parameters are a function of time. The calibration mentioned above procedures rely on a certain stability of those values in the course of the measurement procedure. This disadvantage can be seen in the case of the measurement procedures with gyros which are used for deep boring in the inner of the earth. In this case the temperature and thus drifting conditions change drastically and extremely for the gyros during the measuring process, and the calibration data obtained in the beginning or towards the end of the procedure are not representative for the whole measurement series.
At the present state of technical development the application of so-called aiding procedures comprises the use of known external reference data during the measuring process together with special mathematical algorithms (e.g. Kalman filter) [Gyroscopic Instruments and their Application to Flight Testing, AGARDograph No. 160, Vol. 15, September 1982, Chapter 8]. Compared with the calibration procedures mentioned above they can successfully be applied even if sensors of inferior quality, i.e. with instable error parameters are used. A disadvantage of this procedure is, of course, the provision of such external measurement data, which generally requires the availability of measuring instruments, or which is beyond any possibilities. While in the case of flight tests signals from radio navigation aids are available for positional aiding of inertial systems, those reference data are frequently not at hand for the positional measurement of drill stems. For geodetic measurements based on inertial systems (inertial geodesy) the aiding is based on accurately defined reference points and, in addition, on "zero velocity updating (ZUPT)", which means that the measurement vehicle is stopped and the velocity zero is fed into the computer as aiding information. It is true that the latter is an aiding method which can easily be implemented, but it requires an increased amount of time for the measurement process as a whole, and it is limited in its accuracy for the subsequent definition of the reference points, as the aiding does not comprise any external reference point measurements. Aiding information for the definition of gravity anomalies in a test area by means of an INS requires comprehensive and time consuming measurements at clearly defined reference points preliminary to the measurement series itself by means of gravimeters, and is therefore only rarely available. The invention constitutes however a valuable supplement to all the described aiding procedures.
In the U.S. Pat. No. 4,799,391 a procedure for the measurement of the curvature of pipelines is described using so-called pigs, which are taken along the pipeline by the medium transported as separating elements between the individual charges. Like an aircraft these pigs are equipped with an INS with three gyros, three accelerometers and a digital computer. For the definition of positions by means of an INS external measurements for the INS aiding are employed such as indicators along the pipeline, for instande magnetic anomalies in form of girth welds or similar markers. The measurments are taken at a high sampling frequency during the one time travel of the pig along the pipeline.
Further reference is made to commonly owned U.S. patent application Ser. No. 07/699,481.

Procedure for measuring angles and trajectories by means of gyros and inertial systems

Deutsche Forschungsanstalt fur Luft- und Raumfahrt e.V.


The seal for sealing off the bearing interior of a bearing has a first sealing lip angled outward from a base of the seal and forming a first sealing contact, and a second sealing lip angled inward from the base and forming a second sealing contact. An annular chamber is formed between the first sealing lip and the second sealing lip. The first sealing lip has at least one ventilation opening which leads into the chamber from the outside. The ventilation opening is positioned at the first sealing contact.

The mountings of wheels on vehicles have, as a rule, one seal subjected to mostly high load due to dirt and due to other influences of the external surroundings and, axially on the other side of the mounting, one seal subjected to less load. On account of the different loads on the seal caused by the environment, the seal subjected to higher load therefore, as a rule, as what is known as a cartridge seal, with at least two sealing lips, seals off the interior of the wheel mounting in a multiple way, leaktight, inwardly with respect to the external surroundings.
The sealing lips of the seals are prestressed elastically against a sealing surface. The sealing surfaces are cylindrical surface areas (inner cylindrical, preferably outer cylindrical), the axis of symmetry of which is the axis of rotation of the bearing. The sealing lips run on the sealing surface about the axis of symmetry in the direction of rotation in relation to the sealing surface. It is possible that the seal is fixed in relation to the surroundings and the sealing surface rotates with respect to the sealing lip or that the sealing surface is fixed in relation to the surroundings and the sealing lip runs on the sealing surface about the axis of symmetry in the circumferential direction. In both instances, friction arises during contact between the sealing surface and the contact zone of the sealing lip with the sealing surface. The intensity of the friction depends on many different factors, Mention is made here, as examples, of the relative speeds, the materials and the structures of the surfaces of the seal/frictional-surface friction partners and lubrication during frictional contact.
The prestress with which the seal is prestressed against the sealing surface has an important influence on the frictional behavior. The prestress is determined by tolerances and by the function of the sealing lip and is preselected correspondingly, but also as a function of influences, described below, which occur when the seal is in operation.
The seals, as a rule, are subjected to load due to pressure drops between the bearing interior and the external surroundings. Depending on the design of the seal and on the operating conditions, the bearing interior is loaded with underpressures or overpressures, as compared with the pressure in the external surroundings. Temperature rises, for example during driving, lead to overpressures in the inner space of the bearing. When the bearing is at a standstill, the bearing interior cools down again to the temperature of the external surroundings, underpressure occurring in the bearing interior. Both overpressures and underpressures have disadvantageous effect on the operating behavior of the mounting or of the seals and therefore have to be compensated.
The sealing lips of the seals are designed, as a rule, such that they block against pressure in the axial direction and yield in a directed way to overpressures or underpressures in the other direction. The primary task of the seals and therefore of the sealing lips is to protect the interior of the wheel mounting against influences arising from the external surroundings by sealing of the bearing interior with respect to the influences, such as dirt and water, from outside. Overpressure on the outside because of underpressure in the interior of the bearing presses the sealing lips onto the sealing surface to a greater extent and increases the sealing action, that is to say, in this case, the sealing lips also block inwardly against overpressure from outside. The underpressure in the bearing interior cannot be compensated by means of these inward-blocking sealing lips. On account of the higher pressing force on the sealing lips from outside, the above-mentioned radial prestress and, consequently, the friction between the seal and sealing surfaces increases. This results in undesirable wear and higher operating temperatures.
However, inward-blocking sealing lips compensate when there is a pressure drop from the inside outward. Overpressures from inside lift off the sealing lips in sealing contact from the sealing surfaces elastically. Overpressures in the bearing interior are thus compensated outwardly.
The bearing interior, as a rule, is greased. At high temperatures, the grease becomes liquid and possibly, during pressure compensation, escapes outward via the above-mentioned sealing lips. This may lead to a deficient lubrication of the rolling bearing. It is therefore expedient to provide seals with at least one sealing lip which holds the grease in the bearing in the event of the compensation of overpressures from the interior of the bearing outward. Sealing lips of this type block the bearing interior against the emergence of grease from the inside outward, but also, in the event of overpressures in the bearing interior, against pressure compensation from the inside outward. However, underpressure prevailing in the bearing interior can be compensated via these outward-blocking sealing lips, in that these sealing lips lift off from the sealing surface elastically on account of overpressure in the external surroundings.
As mentioned initially, the primary task of the cartridge seals is, on that side of the wheel mounting which is subjected to a high load due to environmental influences, to block the bearing interior inwardly against the influences from outside. The introduction of a device for the compensation of pressure drops from the outside inward needlessly increases the cost of the cassette seal which already has a complex construction. Therefore, it lends itself to integrate an arrangement for the compensation of underpressures in the bearing interior into the seal which is subjected to less load and therefore has a simpler design.
A seal of this type is described in U.S. Pat. No. 4,844,480. The seal of the generic type has one or more diaphragm orifices as ventilation orifices on the inward-blocking first sealing lip lying axially on the outside in the sealing arrangement. The ventilation orifices provide, in the sealing lips blocking further inward against dirt and water, an axial passage for pressure compensation into an annular prechamber of the seal. However, because of the small size of the orifices, dirt can scarcely enter the prechamber. The second seal follows the first sealing lip axially toward the bearing interior and blocks against the emergence of grease outward to the prechamber. Overpressures in the prechamber act on the second sealing lip until the latter lifts off and the underpressure in the bearing inner space is compensated.
A seal of this type is unsuitable or is suitable to only a limited extent for use on wheel mountings of vehicles, since the diaphragm orifices may become clogged with dirt during driving and the functioning of the seal therefore is adversely influenced.


A MOS power device having: a body; gate regions on top of the body and delimiting therebetween a window; a body region, extending in the body underneath the window; a source region, extending inside the body region throughout the width of the window; body contact regions, extending through the source region up to the body region; source contact regions, extending inside the source region, at the sides of the body contact regions; a dielectric region on top of the source region; openings traversing the dielectric region on top of the body and source contact regions; and a metal region extending above the dielectric region and through the first and second openings.

As is known, MOS power devices have the need to form metal regions with low contact resistances on the front of the chip both on P-type regions (body regions) and on N-type regions (source regions). In fact, two of the fundamental characteristics for good operation of a MOS power transistor are the output resistance (Ron) and the direct voltage drop on the body-drain internal diode (Vf).
For a better understanding of the problems involved, reference may be made to FIG. 1, which illustrates a perspective cross-sectional view of a known MOS power transistor. In detail, the transistor is formed in a body 1 of semiconductor material comprising an N+-type substrate 2 and an N−-type epitaxial layer 3. P-type body regions 4 extend within the epitaxial layer 3 and house N+-type source regions 5. A rear metal region 7 extends on the back of the wafer, in contact with the substrate 2.
Gate regions 10, of polysilicon, extend on top of the body 1 and are electrically insulated from the latter by gate-oxide regions 11. The body regions 4 extend between adjacent gate regions 10, and two source regions 5 housed in two different body regions 4 extend along the edges of each gate region 10. Intermediate-dielectric regions 12 cover the gate regions 10 both at the top and at the sides. A source metal region 13, shown only partially for clarity, covers the surface of the body 1 and, on top of the body regions 4, electrically connects the body region 4 with the source regions 5 housed therein.
The portions of body regions 4 underneath the gate regions 10 (between each source region 5 and the edge of the body region 4 facing it) form channel regions 14.
To have low contact resistances, it is necessary to heavily dope both the N-type surface regions (source regions 5) and the P-type surface regions (body regions 4) in contact with the source metal region 13. The need for heavy doping of these regions gives, however, rise basically to two different problems.
A first problem is linked to the annealing processes subsequent to the implantation process and to their compatibility with the "scaled" thermal processes employed, for instance, in the manufacture of low-voltage submicrometric devices integrated in the same wafer.
The second problem is linked to the need to have low threshold voltages (1–2 V or even less) and hence low concentrations in the channel regions and, at the same time, high doping levels in the surface regions in contact with the metal regions.
In particular, in this regard, carrying out of an additional implantation for enrichment of the surface of the body regions 4 and of the source regions 5, through the windows in the polysilicon layer that forms the gate regions 10, would affect the surface concentration of the channel region 14 after the necessary annealing process. This has adverse effects on the threshold voltage, since both its mean value and the dispersion of its values would increase. In fact, the peak concentration in the channel region 14 is of the order of approximately 1017 atoms/cm3, while the surface concentrations in the contact area of the source 5 and body 4 regions must be higher than 1018 atoms/cm3, as may be seen from the plot of the doping profiles along the directions A and B, shown in FIGS. 1a and 1b, respectively.
The implantation dose further affects the defectiveness of the layers. In fact, as the dose increases, the likelihood of having precursor nuclei of extensive defects increases. On the other hand, these cannot be eliminated or in any case reduced to acceptable levels by using intensive thermal treatment, since this treatment could damage other parts or other devices integrated in the same chip.
In the above structure, the source regions 5 are obtained using an appropriate mask aligned inside the windows formed in the polysilicon layer. The above solution maximizes the channel perimeter (i.e., the facing perimeter between the source regions 5 and the channel regions 14) but may be used only when the distance between the gate regions is greater than 1 μm.
However, in case of structures of submicrometric size, the distance between the gate regions tends to be as small as possible, lower than 1 μm. For such devices, it is no longer possible to use the structure of FIG. 1, and the electrical connection between the source and body regions is obtained in two different ways.
For example, FIG. 2 (where L<1 μm) shows a solution wherein short-circuit is obtained through the use of an appropriate source mask. In practice, inside each body region 4, various source regions 5′ are formed, that, instead of extending in a continuous way along the edges of the gate regions 10, extend piece-wise in the direction Z for the entire width L (i.e., the width of the implantation windows of the body regions). In this way, body regions 4 have surface portions 4′, which face the top surface 6 of the body 1 and are electrically connected with the source regions 5′ through the metal layer 13. The above solution leads to a loss of channel perimeter even as much as 30% on account of the perimeter lost at the surface portions 4′. Furthermore, the problem of reducing the concentration of dopants in the source regions 5′ and hence of eliminating the problem of defectiveness is not solved.
A second solution, illustrated in FIG. 3, consists in carrying out an etch for partial removal of the source regions in the region facing the surface 6 of the body 1. In practice, in the above solution, the source regions are implanted in the polysilicon over the entire area of the windows. Then, after forming spacers 15 on the sides of the gate regions 10, the portions of the source regions not covered by the spacers 15 are removed for a depth greater that that of the source junction 5. At the end of the process, in each body region 4 just two thin source strips 5″ are present underneath the spacers 15, and the surface 6′ of the body 1 is no longer planar. In this case, etching of the silicon of the source regions 5 entails the need for contacting the source strips 5″ only along their vertical sides, with a considerable reduction in the contact area. Also in the above case, it is not possible to further reduce the defectiveness caused by the heavy doping of the source regions.
In all of the above cases, the source metal region 13 extends along the entire side edge of the gate regions 10 and is insulated from these by the side portions of the intermediate-dielectric regions 12 (see FIG. 1) or by the spacers 15 (see FIGS. 2 and 3). This facing area, hereinafter referred to as "insulation region", is particularly critical and may be the cause of short-circuiting between the gate regions and the source regions on account of poor insulation. The insulation region plays an important role in the percentage of rejects since this percentage is proportional to the perimeter of the region, also referred to as "insulation perimeter". The presence of a high insulation perimeter in known devices is therefore disadvantageous.
The aim of the invention is therefore to provide a MOS power device which will solve the problems outlined above.

MOS power device with high integration density and manufacturing process thereof


A system and method for is provided to determine a fuel flow cutout delay between transmitting a signal to stop a fuel flow to a fuel accumulator of a fuel system and the actual stop of fuel flow to the fuel accumulator. The fuel flow cutout delay is used to determine when pressure data from a sensor associated with the fuel accumulator is unaffected by fuel flow to the fuel accumulator.

As with all mechanical devices, fuel injectors have physical dimensions that lead to variations between fuel injectors. In addition, each fuel injector has different rates of wear and responds to temperature changes differently. Since the fuel delivered by each fuel injector during a fuel injection event varies enough to affect the performance of an associated engine, it is useful to measure or calculate the fuel delivery by each fuel injector. One challenge with these measurements and calculations is optimizing the window for the collection of data.

System and method for adapting to a variable fuel delivery cutout delay in a fuel system of an internal combustion engine


The present invention relates to a method for protecting a space vehicle inst directed energy, and to the resultant thermally protected space vehicle.

In U.S. Pat. No. 3,861,425 a flame retardant coating is used to coat fiber glass insulation. The coating of the '425 patent contains a flame retardant filler. The coating of the '425 patent also contains a fire retardant borate. The coating of the '425 patent is used to reduce flaming in an atmosphere that contains oxygen.
There is no teaching in the '425 patent of the use of a covering on a space vehicle to protect the space vehicle from the effects of directed energy in an oxygen free environment. Such directed energy may be in the form of optical radiation. The disclosed covering does not use a flame retardant filler, as used by the '425 patent.

Method for protecting a space vehicle and resultant vehicle

The United States of America as represented by the Secretary of the Navy


A computer system with an advanced power management which includes a PnP compatible operating system, an ISA bus, and a system BIOS for searching a read data port for all PnP ISA devices, which is used to read information from the PnP ISA devices. The computer system is able to save and restore the resource configuration information of the PnP ISA devices into/from a non-volatile storage by use of the searched read data port during a suspend/resume mode of the advanced power management.

1. Technical Field
The present invention relates to a computer system having the Industry Standard Architecture (ISA) bus, more particularly, to a computer system with the automatic configuration capability for the ISA cards and with so-called Advanced Power Management by which its power usage is controlled.
2. Related Art
Computer systems may be provided with provisions for adding devices thereto. For example, an ISA (Industry Standard Architecture) type personal computer system may be provided with expansion slots coupled to the ISA system bus for receiving expansion device cards which plug into such expansion slots. Other types of expansion techniques may also be used, such as PCI (Peripheral Component Interconnect) slots, PCMCIA (Personal Computer Memory Card Interface Association) slots, Micro Channel slots, EISA slots, orthelike. Examples of such expansion devices include keyboard controllers, hard drive controllers, floppy drive controllers, video controllers, modems, network cards, add-on memory cards, multimedia cards, sound cards, I/O devices, or the like. An expansion device may comprise one or more logical devices each of which may be assigned system resources such as an I/O address, interrupt level, and DMA channel.
The ISA bus is one of the popular expansion bus standards in the personal computer (PC) industry. The ISA bus requires the allocation of memory and I/O address spaces, DMA channels and interrupt levels among multiple ISA expansion cards. However, ISA does not define a hardware or software mechanism for allocating these resources. Consequently, configuration of ISA cards is typically done with switches or jumpers that change the decode maps for memory and I/O space and steer the DMA and interrupt signals to different pins on the bus. In addition, system configuration files need to be updated to reflect the configuration changes. When more than one expansion card is placed onto an ISA bus, conflicts may arise as a result of the different resource requirements of the expansion cards. To address these potential conflicts, users had to refer to instruction manuals provided by the expansion card manufacturers. From the user's perspective, the configuration process was time consuming and unreliable.
Automated expansion card configuration systems for automatically configuring newly installed expansion cards on standard ISA bus were recently developed. Examples of such configuration systems are disclosed in U.S. Pat. No. 5,517,646 for Expansion Device Configuration System Having Two Configuration Modes Which Uses Automatic Expansion Configutration Sequence During First Mode And Configures The Device Individually During Second Mode issued to Piccirillo et al., U.S. Pat. No. 5,559,965 for Input/Output Adapter Cards Having A Plug And Play Compliant Mode And An Assigned Resources Mode issued to Oztaskin et al., U.S. Pat. No. 5,628,027 for Method Of Determining The Configuration Of Devices Installed On A Computer Bus issued to Belmont, and U.S. Pat. No. 5,634,075 for Baclkward Compatibility For Plug And Play Systems issued to Smith et al. Computer systems that contain a standard bus conforming to the ISA standard may implement a Plug and Play specification, Version 1.0a", May 5, 1994 for automatically configuring Plug and Play expansion cards on the ISA bus without user intervention. The specification, which is incorporated by reference herein, defines a mechanism that provides automatic configuration capability for PnP ISA expansion cards with identification, resource usage determination, conflict detection, and conflict resolution.
In a first kind of PnP compatible ISA PC system, software stored in its ROM BIOS may configure a system after power up to assign system resources such as memory space, I/O addresses, interrupt levels, and DMA channels to each PnP ISA expansion card plugged in the system. The PnP ISA expansion cards built according to the PnP ISA specification may operate in conjunction with such software stored in the BIOS (i.e., PnP BIOS). In such a PC system, when power is applied to the system, PnP expansion cards required for system boot may become active on power up using power-up default system resources. Examples of the devices required for system boot may include hard and floppy disc drive controllers, keyboard controllers, display controllers or the like. Other PnP ISA devices not required for system boot may power up in an inactive state. Examples of PnP devices not required for system boot may include modems, sound cards, or the like. Such devices may not be required for system boot and initial loading of operating system and the like.
Then, the PnP BIOS may isolate each PnP device, assign a handle (i.e., Card Select Number) to each expansion card, and read the resource data from that card. Once each card had been isolated, assigned a handle and read, the PnP BIOS will check for conflict in the devices required for boot, and activate each boot device. The PC system may then boot, for example, from a hard drive and load and execute an operating system (e.g., MS-DOS.RTM., WINDOWS.RTM., OS/2.RTM., UNIX.RTM., or the like). Optionally, the BIOS may configure all other logical devices and configure or leave them in active state.
The operating system may then get PnP information from the ROM BIOS, read resource data from all PnP devices, and arbitrate system resources for all PnP devices. Conflict-free resources may then be assigned for all activated devices and the inactivated devices. Finally, appropriate device drivers may be loaded and thus the system is configured.
In another type of PnP compatible ISA PC system, a PnP compatible operating system (e.g., WINDOWS 95.RTM.) may assign the system resources to PnP ISA devices in the PC system. In such a PC system, the PnP ISA devices required for system boot become active by a ROM BIOS on power up using power up default system resources, while other PnP ISA devices not required for system boot come up inactive on power up. Next, a ROM BIOS of the PC system may be executed and the PC system will boot from its boot devices. Then, the PnP compatible operating system may be loaded. The operating system software is provided with support for PnP devices. In a similar manner to the PnP BIOS, the operating system will isolate each PnP device, assign a handle to each PnP device card, and read the resource data from that card. Once each card had been isolated, assigned a handle and read, the operating system software will arbitrate system resources for all PnP devices. Conflict-free resources may then be assigned and the devices activated. Finally, appropriate device drivers may be loaded and the system is thus configured.
Each above-described PnP software identifies and configures devices using a set of commands executed through three 8-bit I/O ports, that is, ADDRESS port, WRITE.sub.-- DATA port, and READ.sub.-- DATA port. The ADDRESS and WRITE.sub.-- DATA ports are located at fixed addresses. The WRITE.sub.-- DATA port is located at an address alias of the ADDRESS port. The READ.sub.-- DATA port is re-locatable within the I/O range from 0x0203h to 0x03FFh (hexadecimal). This is the only readable auto-configuration port. A special sequence of data writes to one of the ports enables the logic on all the PnP cards in the PC system. This sequence is referred to as the initiation key.
All PnP cards respond to the same I/O port addresses. Consequently, the PnP software needs an isolation mechanism to address one particular card at a time. The isolation protocol uses a unique number built into each card called serial identifier to isolate one PnP card at a time. After isolation, the PnP software assigns each card a unique handle, called the Card Select Number (CSN), which is used to select that PnP card. Using a handle eliminates the need to use a more elaborate and time-consuming isolation protocol in order to select a unique card.
Each card supports a readable data structure that describes the resources supported and those requested by the functions on that card. The data structure supports the concept of multiple functions per ISA card. Each function is defined as a logical device. Plug and Play resource information is provided for each logical device, and each logical device is independently configured through the PnP standard registers of corresponding card. Following isolation, the PnP software reads the resource data structure on each card. When all resource capabilities and demands are known, a resource arbitration process is invoked to determine the resources allocation to each ISA card.
The configuration of ISA cards is performed using the command registers specified for each resource type. However, some ISA functions may not be re-configurable. In these situations, the resources requested will be equivalent to the resources supported. The resource data structure informs the arbiter that it cannot assign these resources to other PnP cards in the PC system. After the assignment of resources, an I/O conflict detection mechanism may be invoked. This mechanism provides a means to insure that I/O resources assigned are not in conflict with standard ISA cards. The command set also supports the ability to activate or deactivate the function(s) on the card. After configuration is completed, PnP cards are removed from configuration mode. The initiation key needs to be re-issued in order to re-enable configuration mode. The details of the Plug and Play logic flow and isolation process will be omitted herein for brevity's sake, and they can be found in the Plug and Play ISA specification.
Meanwhile, a technology closely related to PnP is Power Management. Many PC systems now use some type of power management (often called Advanced Power Management) to temporarily place the computer system in a suspend mode in which power is conserved. In such a system, when it has never been used for a predetermined time, the computer system goes into a suspend mode in which contents of all devices therein are stored in a non-volatile storage such as a hard disk drive and the entire system is substantially turned off for reducing power consumption. In this mode, the contents of all expansion devices are saved indefinitely until the system is resumed by, for example, turning the power switch on, pressing keyboard, or the like. If the system awakes from the suspend mode, a resume mode is entered. In the resume mode, the computer system retrieves the saved contents from the non-volatile storage in order to go back into the previous state that it was in before it entered the suspend mode. This power management scheme is most useful for portable computers using battery power in order to conserve power and prolong the life of the battery.
Typically, when a computer system using an advanced power is booted, either a resume boot process or a BIOS boot process is performed depending upon whether the system is in a resume mode. If the BIOS boot process is performed, an operating system is loaded and executed. After the operating system is executed or after the resume boot process is performed, the system enters a normal mode of operation.
For many PC systems using PnP incompatible operating systems (e.g., MS-DOS.RTM. and OS/2.RTM.) which do not support the PnP automatic configuration mechanism, the system BIOS may directly save and restore the PnP card information during suspend and resume modes. However, unlike PC systems using PnP incompatible operating systems, PC systems having PnP compatible operating system (e.g., WINDOWS 95.RTM., or the like) and PnP ISA device cards, and employing such a power management scheme experience significant problems when the PC system enters into a suspend mode. The configuration of PnP ISA device cards is cleared when the PC system is powered off in a suspend mode. During a resume mode, the information of each PnP ISA device card needs restoring when the corresponding device driver receives the resume message from the BIOS through the operating system. However, most of the device drivers do not support this function. Further, in such a PnP compatible PC system, the system BIOS cannot find the address of the READ.sub.-- DATA port since the PnP compatible operating system (specifically, WINDOWS 95.RTM.) directly configures the READ.sub.-- DATA port of PnP ISA cards and does not re-configure the PnP cards. Thus, it is impossible for the system BIOS to save/restore the PnP ISA card information when the PC system is entering the suspend/resume mode, thereby disabling the PnP ISA cards after the system resume.

Computer system with automatic configuration capability for industry standard architecture(ISA) cards


Disclosed herein are methods for enhancing hematopoietic reconstitution of a subject. One method involves administering a therapeutically effective amount of an inhibitor of Embigin to a recipient subject and can also optionally include administering hematopoietic stem/progenitor cells to the subject. Another method involves administering an inhibitor of Embigin to a donor prior to harvest of hematopoietic stem/progenitor cells. Pharmaceutical compositions relating to the methods are also described.

Hematopoiesis refers to the proliferation and differentiation process, in which different types of blood cells develop from multipotent stem cells having the capacity to proliferate and differentiate. Most of the blood cells in the blood are short lived and thus need to be replaced constantly throughout life. The levels of mature blood cells in the circulation can change rapidly in response to different environmental stress ranging from blood loss, infections, and the like. The major site of hematopoiesis in humans, after about 20 weeks of fetal life, is the bone marrow (BM), a tissue consisting of a heterogeneous population of cells including hematopoietic stem cells (HSCs), endothelial cells (ECs), and other stromal cells as well as cells involved in bone homeostasis, including chondroclasts and osteoblasts. Gerber and Ferrara, 2003, J. Mol. Med., 81:20-31.
Normal hematopoiesis is based on the dual functioning of multipotent stem cells. Extensive self-renewal maintains the population of undifferentiated stem cells, whereas differentiation results in the formation of various types of mature blood cells that are grouped into one of three major blood cell lineages: lymphoid, myeloid and erythroid cell lineages. The lymphoid lineage is comprised of B cells and T cells, which collectively function in antibody production and antigen detection, thereby functioning as a cellular and humoral immune system. The myeloid lineage is comprised of monocytes (macrophages), granulocytes (including neutrophils), and megakaryocytes, and monitors the bloodstream for antigens, scavenges antigens from the bloodstream, fights off infectious agents, and produces platelets that are involved in blood clotting. The erythroid lineage is comprised of red blood cells that carry oxygen throughout the body.
Hematopoietic system is hierarchically organized and consists of 3 main compartments—slow dividing long-term stem cells, very rapidly dividing progenitors and non-dividing mature cells (the "effector" compartment)—all of which have distinct cell-surface marker profile. Stem cells support hematopoiesis throughout the life-time, while progenitors have a capacity for massive short-term expansion in response to environmental stimuli such as infection or stress in order to generate a large number of mature blood cells. Long-term stem cells are absolutely required and sufficient for hematopoietic reconstitution following myeloablation. However, they are not as efficient at giving rise to mature cells as compared to more differentiating progenitors (Yang et al. Blood. 2005; 105:2717-2723). Cord blood, mobilized peripheral blood stem cells and bone marrow are currently used as a source of long-term hematopoietic stem cells in clinical bone marrow transplantation. All these products contain, together with stem cells, a variable proportion of hematopoietic progenitors.
There are a variety of disorders that involve the failure of a person's hematopoietic system, in which enhancement of proliferation of stem cells and progenitors (HSPC) would be therapeutic. In addition, post-transplant bone marrow aplasia is a major cause of morbidity and mortality after bone marrow transplant (BMT) Enhancing HSPC proliferation is an attractive strategy to improve the bone marrow function.

Embigin inhibition for promotion of hematopoietic stem and progenitor cell expansion

PRESIDENT AND FELLOWS OF HARVARD COLLEGE


The invention provides human G-protein coupled receptors (GCREC) and polynucleotides which identify and encode GCREC. The invention also provides expression vectors, host, cells, antibodies, agonists, and antagonists. The invention also provides methods for diagnosing, treating, or preventing disorders associated with aberrant expression of GCREC.

Signal transduction is the general process by which cells respond to extracellular signals. Signal transduction across the plasma membrane begins with the binding of a signal molecule, e.g., a hormone, neurotransmitter, or growth factor, to a cell membrane receptor. The receptor, thus activated, triggers an intracellular biochemical cascade that ends with the activation of an intracellular target molecule, such as a transcription factor. This process of signal transduction regulates all types of cell functions including cell proliferation, differentiation, and gene transcription. The G-protein coupled receptors (GPCRs), encoded by one of the largest families of genes yet identified, play a central role in the transduction of extracellular signals across the plasma membrane. GPCRs have a proven history of being successful therapeutic targets.
GPCRs are integral membrane proteins characterized by the presence of seven hydrophobic transmembrane domains which together form a bundle of antiparallel alpha (α) helices. GPCRs range in size from under 400 to over 1000 amino acids (Strosberg, A. D. (1991) Eur. J. Biochem. 196:1-10; Coughlin, S. R. (1994) Curr. Opin. Cell Biol. 6:191-197). The amino-terminus of a GPCR is extracellular, is of variable length, and is often glycosylated. The carboxy-terminus is cytoplasmic and generally phosphorylated. Extracellular loops alternate with intracellular loops and link the transmembrane domains. Cysteine disulfide bridges linking the second and third extracellular loops may interact with agonists and antagonists. The most conserved domains of GPCRs are the transmembrane domains and the first two cytoplasmic loops. The transmembrane domains account, in part, for structural and functional features of the receptor. In most cases, the bundle of a helices forms a ligand-binding pocket. The extracellular N-terminal segment, or one or more of the three extracellular loops, may also participate in ligand binding. Ligand binding activates the receptor by inducing a conformational change in intracellular portions of the receptor. In turn, the large, third intracellular loop of the activated receptor interacts with a heterotrimeric guanine nucleotide binding (G) protein complex which mediates further intracellular signaling activities, including the activation of second messengers such as cyclic AMP (cAMP), phospholipase C, and inositol triphosphate, and the interaction of the activated GPCR with ion channel proteins. (See, e.g., Watson, S. and S. Arkinstall (1994) The G-protein Linked Receptor Facts Book, Academic Press, San Diego Calif., pp. 2-6; Bolander, F. F. (1994) Molecular Endocrinology, Academic Press, San Diego Calif., pp. 162-176; Baldwin, J. M. (1994) Curr. Opin. Cell Biol. 6:180-190.)
GPCRs include receptors for sensory signal mediators (e.g., light and olfactory stimulatory molecules); adenosine, γ-aminobutyric acid (GABA), hepatocyte growth factor, melanocortins, neuropeptide Y, opioid peptides, opsins, somatostatin, tachykinins, vasoactive intestinal polypeptide family, and vasopressin; biogenic amines (e.g., dopamine, epinephrine and norepinephrine, histamine, glutamate (metabotropic effect), acetylcholine (muscarinic effect), and serotonin); chemokines; lipid mediators of inflammation (e.g., prostaglandins and prostanoids, platelet activating factor, and leukotrienes); and peptide hormones (e.g., bombesin, bradykinin, calcitonin, C5a anaphylatoxin, endothelin, follicle-stimulating hormone (FSH), gonadotropic-releasing hormone (GnRH), neurokinin, and thyrotropin-releasing hormone (TRH), and oxytocin). GPCRs which act as receptors for stimuli that have yet to be identified are known as orphan receptors.
The diversity of the GPCR family is further increased by alternative splicing. Many GPCR genes contain introns, and there are currently over 30 such receptors for which splice variants have been identified. The largest number of variations are at the protein C-terminus. N-terminal and cytoplasmic loop variants are also frequent, while variants in the extracellular loops or transmembrane domains are less common. Some receptors have more than one site at which variance can occur. The splicing variants appear to be functionally distinct, based upon observed differences in distribution, signaling, coupling, regulation, and ligand binding profiles (Kilpatrick, G. J. et al. (1999) Trends Pharmacol. Sci. 20:294-301).
GPCRs can be divided into three major subfamilies: the rhodopsin-like, secretin-like, and metabotropic glutamate receptor subfamilies. Members of these GPCR subfamilies share similar functions and the characteristic seven transmembrane structure, but have divergent amino acid sequences. The largest family consists of the rhodopsin-like GPCRs, which transmit diverse extracellular signals including hormones, neurotransmitters, and light. Rhodopsin is a photosensitive GPCR found in animal retinas. In vertebrates, rhodopsin molecules are embedded in membranous stacks found in photoreceptor (rod) cells. Each rhodopsin molecule responds to a photon of light by triggering a decrease in cGMP levels which leads to the closure of plasma membrane sodium channels. In this manner, a visual signal is converted to a neural impulse. Other rhodopsin-like GPCRs are directly involved in responding to neurotransmitters. These GPCRs include the receptors for adrenaline (adrenergic receptors), acetylcholine (muscarinic receptors), adenosine, galanin, and glutamate (N-methyl-D-aspartate/NMDA receptors). (Reviewed in Watson, S. and S. Arkinstall (1994) The G-Protein Linked Receptor Facts Book, Academic Press, San Diego Calif., pp. 7-9, 19-22, 32-35, 130-131, 214-216, 221-222; Habert-Ortoli, E. et al. (1994) Proc. Natl. Acad. Sci. USA 91:9780-9783.)
The galanin receptors mediate the activity of the neuroendocrine peptide galanin, which inhibits secretion of insulin, acetylcholine, serotonin and noradrenaline, and stimulates prolactin and growth hormone release. Galanin receptors are involved in feeding disorders, pain, depression, and Alzheimer's disease (Kask, K. et al. (1997) Life Sci. 60:1523-1533). Other nervous system rhodopsin-like GPCRs include a growing family of receptors for lysophosphatidic acid and other lysophospholipids, which appear to have roles in development and neuropathology (Chun, J. et al. (1999) Cell Biochem. Biophys. 30:213-242).
The largest subfamily of GPCRs, the olfactory receptors, are also members of the rhodopsin-like GPCR family. These receptors function by transducing odorant signals. Numerous distinct olfactory receptors are required to distinguish different odors. Each olfactory sensory neuron expresses only one type of olfactory receptor, and distinct spatial zones of neurons expressing distinct receptors are found in nasal passages. For example, the RA1c receptor which was isolated from a rat brain library, has been shown to be limited in expression to very distinct regions of the brain and a defined zone of the olfactory epithelium (Raming, K. et al. (1998) Receptors Channels 6:141-151). However, the expression of olfactory-like receptors is not confined to olfactory tissues. For example, three rat genes encoding olfactory-like receptors having typical GPCR characteristics showed expression patterns not only in taste and olfactory tissue, but also in male reproductive tissue (Thomas, M. B. et al. (1996) Gene 178:1-5).
Members of the secretin-like GPCR subfamily have as their ligands peptide hormones such as secretin, calcitonin, glucagon, growth hormone-releasing hormone, parathyroid hormone, and vasoactive intestinal peptide. For example, the secretin receptor responds to secretin, a peptide hormone that stimulates the secretion of enzymes and ions in the pancreas and small intestine (Watson, supra, pp. 278-283). Secretin receptors are about 450 amino acids in length and are found in the plasma membrane of gastrointestinal cells. Binding of secretin to its receptor stimulates the production of cAMP.
Examples of secretin-like GPCRs implicated in inflammation and the immune response include the EGF module-containing, mucin-like hormone receptor (Emr1) and CD97 receptor proteins. These GPCRs are members of the recently characterized EGF-TM7 receptors subfamily. These seven transmembrane hormone receptors exist as heterodimers in vivo and contain between three and seven potential calcium-binding EGF-like motifs. CD97 is predominantly expressed in leukocytes and is markedly upregulated on activated B and T cells (McKnight, A. J. and S. Gordon (1998) J. Leukoc. Biol. 63:271-280).
The third GPCR subfamily is the metabotropic glutamate receptor family. Glutamate is the major excitatory neurotransmitter in the central nervous system. The metabotropic glutamate receptors modulate the activity of intracellular effectors, and are involved in long-term potentiation (Watson, supra, p. 130). The Ca2+-sensing receptor, which senses changes in the extracellular concentration of calcium ions, has a large extracellular domain including clusters of acidic amino acids which may be involved in calcium binding. The metabotropic glutamate receptor family also includes pheromone receptors, the GABAB receptors, and the taste receptors.
Other subfamilies of GPCRs include two groups of chemoreceptor genes found in the nematodes Caenorhabditis elegans and Caenorhabditis briggsae, which are distantly related to the mammalian olfactory receptor genes. The yeast pheromone receptors STE2 and STE3, involved in the response to mating factors on the cell membrane, have their own seven-transmembrane signature, as do the cAMP receptors from the slime mold Dictyostelium discoideum, which are thought to regulate the aggregation of individual cells and control the expression of numerous developmentally-regulated genes.
GPCR mutations, which may cause loss of function or constitutive activation, have been associated with numerous human diseases (Coughlin, supra). For instance, retinitis pigmentosa may arise from mutations in the rhodopsin gene. Furthermore, somatic activating mutations in the thyrotropin receptor have been reported to cause hyperfunctioning thyroid adenomas, suggesting that certain GPCRs susceptible to constitutive activation may behave as protooncogenes (Parma, J. et al. (1993) Nature 365:649-651). GPCR receptors for the following ligands also contain mutations associated with human disease: luteinizing hormone (precocious puberty); vasopressin V2 (X-linked nephrogenic diabetes); glucagon (diabetes and hypertension); calcium (hyperparathyroidism, hypocalcuria, hypercalcemia); parathyroid hormone (short limbed dwarfism); β3-adrenoceptor (obesity, non-insulin-dependent diabetes mellitus); growth hormone releasing hormone (dwarfism); and adrenocorticotropin (glucocorticoid deficiency) (Wilson, S. et al. (1998) Br. J. Pharmocol. 125:1387-1392; Stadel, J. M. et al. (1997) Trends Pharmacol. Sci. 18:430-437). GPCRs are also involved in depression, schizophrenia, sleeplessness, hypertension, anxiety, stress, renal failure, and several cardiovascular disorders (Horn, F. and G. Vriend (1998) J. Mol. Med. 76:464-468).
In addition, within the past 20 years several hundred new drugs have been recognized that are directed towards activating or inhibiting GPCRs. The therapeutic targets of these drugs span a wide range of diseases and disorders, including cardiovascular, gastrointestinal, and central nervous system disorders as well as cancer, osteoporosis and endometriosis (Wilson, supra; Stadel, supra). For example, the dopamine agonist L-dopa is used to treat Parkinson's disease, while a dopamine antagonist is used to treat schizophrenia and the early stages of Huntington's disease. Agonists and antagonists of adrenoceptors have been used for the treatment of asthma, high blood pressure, other cardiovascular disorders, and anxiety; muscarinic agonists are used in the treatment of glaucoma and tachycardia; serotonin 5HT1D antagonists are used against migraine; and histamine H1 antagonists are used against allergic and anaphylactic reactions, hay fever, itching, and motion sickness (Horn, supra).
Recent research suggests potential future therapeutic uses for GPCRs in the treatment of metabolic disorders including diabetes, obesity, and osteoporosis. For example, mutant V2 vasopressin receptors causing nephrogenic diabetes could be functionally rescued in vitro by co-expression of a C-terminal V2 receptor peptide spanning the region containing the mutations. This result suggests a possible novel strategy for disease treatment (Schöneberg, T. et al. (1996) EMBO J. 15:1283-1291). Mutations in melanocortin-4 receptor (MC4R) are implicated in human weight regulation and obesity. As with the vasopressin V2 receptor mutants, these MC4R mutants are defective in trafficking to the plasma membrane (Ho, G. and R. G. MacKenzie (1999) J. Biol. Chem. 274:35816-35822), and thus might be treated with a similar strategy. The type 1 receptor for parathyroid hormone (PTH) is a GPCR that mediates the PTH-dependent regulation of calcium homeostasis in the bloodstream. Study of PTH/receptor interactions may enable the development of novel PTH receptor ligands for the treatment of osteoporosis (Mannstadt, M. et al. (1999) Am. J. Physiol. 277:F665-F675).
The chemokine receptor group of GPCRs have potential therapeutic utility in inflammation and infectious disease. (For review, see Locati, M. and P. M. Murphy (1999) Annu. Rev. Med. 50:425-440.) Chemokines are small polypeptides that act as intracellular signals in the regulation of leukocyte trafficking, hematopoiesis, and angiogenesis. Targeted disruption of various chemokine receptors in mice indicates that these receptors play roles in pathologic inflammation and in autoimmune disorders such as multiple sclerosis. Chemokine receptors are also exploited by infectious agents, including herpesviruses and the human immunodeficiency virus (HIV-1) to facilitate infection. A truncated version of chemokine receptor CCR5, which acts as a coreceptor for infection of T-cells by HIV-1, results in resistance to AIDS, suggesting that CCR5 antagonists could be useful in preventing the development of AIDS.
The discovery of new G-protein coupled receptors and the polynucleotides encoding them satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention, and treatment of cell proliferative, neurological, cardiovascular, gastrointestinal, autoimmune/inflammatory, and metabolic disorders, and viral infections, and in the assessment of the effects of exogenous compounds on the expression of nucleic acid and amino acid sequences of G-protein coupled receptors.

Isolated polynucleotide encoding a G-protein coupled receptor