A mapping algorithm for efficient access to a flash memory, wherein block state information that is changed through logical operations required by a processor is written in the flash memory according to a predetermined state transition algorithm and the changed information is referred to upon read/write operations. A mapping control apparatus for a flash memory according to the present invention includes a flash memory having regions divided on a block basis and containing block state information indicating the state of each block, each block including a predetermined number of sectors; and a processor for determining a sector on which a predetermined logical operation is to be performed based on the block state information and updating the block state information according to a predetermined state transition algorithm, when the logical operation is required for the flash memory.

1. Field of the Invention
The present invention relates to a flash memory and a mapping control apparatus and method for the flash memory, and more particularly, to enabling efficient access to a flash memory by updating block state information, which is changed through logical operations required by a processor, in the flash memory based on a predetermined state transition algorithm and referring to the updated information upon read/write operations.
2. Description of the Related Art
A flash memory has an advantage of RAM (Random Access Memory) which data can be written into and deleted from freely as well as that of ROM (Read Only Memory) that can maintain data stored therein without power. Therefore, flash memory has been widely used as a storage medium for portable electronic devices such as digital cameras, PDAs and MP3 players.
In such a flash memory, random access can be utilized for data stored in a specific location as in conventional RAMs, non-volatile storage devices, magnetic media and the like. However, the flash memory differs from existing storage devices in that access is gained on a block basis during the process of modifying or erasing data.
In other words, if previous data are intended to be modified or erased, it is required that a block containing the corresponding data be erased and data be then written again. As an example, it is performed in the same manner that an entire word is deleted completely by pressing the 'Delete' key and a modified word is then retyped instead of correcting a character or letter one-by-one.
As used herein, the term 'sector' refers to bytes having physically consecutive addresses. The sector is a basic unit of a read/write operation on a flash memory. A block including a plurality of sectors is a basic unit of a delete operation, which can be erased through a single erase operation.
Such a flash memory supports a logical-physical mapping method by which even though a physical address of a piece of data written in a flash memory is changed due to the erase-before-write, the piece of data written in the flash memory can be accessed with the same logical address.
That is, the mapping scheme manages information on mapping between a logical address and a physical address for a specific piece of data by means of a predetermined mapping table. The mapping scheme is classified roughly into a sector mapping method, a block mapping method, and a hybrid method.
FIG. 1A schematically illustrates an access architecture for a flash memory in accordance with a conventional sector mapping method.
As shown in FIG. 1A, the sector mapping method maintains mapping information on a sector basis in a flash memory to enable access to a physical sector of the flash memory using logical sector information.
As an example, if a logical sector number (LSN) is designated as 9 together with a request for a write operation of specific data, a flash memory access device searches for physical sector number (PSN) 6 corresponding to LSN 9 by referring to a mapping table.
Then, the relevant data are written in sector 6 of the flash memory. If other data have been written in this sector, the data are written in an empty physical sector of the flash memory and PSN corresponding to LSN 9 is changed in the mapping table.
FIG. 1B schematically illustrates an access architecture for a flash memory in accordance with a conventional block mapping method.
As shown in FIG. 1B, the block mapping method maintains mapping information on a block basis in a flash memory and translates logical sector information into logical block information, thereby enabling access to a physical sector of the flash memory using the logical block information and offset information.
As an example, if an LSN is designated as 9 together with a request for a write operation of specific data, a flash memory access device calculates a logical block number (LBN) (i.e., 9/4=2) for LSN 9 and then a physical block number (PBN) corresponding to LBN by referring to a mapping table.
In such a case, data are written in a sector corresponding to Offset 1 within PBN 1 obtained by matching the offset of the logical block with that of the physical block.
If other data have been written in this sector, the flash memory access device writes data in an empty physical sector of the flash memory while matching the offsets and then changes PBN corresponding to LBN 2 in the mapping table.
At this time, effective data remaining in the existing PBN should be copied to a new PBN while matching the offsets.
FIG. 1C schematically illustrates an access architecture for a flash memory in accordance with a conventional hybrid mapping method.
As shown in FIG. 1C, the hybrid mapping method performs mapping on a block basis units as in the block mapping method and then stores sector mapping information in a physical block to obtain the property of the sector mapping.
As an example, if an LSN is designated as 9 together with a request for a write operation of specific data, a flash memory access device calculates an LBN (i.e., 9/4=2) for LSN 9 and then obtains PBN 1 corresponding to the LBN by referring to a mapping table.
Thereafter, the flash memory access device writes data in an empty sector of PBN 1 and writes LSN 9.
Among these conventional mapping methods, the sector mapping method has difficulty in being practically applied to flash memories since there is a great deal of mapping information required for maintenance on the sector basis in the flash memory.
Accordingly, recent technologies are based on the block mapping method that requires less mapping information.
However, since the offsets should be matched in the block mapping method, a new block should be allocated to write data in the same sector and even effective data of a different sector in the same block as well as those of the relevant sector should be copied if write operations frequently occur in the same sector. Thus, there is a problem in that write and erase operations frequently occur, resulting in considerable deterioration of the performance of the system.
Meanwhile, although the hybrid mapping method does not require matching of the offsets due to storage of the sector mapping information after block mapping has occurred, it has a problem in that a predetermined memory capacity for writing the sector mapping information should be secured and thus the required amount of memory increases compared to the block mapping method.
To solve the aforementioned problems in the prior art, Korean Laid-Open Patent Publication No. 2002-0092487 entitled "Method of Managing Flash Memory" that was previously proposed discloses prevention of degradation of the performance of a system even in an environment where data are frequently updated by allocating a specific log block and writing data, which require a write operation during an updating process, in the log block. However, the invention of the publication is not sufficient to prevent the performance of the flash memory system from deteriorating due to repeated write operations since write/erase operations are required during the process of transferring the data written in the log block to a data block.
Therefore, there is a need for a method of accessing a flash memory, which enables improvement of the performance of a flash memory system by reducing the number of write/erase operations involved in write operations requested by a processor.

Flash memory and mapping control apparatus and method for flash memory


A hand-held, self-contained motor-driven trenching device (100) for cutting a slit or trench within a substrate is based on a chain-saw motor unit together with a purpose-built attachment. An unmodified chain-saw drive unit provides both motive force and a holder, although purpose-built units may employ other forms of motive power. A chain-driven reduction drive matches the chain-saw drive sprocket (101) speed to a suitable toothed digging chain cutting speed; the reduction drive being coupled to a sprocket wheel (102) aligned at one end of a sturdy, hardened steel blade (106) over which a heavy roller chain (200) bearing soil-cutting teeth (203) is pulled. The resulting trench is about 30-35 mm wide, up to 1 meter deep, and of indefinite length. The invention provides an optimized solution to a need for burying narrow cables, fiber-optic conduits, water pipes, and the like well into the ground.

This invention relates to portable motorised equipment for digging a trench into the ground, particularly hand-held equipment, and includes attachments for existing hand-held power units.
The power digging of holes or trenches is many times faster than manual digging with hand tools. Because of the considerable horsepower needed to drive a chain or mechanical digger, its weight and size, and the need for stable control of the digging bar or bucket, virtually all mechanical digging tools are mounted on a custom made vehicle. This makes them physically large, expensive, impractical, or uneconomic to own or to use for small jobs, and difficult to transport, typically requiring a second vehicle to take them from place to place.
On many occasions about a house, a farm, or at construction sites, there is a need to bury a relatively small conduit down to perhaps 1 meter deep within the groundxe2x80x94typical conduit diameters being about 25 mm for examples such as telephone cables, for water pipes about a farm, or small mains power cables. It is wasteful to dig a trench for such a thin conduit with hand tools which are usually about 150 mm wide or more, or to use one of the previously mentioned chain or mechanical diggers.
Observing the power and degree of control available from a chain saw style power unit, experiments have taken place to ascertain whether a useful and cost-effective trench digger could be created using a chain-saw as a power unit. Chain-saws are widely distributed, there being about 25,000 chain-saws sold in New Zealand (about one per 120 persons) per annum. It appears preferable to direct the invention towards providing an attachment capable of being reversibly attached to an existing chain-saw, for those who already possess a chain-saw. The blade is usually held in place with two bolts.
A review of the prior art in this general area reveals: (1) U.S. Pat. No. 4,429,477 Tice et al, who describe a modified chain-saw, including a gear reducer, for digging (and particularly deals with digger chain tooth design) (2) U.S. Pat. No. 4,651,449 Rose. (3) U.S. Pat. No. 4,922,763 Ashworth where an ordinary chain-saw is provided with a catcher for dragged-up soil, to serve as a soil sampler, and (4) the more extreme U.S. Pat. No. 4,799,320 West et al (which provides horizontally aimed augers to each side of the far end of a chain-saw blade). (5) U.S. Pat. No. 4,660,306 Bruce et al describes a trencher attachment for use on the arm of a hydraulic excavator. There is a group of patents for digging chains for dedicated excavators. Example chain patents are: U.S. Pat. No. 6,154,987 Rumer et al, U.S. Pat. No. 4,924,609 Martin, U.S. Pat. No. 4,893,464 Thuerman, U.S. Pat. No. 4,651,449 Rose (this chain is for a chain-saw), U.S. Pat. No. 3,913,979 Strauss et al, and U.S. Pat. No. 3,846,922 Horton.
The problem to be solved might be stated as xe2x80x9cto provide a cheap, portable powered trenching machine able to be held by a person while in usexe2x80x9d.
It is an object of this invention to provide means for the portable, motorised digging of a trench or at least to provide the public with a useful choice.
In a first broad aspect this invention provides a hand-held, self-contained motor-driven trenching device for cutting a slit within a substrate, wherein the trenching device includes a driven digging chain in the form of an endless loop, having attached teeth, the chain surrounding an outwardly and downwardly protruding cutting beam and being capable of being pulled along a side of the cutting beam by means of a driven rotatable chain engagement means, and wherein the cutting beam is placed substantially in line with the centre of mass of the trenching device, so that the weight of the trenching device falls evenly on the cutting beam when in use to cut a slit in the substrate, and so that in use a person holding the motor-driven trenching device does not experience undue sideways pressure.
Preferably the spacing along the shaft between the driven sprocket and the primary chain receiving sprocket is sufficient to place the driven sprocket in line with the centre of gravity of the assembled chain-saw and attachment, so that in use a person holding the assembly does not experience a sideways torque caused by an unbalanced mass.
Optionally that spacing along the shaft may be adjustable, so that different chain-saw drive units can be employed.
Preferably the driven sprocket is attached to the shaft using a key or spline.
In a second broad aspect this invention provides a for use in cutting a groove or trench in a substrate, wherein the trenching device is comprised of a chain-saw motor drive unit and a trenching attachment adapted for use with the chain-saw motor drive unit; said trenching attachment being capable of repeated attachment to and removal from the chain-saw motor drive unit as a substitute for the original cutting chain and saw blade of the chain-saw.
In a related aspect the trenching attachment includes coupling means capable of being firmly yet reversibly attached to the chain-saw drive unit by means of at least one fastener; said coupling means being attached to a digging chain support means, comprising a first driven sprocket and a nose (idler) sprocket held apart by an elongated cutting beam lying in line with and between the sprockets, wherein the distance between the first driven sprocket and the nose sprocket is adjustable (so that a digging chain in the form of an elongated loop can be tightened and held tightly between the sprockets and around the elongated beam), digging chain support means also comprising at least one sliding surface along at least one side of said elongated beam, drive connection means to couple the first driven sprocket with a second driven sprocket capable of accepting the output of the chain-saw motor by means of an endless primary drive chain capable of being attached to the powered sprocket of the chain-saw drive unit, said means comprising a rotatable shaft supported in perpendicular relationship to the elongated beam, the shaft having the first driven sprocket affixed in line with the elongated beam, the shaft also serving to laterally displace the primary drive chain to one side of the digging chain, so that the cutting beam may be placed substantially in line with the centre of mass of the trenching device regardless of the position of the powered sprocket of the chain-saw drive unit.
Preferably the trenching attachment further includes shaft speed reduction means, so that when in use the digging chain is pulled along the elongated beam at a velocity which is slower than that of the primary drive chain while the motor of the chain-saw drive unit is able to rotate at a preferred rate.
In a related aspect the second driven sprocket capable of accepting the output of the chain-saw motor has a larger circumference than that of the powered sprocket of the chain-saw drive unit.
Preferably a shaft speed reduction means is included within the accessory, so that when in use the digging chain is pulled along the elongated beam at a velocity which is slower than that of the primary endless chain, yet with more force, and a preferred reduction of velocity is to about 40% of initial velocity, although this factor depends on digging chain configuration and soil characteristics.
In a further related aspect the second driven sprocket has about three tines as many teeth as does the powered sprocket of the chain-saw drive unit.
In a third broad aspect the trenching attachment is further provided with ground rest means, said ground rest means comprising one or more bars attached at one end to the trenching attachment, each bar including intermediate ground contact areas, and each bar terminating in a handle.
Preferably each intermediate ground contact area comprises a wheel.
In a fourth broad aspect the attachment further includes a first guard capable of enclosing the primary chain, when in use, and a second guard capable of partially enclosing the first driven sprocket, so that when using the device a person is reasonably protected from injury and from flying debris.
In a fifth broad aspect the invention provides an attachment further including means for sensing electric current flow, so that a person is warned of electrical hazards derived from underground cables when using the device.
In a sixth broad aspect the invention provides a digging chain, the digging chain being in the form of an endless loop of roller chain, provided with projecting teeth on one side; the teeth including a left-hand, a right-hand and a central cutting type of tooth.
The descriptions of the invention to be provided herein are given purely by way of example and are not to be taken in any way as limiting the scope or extent of the invention.


A mobile communication terminal with an integrated photographic apparatus is disclosed. The photographic apparatus is rotatively connected to the terminal. Further, a magnet, which generates a flux, is connected to the photographic apparatus. A magnetic flux sensor is also connected to the terminal so that an image produced by the photographic apparatus is inverted when the magnetic flux sensor detects the magnetic flux. Rotation of the photographic apparatus at a predetermined angle approximates the magnet to the magnetic flux detecting sensor.

1. Field of the Invention
The present invention relates to an image reversing apparatus of a mobile communication terminal with an integrated photographic apparatus and method thereof, and more particularly, to an image reversing apparatus of a mobile communication terminal with an integrated photographic apparatus and method thereof to correctly reproduce an inverted image.
2. Description of Related Art
In general, mobile communication terminals include cellular phones or Personal Communication Systems (PCS) having wireless communication capabilities. As the need for video/image communication emerges along with voice communication, several types of mobile communication terminals with an integrated photographic apparatus have been suggested to satisfy this demand.
Referring to FIG. 1, a folding type mobile terminal 10 is shown with a rotatable camera 16 mounted on the terminal 10. The folding type conventional mobile terminal 10 comprises a body 11, in which a printed circuit board 12 (partially shown) is installed. The terminal further comprises an upper folding portion 13 rotatably coupled to the lower folding portion 11 by using a hinge 15. The camera 16 is mounted at the hinge 15 and can rotate 180°. A liquid crystal display (LCD) screen 14 is mounted on the upper folding portion 13.
Generally, when the rotation angle of the camera 16 is approximately within 330° to 90° (based on 0° corresponding to the twelve o'clock position), such that the camera 16 is generally directed in a direction opposite the LCD screen 14, the reproduced image created by the camera 16 is correctly reproduced on the LCD screen 14 with respect to orientation. However, when the rotation angle of the camera 16 ranges approximately less than 330°, such that the camera 16 is generally directed in the same direction as the LCD screen 14, the reproduced image created by the camera is inversely reproduced on the LCD screen 14 with respect to orientation. In other words, the image is inverted so that it appears upside-down. Consequently, a correcting apparatus is required to allow for proper image reproduction.
An example of an image correcting apparatus in a mobile communication terminal having an integrated photographic apparatus is described in Japanese Patent No. 3116822, wherein a construction for reversing an inverse image is disclosed. Japanese Patent No. 3116822 describes the use of an angle sensor to detect an angle displacement that is generated when a camera body rotates on the basis of an optical axis of the lens. However, this construction is relatively complicated and large, resulting in increased fabrication cost and possibly degraded accuracy. Therefore, an improved solution is needed to correctly display an inverted image reproduced by a rotating photographic apparatus of a mobile communication terminal.

Inverse image reversing apparatus of a mobile communication terminal with integrated photographic apparatus and method thereof


The invention is directed to chimeric polypeptides, e.g., bispecific antibodies, comprising a chemokine receptor binding domain and a T cell surface polypeptide or cell toxin binding domain, nucleic acids that encode them, and methods of making and using them. The chimeric polypeptides of the invention can include, be bound to, or attached to, a cell toxin. The invention is also directed to pharmaceutical compositions and methods for making and using them, including the treatment of immunological disorders, such as autoimmune diseases, and for the targeted elimination of cells, e.g., T lymphocytes and other cells latently infected with a primate immunodeficiency virus, such as a human immunodeficiency virus, e.g., HIV-1.

This invention relates generally to cell biology, virology and medicine. In particular, the invention is directed to chimeric polypeptides, e.g., bispecific antibodies, comprising a chemokine receptor binding domain and a T cell surface polypeptide, a cell toxin, or a cell toxin binding domain, nucleic acids that encode them, and methods of making and using them. The chimeric polypeptides of the invention can include, be bound to, or attached to, a cell toxin. The invention is also directed to making and using pharmaceutical compositions, for example, for the treatment of immunological (e.g., autoimmune) disorders and for the targeted elimination of cells, e.g., T lymphocytes and other cells latently infected with a primate immunodeficiency virus, such as a human immunodeficiency virus, e.g., HIV-1. The pharmaceutical compositions and methods of the invention can be used for the treatment, prevention and/or alleviation of inflammatory joint and renal diseases, inflammatory bowel diseases, multiple sclerosis, skin diseases, diabetes or transplant rejection.
Immunological diseases/disorders, like autoimmune diseases, inflammation disorders as well as infectious diseases are not only increasing but represent substantial threats to global health. For example, in Germany, about 1% of the population suffer from the autoimmune disease rheumatoid arthritis. In addition, there is a number of other joint diseases also leading to arthritis. Currently, three groups of drugs-non-steroidal anti-rheumatics, cortisone preparations and second-line agents- and TNFxcex1 blocking agents are used for treating inflammatory joint diseases. Up to now, the therapy has focused on the local injection of cortisone preparations in combination with a systemic administration of anti-phlogistics or second-line agents.
Non-steroidal anti-rheumatics have a mild analgetic and anti-inflammatory effect, but they have many side effects when applied frequently (e.g. gastric ulcers, nephroses). In high dosages, cortisone preparations have a strong decongestant and analgetic effect, however, leading to a quick relapse after discontinuation of the therapy. Moreover, cortisone preparations cannot stop the destruction process of the joint disease. A long-term therapy with cortisone usually entails severe side effects, such as infections, Cushing""s phenomenon, osteoporosis, parchment-like skin, metabolic and hormonal disorders. The local injection of cortisone also has the essential disadvantage that the activity of the migrated white blood cells is only reduced. As the infiltrating cells are not destroyed, a quick relapse occurs after discontinuation of the therapy. As mentioned above, the same applies to the systemic application. Rarely, inflammation due to the irritative effect of cortisone crystals is aggravated after injection of cortisone. The duration of effect of a cortisone injection varies tremendously and ranges from primary ineffectiveness to a duration of effect of several weeks.
In rheumatology, second-line agents are used to achieve a long-term suppression of the inflammation and a reduction in cortisone preparations. Due to the considerable toxicity (e.g., allergies, infections, malignant diseases, renal insufficiency, blood pressure crises, pulmonary diseases) it is necessary for medical specialists to attend closely to the patients. After beginning treatment, no therapeutic effect may be apparent for the first three months. Currently, there are 4 or 5 of such second-line agents at disposal, which are used individually at first or are combined if the therapy is not effective. Mostly, there is hardly anything known about the mode of action of second-line agents. It is not yet entirely clear whether the application of second-line agents can diminish the destruction of the joint.
In recent years, a new group of substances has been introduced into the treatment of rheumatoid arthritis, which is based on the blocking of cell signal substances, particularly TNFxcex1, by means of monoclonal antibodies or soluble receptor constructs.
In addition, there are patients that do not respond to currently available therapies. In other cases, the conventional therapy has to be stopped due to intolerable side effects.
A similar situation exists for many other inflammatory and autoimmune diseases like inflammatory renal diseases, inflammatory bowel diseases, multiple sclerosis and transplant rejection, where current treatments have many limitations. For example, agents used in inflammatory and autoimmune diseases include anti-inflammatory and immunosuppressive agents like azathioprine, cyclophosphamide, glucocorticoids like prednisone; immunosuppressants like cyclosporin A, Tacrolimus (FK506), Sirolimus (Rapamycin); and protein drugs like calcineurin, beta-interferon, anti-TNF alpha monoclonal antibodies (remicade). These agents show general immunomodulating effects and therefore efficacy and side effects profiles can pose severe limitations for the treatment options; see, e.g., Harrison""s Principles of Internal Medicine, eds. Fauci et al., 14th edition, McGraw-Hill publisher.
Inflammatory bowel diseases, such as Crohn""s disease, ulcerative colitis, are treated with the anti-inflammatory agents sulfazsalazine (Azulfidine) and glucocorticoids, like prednisone and, in selected cases, with TNF-xcex1 blocking agents. In ulcerative colitis immunosuppressive therapy with drugs such as azathioprine is well established, in severely ill patients the potent immunosuppressive agent cyclosporine is used (see, e.g., Harrison""s Principles of Internal Medicine, eds. Fauci et al., 14th edition, McGraw-Hill publisher). In many cases no sufficient reduction of disease activity is achieved with current drugs, such that even surgical intervention is sometimes necessary.
Inflammatory renal diseases (nephritis) are treated with e.g. glucocorticoids, alkylating agents and/or plasmapheresis. Additional diseases with similar treatment options include systemic lupus erythematosus (SLE), Sjogren""s syndrome, polymyositis, dermatomyositis, mixed connective tissue disease, anti-phospholipid-antibody syndrome.
For some of these diseases, few therapeutic options have been available up to now. All these diseases share an inflammatory component. However, the inflammatory component cannot be sufficiently suppressed by the currently available drugs. For some drugs, e.g. alkylating agents a maximal lifetime dose per patient cannot be exceeded.
Transplant rejection is treated using immunosuppressive agents including azathioprine, mycophenolate mofetil, glucocorticoids, cyclosporine, Tacrolimus (FK506), Sirolimus (Rapamycin). A combination of steroids and a low dose of mouse monoclonal antibody OKT3 binding to CD3 on T-cells is used to anergize and deplete T-cells. Therapy is continued using immunosuppressants like cyclosporine. Mouse anti-human antibodies (MAHAs) have common side effects and limit the use of OKT3 (Fauci et al., supra, pp. 2374-2381).
Approaches to treat multiple sclerosis include treatments which effect the overall immune system like anti-inflammatory agents including azathioprine, cyclophosphamide, prednisone, corticosteroids, cyclosporin A, calcineurin, Rapamycin, beta-interferon (see, e.g., Fauci et al., supra, pp. 2415-2419; Wang (2000) J. Immunol. 165:548-557). In addition, a number of non-specific treatments are administered that may improve the quality of life including physical therapy and psycho-pharmacological agents. None of the treatment options mentioned above has a curative effect. Even the most promising compound, xcex2-interferon, leads only to a slower disease progression, while exhibiting significant side effects.
Furthermore, human immunodeficiency virus-type 1 (HIV-1), the most common cause of AIDS, has infected more than 50 million individuals (including those who have died), and the rate of new infections is estimated at nearly 6 million per year (AIDS Epidemic Update: December 1999 (UNAIDS, Geneva, 1999), www.unaids.org). Equally disturbing are the uncertainties of the epidemic to come. Although sub-Saharan Africa remains the global epicenter, rates of infection have increased in recent times in the former Soviet Union and parts of south and southeast Asia, including India and China, where literally hundreds of millions of individuals are potentially at risk. In the United States, new waves of infection have been recognized in women, minorities, and younger generations of gay men. Combination antiretroviral therapy has afforded many people clinical relief, but the costs and toxicities of treatment are substantial, and HIV-1 infection remains a fatal disease. Moreover, the vast majority of infected people worldwide do not have access to these agents. Thus, although the demographics (and, in some instances, the natural history) of AIDS have changed, the epidemic is far from over; instead, it is evolving, expanding, and posing ever greater challenges.
Human immunodeficiency virus (HIV) cannot enter human cells unless it first binds to two key molecules on the cell surface, CD4 and a co-receptor. The co-receptor that is initially recognized is chemokine receptor 5 (CCR5). Later in the life cycle of the virus, another chemokine receptor, CXCR4, becomes the co-receptor for HIV-1; see, e.g., D""Souza, Nature Med. 2:1293 (1996); Premack, Nature Med. 2:1174; Fauci, Nature 384:529 (1996).
The HIV-1 strains that cause most transmissions of viruses by sexual contact are called M-tropic viruses. These HIV-1 strains, also known as NSI primary viruses, can replicate in primary CD4+ T-cells and macrophages and use the chemokine receptor 5 (CCR5), and, less often, CCR3, as their entry co-receptor. The T-tropic viruses, sometimes called SI primary, can also replicate in primary CD4+ T-cells, but can, in addition, infect established CD4+ T-cell lines in vitro, which they do via the chemokine receptor CXCR4 (fusin). Many of these T-tropic strains can use CCR5 in addition to CXCR4, and some can enter macrophages via CCR5, at least under certain in vitro conditions; see, e.g., D""Souza, Nature Med. 2, 1293 (1996); Premack, Nature Med. 2, 1174; Fauci, Nature 384, 529 (1996).
Whether other co-receptors contribute to HIV-1 pathogenesis is unresolved, but the existence of another co-receptor for some T-tropic strains can be inferred from in vitro studies. Because M-tropic HIV-1 strains are implicated in about 90% of sexual transmissions of HIV, CCR5 is the predominant co-receptor for the virus in patients; transmission (or systemic establishment) of CXCR4-using (T-tropic) strains is rare (D""Souza, Nature Med. 2, 1293 (1996); Premack, Nature Med. 2, 1174; Fauci, Nature 384, 529 (1996), Paxton, Nature Med. 2, 412 (1996); Liu, Cell 86, 367 (1996); Samson, Nature 382, 722 (1996); Dean, Science 273, 1856 (1996); Huang, Nature Med. 2, 1240 (1996)). However, once SI viruses evolve in vivo (or if they are transmitted), they are especially virulent and cause faster disease progression; see, e.g., D""Souza, Nature Med. 2, 1293 (1996); Premack, Nature Med. 2, 1174; Fauci, Nature 384, 529 (1996), Schuitemaker, J. Virol. 66, 1354 (1992); Connor, J. Virol. 67, 1772 (1993); Richman, J. Infect. Dis. 169, 968 (1994); R. I. Connor (1997) J. Exp. Med. 185:621; Trkola, Nature 384, 184 (1996).
The numbers and identity of co-receptor molecules on target cells, and the ability of HIV-1 strains to likely enter cells via the different co-receptors, seem to be critical determinants of disease progression. These factors are major influences on both host- and virus-dependent aspects of HIV-1 infection. For example, a homozygous defect (delta 32) in CCR5 correlates strongly with resistance to HIV-1 infection in vivo and in vitro. Individuals who are heterozygous for a defective CCR5 allele are not protected against infection and have only a modestly slowed disease progression (Paxton, Nature Med. 2, 412 (1996); Liu, Cell 86, 367 (1996); Samson, Nature 382, 722 (1996); Dean, Science 273, 1856 (1996); Huang (1996) Nature Med. 2:1240).
However, other factors can influence the level of CCR5 expression on activated CD4+ T-cells and thereby affect the efficiency of HIV-1 infection in vitro (Trkola, Nature 384, 184 (1996); Bleul, Proc. Natl. Acad. Sci. U.S.A. 94, 1925 (1997)). For reasons that are not yet clear, the amount of CCR5 expression on the cell surface (as measured by MIP-1 binding) varies by 20-fold on CD4+ T-cells from individuals with two wild-type CCR5 alleles (Trkola, Nature 384, 184 (1996)). Staining with a CCR5-specific monoclonal antibody indicates a similar large variability (Wu, J. Exp. Med. 186:1373-81 (1997)). Such variation may far outweigh any effect of one defective allele for CCR5. The causes of this variation should be the subject of intensive studies, as they point to controllable factors that could increase resistance to disease.
Most primary, clinical isolates of primate immunodeficiency viruses use the chemokine receptor CCR5 for entry (see, e.g., Feng, Science 272, 872 (1996); Choe, Cell 85, 1135 (1996); Deng, Nature 381, 661 (1996); Dragic et al., Nature 381, p. 667; Doranz, Cell 85, 1149 (1996); Alkhatib, Science 272, 1955 (1996)). For most HIV-1 isolates that are transmitted and that predominate during the early years of infection, CCR5 is an obligate co-receptor, and rare individuals that are genetically deficient in CCR5 expression are relatively resistant to HIV-1 infection (see, e.g., Connor, J. Exp. Med. 185, 621 (1997); Zhang, Nature 383, 768 (1996); Bjxc3x6rndal, J. Virol. 71, 7478 (1997); Dean, Science 273, 1856 (1996); Liu, Cell 86, 367 (1996); Paxton, Nature Med. 2, 412 (1996); Samson, Nature 382, 722 (1996)). HIV-1 isolates arising later in the course of infection often use other chemokine receptors, frequently CXCR4, in addition to CCR5. Studies of chimeric envelope glycoproteins demonstrated that the third variable (V3) loop of gp 120 is a major determinant of which chemokine receptor is used as a viral entry co-receptor (see, e.g., Cocchi, Nature Med. 2, 1244 (1996); Bieniasz, EMBO J. 16, 2599 (1997); Speck, J. Virol. 71, 7136 (1997)). V3-deleted versions of gp120 do not bind CCR5, even though CD4 binding occurs at wild-type levels. Antibodies to the V3 loop interfere with gp120-CCR5 binding (see, e.g., Trkola, Nature 384, 184 (1996); Wu, Nature 384, 179 (1996); Lapham, Science 274, 602 (1996); Bandres, J. Virol. 72, 2500 (1998); Hill, Science 71, 6296 (1997)). These results support an involvement of the V3 loop in chemokine receptor binding.
Latency of HIV is established very early in the course of an infection, when M-tropic strains predominate. M-tropic strains depend on the presence of CCR5 on the target cell for infection. The importance of CCR5 as an essential co-receptor for M-tropic HIV-1 is emphasized by the fact that individuals lacking CCR5 due to a homozygous 32 base pair deletion (delta32) are highly resistant to HIV-1 infection. In contrast to other markers like CD4 or CD45RO, CCR5 is only present on a subset of lymphocytes and other cells that are prone to HIV-1 infection (Rottmann (1997) Am. J. Pathol. 151:1341-1351; Naif (1998) J. Virol. 72:830-836; Lee (1999) Proc. Natl Acad. Sci. USA 96:5315-5220).
Several approaches have been postulated to eliminate latent infected cells. One strategy is to drive the latently infected cells to virus production and subsequent cell death. In this context, one approach is IL-2 (or TNF-alpha or IL-6) administration in the presence of HAART until the viral reservoir is exhausted (Chun (1998) J. Exp. Med. 188, 83-91; Chun (1999) Nat. Med. 5, 651-655; Stellbrink (1999) Abstracts of the 6th Conference on Retroviruses and Opportunistic Infections (Foundation for Retrovirology and Human Health, Alexandria, Va.), abstr. 356. p. 135; Imamichi (1999) Abstracts of the 6th Conference on Retroviruses and Opportunistic Infections (Foundation for Retrovirology and Human Health, Alexandria, Va.), abstr. 358, p. 135). These cells are believed to die after activation. Whether the entire pool of latent infected cells can be exhausted is questionable.
Another strategy tried was to specifically kill latently infected cells based on gp-120 expression on the cell surface. Immunotoxins recognizing gp-120 have been proposed but failed for two reasons. The one construct tested in humans was a protein consisting of soluble CD4 linked to Pseudomonas aeroginosa exotoxin A (PE). The clinical results were disappointing due to dose-limiting hepatotoxicity without showing signs of efficacy and the program was terminated (Ashorn (1990) Proc. Natl Acad. Sci 87, 8889-8893; Berger (1998) Proc. Natl Acad. Sci. 95, 11511-11513). The second reason for failure was that latent infected cells do not express viral surface glycoproteins, e.g. gp-120 and gp-41. Thus, approaches targeting gp-120 or gp-41 for the elimination of latently infected cells cannot work.
Other approaches to eliminate latent infected cells are based on eliminating the entire CD4+ T-cell compartment (Berger (1998) Proc. Natl Acad. Sci. 95, 11511-11513), or the CD25-positive compartment (Bell (1993) Proc. Natl Acad. Sci. 90, 1411-1415), or the CD45RO memory cell compartment (McCoig (1999) Proc. Natl. Acad. Sci 96, 11482-11485). However these markers do not adequately include all potentially infected cells. Such cells also include, besides CD4-positive cells, macrophages, and non-hematopoietic cells.
In Wu, et al., WO 98/18826, an antibody directed against the mammalian (e.g. human) chemokine receptor 5 (CCR5) is described and said antibody is proposed in a method of inhibiting the interaction of cell bearing CCR5 with a potential ligand, like HIV. It is proposed that said method inhibits an HIV infection. Furthermore, treatment options for inflammatory diseases, autoimmune diseases and graft rejection are proposed. Yet, all these treatment options are based on the assumption that specific antibodies, like the immunoglobulin molecules themselves, or functional portions thereof, interfere with receptor-ligand interactions. However, whether these antibodies are capable of depleting the relevant cells is questionable. Furthermore, WO 98/18826 merely envisages the prevention of an interaction of HIV and the CCR5 receptor and thereby preventing an HIV infection.
Leukocytes, in particular T-cells, are believed to be the key regulators of the immune response to infective agents and are critical components for the initiation and maintenance of inflammatory processes, like inflammatory bowel disease inflammatory renal diseases, inflammatory joint disease, autoimmune disorders, like multiple sclerosis and arthritis, skin diseases, like psoriatic lesions, diabetes and in transplant rejection.
Thus, there exists a need for novel means and methods which can lead to the suppression of activated leukocytes involved in immunological pathologies, like autoimmune diseases, inflammation process and/or viral infections of immune cells. The present invention fulfills this and other needs.
The invention provides a chimeric polypeptide, e.g., a bispecific antibody, comprising a first polypeptide domain comprising at least one moiety that specifically binds to a chemokine receptor; and, a second polypeptide domain comprising at least one moiety that specifically binds to a T cell surface polypeptide or a cell toxin, or, a cell toxin. In one aspect of the invention, the chemokine receptor is a chemokine receptor 5 (CCR5), such as a human chemokine receptor 5 (CCR5). In one aspect, the moiety that specifically binds to the chemokine receptor 5 (CCR5) can comprise a RANTES (xe2x80x9cregulated on activation normal T cell expressed and secretedxe2x80x9d) polypeptide, or a fragment thereof capable of binding to a CCR5 receptor. Alternatively, the moiety that specifically binds to the CCR5 chemokine receptor can comprise a MIP-1xcex1, or a fragment thereof capable of binding to a CCR5 receptor. In another aspect, the moiety that specifically binds to the CCR5 chemokine receptor can comprise a MIP-1xcex2, a MCP-2, or a MCP-3 or a fragment thereof, capable of binding to the CCR5 receptor.
In one aspect of the chimeric composition of the invention, the moiety that specifically binds to the chemokine receptor comprises an IP-10 (CXCL-10) (see, e.g., Agostini (2001) Am. J. Pathol. 158:1703-1711; Flier (1999) J. Invest. Dermatol. 113:574-578), or a Mig (CXCL9) (see, e.g., Farber (1997) J. Leukoc. Biol. 61:246-257), or an I-TAC (CXCL11) chemokine ligand (see, e.g., Gasperini (1999) J. Immunol. 162:4928-4937), or a fragment thereof (see Table IV), capable of binding to the CXCR3 chemokine receptor.
In alternative aspects, the chemokine receptor is CXCR4 (see, e.g., Vila-Coro (1999) FASEB J. 13:1699-1710), CXCR5 (see, e.g., Legler (1998) J. Exp. Med. 187:655-660), CXCR6 (see, e.g., Luttichau (2001) Eur. J. Immunol. 31:1217-1220), CCR1 (see, e.g., Hesselgesser (1998) J. Biol. Chem. 273:15687-15692), CCR2 (see, e.g., Monteclaro (1997) J. Biol. Chem. 272:23186-23190), CCR3 (see, e.g., Dairaghi (1997) J. Biol. Chem. 272:28206-28209), CCR4 (see, e.g., Imai (1997) J. Biol. Chem. 272:15036-15042), CCR5 (see, e.g., Ganju (2000) J. Biol. Chem. 275:17263-17268), CCR6 (see, e.g., Baba (1997) J. Biol. Chem. 272:14893-14898), CCR7 (see, e.g., Kim (1999) Cell Immunol. 193:226-235), CCR8 (see, e.g., Roos (1997) J. Biol. Chem. 272:17251-17254), CCR9 (see, e.g., Norment (2000) J. Immunol. 164:639-648), CCR10 (see, e.g., Bonini (1997) DNA Cell Biol. 16:1249-1256), XCR1 (GPR5) (see, e.g., Shan (2000) Biochem. Biophys. Res. Commun. 268:938-941), or CX3CR1 (see, e.g., Combadiere (1998) Biochem. Biophys. Res. Commun. 253:728-732); see Table IV, which includes the corresponding chemokine ligands. The T cell surface polypeptide can comprise a CD3 polypeptide.
In one aspect, the chimeric composition of the invention comprises a cell toxin, or a fragment or domain thereof that remains toxic to cells. The cell toxin can comprise a Pseudomonas exotoxin, or toxic fragment thereof. The Pseudomonas exotoxin can comprise a PE38 exotoxin, a PE40 exotoxin or a PE37 exotoxin. Alternatively, the cell toxin can comprise a diptheria toxin. The cell toxin can be non-covalently or covalently, directly or indirectly, attached or associated with the chimeric composition. In one aspect, the toxin is cross-linked to the chimeric polypeptide. Alternatively, the toxin can comprise a recombinant fusion protein, as all or a portion of the chimeric polypeptide can comprise a recombinant protein, e.g., it can be a fusion protein. In one aspect, the moiety that specifically binds to a chemokine receptor comprises an antigen binding domain derived from an antibody that specifically binds to the chemokine receptor. The moiety that specifically binds to a T cell surface polypeptide can comprise an antigen binding domain derived from an antibody that specifically binds to the T cell surface polypeptide. The moiety that specifically binds to a cell toxin can comprise an antigen binding domain derived from an antibody that specifically binds to the cell toxin.
The invention also provides a recombinant fusion protein comprising a first polypeptide domain comprising at least one moiety that specifically binds to a chemokine receptor; and, a second polypeptide domain comprising at least one moiety that specifically binds to a T cell surface polypeptide or a cell toxin, or, a cell toxin.
The invention also provides a bispecific antibody comprising a first antigen binding domain that specifically binds to a chemokine receptor; and, a second antigen binding domain that specifically binds to a T cell surface polypeptide, a cell toxin, or a third antigen binding domain that specifically binds to or is linked to a T cell surface polypeptide or a cell toxin. The bispecific antibody is not limited to two binding domains. The T cell surface polypeptide can comprise a CD3 antigen.
In one aspect of the bispecific antibody of the invention, the bispecific antibody is a single chain antibody construct. The single chain antibody construct can comprise a VL and a VH domain capable of specifically binding the chemokine receptor and a VH and a VL domain capable of specifically binding a T cell surface polypeptide. In one aspect, the antigen binding domain that specifically binds to a chemokine receptor can comprise a murine anti-human CCR5 antibody MC-1. In one aspect, the VL and VH domains are arranged in the order VL(MC-1)-VH(MC-1)-VH(CD3)-VL(CD3). The VL(MC-1) domain can comprise an amino acid sequence as set forth in SEQ ID NO:12. The VH(MC-1) domain can comprise an amino acid sequence as set forth in SEQ ID NO:16. The VH(CD3) domain can comprise an amino acid sequence as set forth in SEQ ID NO:26. The VL(CD3) domain can comprise an amino acid sequence as set forth in SEQ ID NO:28. The amino acid sequence of the bispecific antibody can be encoded by a nucleic acid as set forth in SEQ ID NO: 17, or comprising an amino acid sequence as set forth in SEQ ID NO: 18.
In one aspect of the bispecific antibody, the second antigen binding domain specifically binds to a cell toxin, or, the second antigen binding domain specifically binds to another domain (e.g., an antibody) that can specifically bind a toxin (or a cell surface protein). Alternatively, the antibody is covalently bound (directly or indirectly) to a cell toxin. The antibody can be bound to a second antibody that binds to a CD3 antigen or a cell toxin.
The invention provides a nucleic acid encoding a chimeric polypeptide (e.g., a bispecific antibody) comprising a first polypeptide domain comprising at least one moiety that specifically binds to a chemokine receptor; and, a second polypeptide domain comprising at least one moiety that specifically binds to a T cell surface polypeptide or a cell toxin, or, a cell toxin.
The invention provides a vector comprising a nucleic acid encoding a chimeric polypeptide (e.g., a bispecific antibody) comprising a first polypeptide domain comprising at least one moiety that specifically binds to a chemokine receptor; and, a second polypeptide domain comprising at least one moiety that specifically binds to a T cell surface polypeptide or a cell toxin, or, a cell toxin.
The invention provides a transformed cell comprising a nucleic acid encoding a chimeric polypeptide (e.g., a bispecific antibody) comprising a first polypeptide domain comprising at least one moiety that specifically binds to a chemokine receptor; and, a second polypeptide domain comprising at least one moiety that specifically binds to a T cell surface polypeptide or a cell toxin, or, a cell toxin.
The invention provides a pharmaceutical composition comprising a chimeric polypeptide of the invention, a nucleic acid of the invention, or a vector of the invention, or a transformed cell of the invention; and, a pharmaceutically acceptable excipient.
The invention provides a kit comprising a chimeric polypeptide (e.g., a bispecific antibody) of the invention, a nucleic acid of the invention, a vector of the invention, a transformed cell of the invention, or a pharmaceutical composition of the invention. The kit can further comprise pharmaceutically acceptable excipients. The kits can further comprise instructions on the specific uses of the pharmaceuticals of the invention, as set forth herein. The kit can further comprise ancillary or other drugs, e.g., where the kit is intended to be used to treat HIV-1 (e.g., AIDS), drugs employed in HAART also can be included in the kit.
The invention provides a use of a chimeric polypeptide (e.g., a bispecific antibody) or a nucleic acid of the invention (e.g., a vector of the invention) to prepare a pharmaceutical composition for the elimination of cells that are latently infected with a primate (e.g., human) immunodeficiency virus, e.g., HIV-1, or a lentivirus.
The invention provides a use of a chimeric polypeptide (e.g., a bispecific antibody) or a nucleic acid of the invention (e.g., a vector of the invention) to prepare a pharmaceutical composition for the treatment of an immunological disorder, such as an autoimmune disease, an allergic disease, a skin disease, an inflammatory disease, diabetes, graft versus host disease and transplant rejections. In alternative aspects, the autoimmune disease is, e.g., multiple sclerosis, type I diabetes and rheumatoid arthritis. In alternative aspects, the skin disease is a skin inflammation, an atopic dermatitis and psoriasis. In alternative aspects, the inflammatory disease is an inflammatory joint disease, such as arthritis (e.g., chronic arthritis), an inflammatory renal disease and an inflammatory bowel disease.
The invention provides a method for eliminating a cell infected with a primate immunodeficiency virus comprising administering a composition comprising a chimeric polypeptide (e.g., a bispecific antibody) or a nucleic acid of the invention (e.g., a vector of the invention), in amounts sufficient to kill the cell. In one aspect, the primate immunodeficiency virus is a human immunodeficiency virus, such as HIV-1. The cell can be infected (e.g., latently infected) with a pathogen, e.g., a virus, such as a primate immunodeficiency virus.
The invention provides a method for the treatment of a primate immunodeficiency virus comprising the following steps: (a) providing a pharmaceutical composition comprising a chimeric polypeptide (e.g., a bispecific antibody) or a nucleic acid of the invention (e.g., a vector of the invention), (b) administering the pharmaceutical composition in amounts sufficient to treat the primate immunodeficiency virus. The treatment can further comprise administration of other drugs, e.g., those employed in HAART, or other treatments.
The invention provides a method for the treatment of an inflammatory renal disease comprising the following steps: (a) providing a pharmaceutical composition comprising a chimeric polypeptide (e.g., a bispecific antibody) or a nucleic acid of the invention (e.g., a vector of the invention), (b) administering the pharmaceutical composition in amounts sufficient to treat the inflammatory renal disease.
The invention provides a method for the treatment of an allergic reaction comprising the following steps: (a) providing a pharmaceutical composition comprising a chimeric polypeptide (e.g., a bispecific antibody) or a nucleic acid of the invention (e.g., a vector of the invention), (b) administering the pharmaceutical composition in amounts sufficient to treat the allergic reaction.
The invention provides a method for the treatment of an inflammatory bowel disease comprising the following steps: (a) providing a pharmaceutical composition comprising a chimeric polypeptide (e.g., a bispecific antibody) or a nucleic acid of the invention (e.g., a vector of the invention), (b) administering the pharmaceutical composition in amounts sufficient to treat the inflammatory bowel disease.
The invention provides a method for the treatment of multiple sclerosis comprising the following steps: (a) providing a pharmaceutical composition comprising a chimeric polypeptide (e.g., a bispecific antibody) or a nucleic acid of the invention (e.g., a vector of the invention), (b) administering the pharmaceutical composition in amounts sufficient to treat the multiple sclerosis.
The invention provides a method for the treatment of a skin disease comprising the following steps: (a) providing a pharmaceutical composition comprising a chimeric polypeptide (e.g., a bispecific antibody) or a nucleic acid of the invention (e.g., a vector of the invention), (b) administering the pharmaceutical composition in amounts sufficient to treat the skin disease.
The invention provides a method for the treatment of diabetes comprising the following steps: (a) providing a pharmaceutical composition comprising a chimeric polypeptide (e.g., a bispecific antibody) or a nucleic acid of the invention (e.g., a vector of the invention), (b) administering the pharmaceutical composition in amounts sufficient to treat the diabetes.
The invention provides a method for the treatment of a transplant rejection comprising the following steps: (a) providing a pharmaceutical composition comprising a chimeric polypeptide (e.g., a bispecific antibody) or a nucleic acid of the invention (e.g., a vector of the invention), (b) administering the pharmaceutical composition in amounts sufficient to treat the transplant rejection.
The invention provides a method for the treatment of inflammatory joint disease comprising the following steps: (a) providing a pharmaceutical composition comprising a chimeric polypeptide (e.g., a bispecific antibody) or a nucleic acid of the invention (e.g., a vector of the invention), (b) administering the pharmaceutical composition in amounts sufficient to treat the inflammatory joint disease. The inflammatory joint disease can comprise arthritis, such as rheumatoid arthritis.
The invention provides a method of making a chimeric composition that can bind to a chemokine receptor and a cell toxin comprising the following steps: (a) providing a first polypeptide comprising at least one moiety that specifically binds to a chemokine receptor and at least one moiety that specifically binds to a second polypeptide comprising an antigen binding domain, wherein the antigen comprises a cell toxin, and a compound comprising a cell toxin; (b) contacting the first and second polypeptide with the compound in vivo or in vitro under conditions wherein the first polypeptide specifically binds to the second polypeptide, and the second polypeptide specifically binds to the compound, thereby making the chimeric composition.
The invention provides a method of making a chimeric composition that can bind to a chemokine receptor and a T cell surface antigen comprising the following steps: (a) providing a first polypeptide comprising at least one moiety that specifically binds to a chemokine receptor and at least one moiety that specifically binds to a second polypeptide comprising an antigen binding domain, wherein the antigen comprises a T cell surface antigen binding domain; (b) contacting the first polypeptide with the second polypeptide in vivo or in vitro under conditions wherein the first polypeptide specifically binds to the second polypeptide, thereby making a chimeric composition. The T cell surface antigen can comprise a CD3 antigen.
The chimeric composition can further comprise a cell toxin covalently bound to the chimeric composition. The cell toxin can be a truncated sequence, e.g., a domain, that remains toxic to the cell, e.g., a Pseudomonas exotoxin A (PE38).
The present invention relates to the use of an antibody and/or a chemokine construct which binds to a chemokine receptor. These compositions are used to eliminate cells that are latently infected with a primate immunodeficiency virus; accordingly, the invention is also directed to pharmaceuticals comprising these compositions. The invention is also directed to use of these compositions for the preparation pharmaceutical compositions. The pharmaceutical compositions and methods using these pharmaceuticals for the treatment, prevention and/or alleviation of inflammatory renal diseases, inflammatory joint diseases, inflammatory bowel diseases, multiple sclerosis, skin diseases, diabetes or transplant rejection.
Furthermore, the invention relates to antibody constructs and/or chemokine constructs, in particular, to constructs wherein said antibody construct comprises a binding site for a chemokine receptor 5 (CCR5) and a binding site for CD3, wherein said chemokine construct comprises RANTES (xe2x80x9cregulated on activation normal T cell expressed and secretedxe2x80x9d) and a toxin. The invention also describes polynucleotides encoding said antibody or chemokine constructs, and vectors and hosts comprising said nucleic acid molecules. Additionally, the present invention relates to compositions comprising said antibody constructs, chemokine constructs, polynucleotides, vectors and/or hosts. The composition can be a pharmaceutical composition. Described is also the use of antibody constructs, the chemokine constructs, the polynucleotides, the hosts and/or the vectors for the preparation of a pharmaceutical composition for treating, preventing and/or alleviating an immunological disorder or for eliminating latently infected cells, wherein said cells are infected with a primate immunodeficiency virus, like HIV-1.
The present invention also relates to a method for treating, preventing and/or alleviating an immunological disorder or for the elimination cells that are latently infected with a primate immunodeficiency virus, such as HIV-1. Furthermore, the invention provides for a kit comprising the compounds of the invention. The kit can also include instructions on the use of pharmaceuticals in the kit.
Several documents are cited throughout the text of this specification. Each of the documents cited herein (including any manufacturers specifications, instructions, etc.) and all publications, patents, patent applications, GenBank sequences and ATCC deposits, cited herein are hereby expressly incorporated by reference for all purposes.

Bispecific antibody and chemokine receptor constructs


This invention discloses a method for preparing rubber compositions that exhibit unique combinations of properties that are desirable for tire tread applications for enhanced snow/ice and wet traction, low rolling resistance and increased treadwear performance in comparison with conventional silica compounds. Specifically, a high reactively silane coupling agent, such as a mercaptosilane, is used in combination with a silane coupling typically used for silica tread compounds such as bis(triethoxylsilylpropyl)disulfide to treat silica pellets in a hydrocarbon solvent at elevated temperatures. The treated silica is then blended with solution elastomer cement in a hydrocarbon solvent. The deposited reactive silanes partially react with the elastomer molecules forming a layer of polymer grafted on the silica surfaced. This structure significantly improves the silica retention during the steam stripping operation. Almost 100% (99+%) silica retention has been achieved by this invention. After solvent removal from steam stripping, the treated silica/elastomer mixer is dewatered and dried using conventional equipment such as shaker screens, expellers and expanders to form a well-dispersed silica masterbatch. This technique results in silica compounds with excellent silica dispersion and increased filler-polymer interaction, hence enhanced compound performance such as better physical properties, more desirable dynamic properties (low hysteresis at high temperatures and high hysteresis at low temperatures) and increased abrasion resistance.

In recent years, a considerable interest in silica reinforced rubber articles, such as tires, has developed. For instance, U.S. Pat. No. 5,227,425 indicates that tires made with tread formulations that contain silica exhibit a number of important performance advantages over tires manufactured using carbon black as the filler. The utilization of silica in tire tread formulations is believed to (a) lower rolling resistance, (b) provide better traction on snow, and (c) lower noise generation, when compared with conventional tires filled with carbon black.
U.S. Pat. No. 5,227,425 discloses a sulfur-vulcanizable rubber composition obtained by thermomechanical work of a conjugated diene compound and an aromatic vinyl compound prepared by solution polymerization in a hydrocarbon solvent having a total content of aromatic vinyl compound of between 5% and 50% and a glass transition temperature (Tg) of between 0° and −80° C. with 30 to 150 parts by weight per 100 parts by weight of elastomer of a silica having a BET surface area of between 100 and 250 m2/g, a CTAB surface area of between 100 and 250 m2/g, an oil absorption measured in DBP of between 150 and 250ml/100 g, and an average projected area of the aggregates greater than 8500 nm2 before use and between 7000 and 8400 nm2 after thermomechanical mixing as well as the additives conventionally employed, with the exception of the sulfur vulcanization system, comprising at least one heat step reaching a temperature of between 130° C. and 180° C. for a suitable period of time of between 10 seconds and 20 minutes which is a function of the temperature selected in order to carry out the mechanical work and of the nature and volume of the components subjected to the mechanical work, followed by a finishing step consisting of the incorporating of the vulcanization system by mechanical work at a temperature below the vulcanization temperature.
Sometimes rubber for tires is supplied by a rubber producer to a tire manufacturer in the form of a masterbatch containing an elastomer, an oil extender, and a filler. The traditional filler has been carbon black in the form of fine particles. These particles have hydrophobic surface characteristics and will therefore disperse easily within the hydrophobic elastomer. In contrast, silica has a very hydrophilic surface and considerable difficulty has been encountered in dispersing silica in the hydrophobic rubbery elastomer.
A number of techniques have been developed to incorporate such reinforcing agents and fillers into the polymer compositions, including both wet and dry blending processes. The incorporation of silica and carbon black as reinforcing agents and/or fillers into rubbery elastomers is far more complex than one might initially believe. One problem in wet blending of silica with latices of such polymers arises from the fact that the hydrophilic silica has a tendency to associate with the aqueous phase and not blend uniformly with the hydrophobic polymer.
To overcome the problems associated with the hydrophilic nature of the silica, U.S. Pat. No. 3,317,458 proposed a process whereby an aqueous solution of silicic acid was treated so as to precipitate silica directly onto the surface of an aqueous carbon black in paste form. One significant limitation of this technique is that the surface of the carbon black is altered thus obviating the utility of the many surface structure characteristics of specialty carbon blacks available to the skilled compounder in designing filled, reinforced polymers for specific end uses.
Attempts have been made to use cationic emulsifiers in an effort to distribute such fillers and/or reinforcing agents in polymeric lattices; notably among them are quaternary alkylated ammonium halides (see German Patent No. 1,188,797). It has been found, however, that such quaternary ammonium compounds have a tendency to react with the carbon black, dispersing it into the aqueous phase; that limiting the ability to blend carbon black with the polymeric components in the latex. In U.S. Pat. No. 3,686,113 aqueously wet silica is treated with oleophilic quaternary ammonium compounds to blend with an aqueous dispersion of an elastomer containing an anionic dispersing agent. In addition to the problem referenced above with carbon black dispersion, unfortunately, such techniques require specific coagulating agents.
Perhaps the most commonly employed practice, used commercially, is the technique of dry blending either silica, carbon black or both of them into rubber and thermoplastic polymers in a high-shear milling operation. That practice has many limitations. Notable among them include the tendency of the filler particles to agglomerate to each other, resulting in nonuniform dispersion of the filler throughout the polymer constituting the continuous phase. Another problem commonly experienced in such high-shear milling operations is the tendency of the polymers to degrade during milling. That necessitates the use of higher molecular weight polymers, which sometimes require the incorporation of various types of processing aids to facilitate mixing and dispersion of the filler particles into the polymer constituting the continuous phase. The cost associated with the use of such processing aids also increases the manufacturing cost of the polymeric compound or article and can lead to diminished product performance. The use of processing aids has the further disadvantage in that such processing aids may have a negative effect on the cure or end use of the polymer. Such dry blending techniques also result in additional processing costs, in part due to excessive equipment wear caused by the abrasive fillers.
To improve dispersion of the silica during dry mixing, it has been proposed that such compounding operations employ a silica which has been treated with an organosilane coupling agent having dual functionality. Representative of such coupling agents are those well known compounds that include both an organic group, such as an amino alkyl group, a mercaptoalkyl group, or a polysulfidic-bis-organo alkoxy silane group bonded directly to the silicon atom along with a readily hydrolyzable group, such as an alkoxy group as represented by a methoxy group or an ethoxy group, likewise bonded directly to the silicon atom. In those systems, it is generally recognized that the alkoxy group hydrolyzes in the presence of moisture typically found on the surface of the silica to form the corresponding silanol which reacts with or condenses in the presence of the silica surface to bond the silicon atom to the silica surface. The organic groups likewise attached to the silicon atom are thus available for chemical reaction with the polymer matrix during vulcanization. As a result, the polymer matrix may become chemically bonded by means of the coupling agent to the silica surface during cure or vulcanization of the polymer. Problems associated with the use of such silanes during compounding are unpleasant odors, premature curing, and/or scorching.
In an effort to overcome the problems associated with the use of silane coupling agents, it has been proposed in U.S. Pat. No. 5,405,897 to employ phenoxy acidic acid along with a methylene donor in place of the conventional organosilanes. The foregoing patent suggests that the use of such a system provides improved physical properties and reduced viscosity of the melt during compounding.
Various other attempts have been made to overcome the problems associated with wet blending such fillers and/or reinforcing agents with polymer latices. For example, it has been proposed, as described in U.S. Pat. No. 3,055,956 and U.S. Pat. No. 3,767,605 to add carbon black in the form of a slurry directly to an emulsion polymerization process of rubbery polymer, at the latex stage, followed by coagulation and recovery of a rubber-carbon black masterbatch. Such processes work well with carbon black, but fail to incorporate substantial amounts of fine particulate silica. U.S. Pat. No. 4,481,329 proposes a process for dispersing carbon black and like fillers into concentrated rubber latices by the use of a low molecular weight conjugated diene/carboxylic acid polymer in the form of an alkali metal salt dissolved in water as the dispersing aid or dispersing latex.
U.S. Pat. No. 4,482,657 describes mixtures of silica and synthetic polymers prepared by treating a polymer latex with a dispersion of silica and an alkyl trimethyl ammonium halide in water. The presence of a quaternary ammonium halide in this process necessitates the slow addition of the silica dispersion to prevent premature coagulation. Other elaborate techniques as described in U.S. Pat. No. 3,907,734 where a partitioning agent in the form of a blend of precipitated silica and hydrophobic fumed silica are incorporated into a concentrated polymer latex have been suggested. The fumed silica adsorbs the water, and the resulting solid mixture is dried with removal of the hydrophobic fumed silica to form a free flowing blend of polymer particles coated with precipitated silica. That process is limited to relatively small scale batch system and requires recovery and recycle of the hydrophobic fumed silica. That process fails to incorporate into the polymer the more desirable hydrophobic fumed silica.
Such processes with concentrated latex, as those skilled in the art can readily appreciate, involve complex procedures not only blending the silica with the polymer latex, but also in effecting its recovery when excess silica or carbon black must be employed. Another limitation of such processes is that recovery of the filled polymer directly from the latex stage without filtration and like treatment steps used to remove byproducts from the emulsion polymerization can have deleterious effects on the end use properties of the polymer thus recovered. Such problems can be seen in French Patent 2,558,008 and French Patent 2,558,874. In the first, the addition to a rubber latex of precipitated silica effects coagulation of the rubber polymer. In the second, a stable latex of derivatized silica and a carboxylated butadiene rubber is prepared to add to natural or synthetic elastomer latices. The derivatization of the silica is accomplished by treatment with polyamines, polyethylene amines or nonionic polyoxyethylene. Such free agents are wholly incompatible with typical coagulation techniques used in the recovery of the emulsion process polymers.
It is well known that mercaptosilanes offer excellent coupling between rubber and silica, resulting in rubber compounds for tire treads with improved wet and ice skid resistance, rolling resistance and treadwear even at low loadings. For instance, U.S. Pat. No. 3,768,537 demonstrates the excellent compound properties that can be attained by the use of mercaptosilanes in silica loaded rubber compounds. However, as revealed by U.S. Pat. No. 6,433,065, the high reactivity of mercaptosilanes makes it impractical to use such silane coupling agents in applications where conventional Banbury mixing is employed. In cases where mercaptosilane coupling agents are used in silica compounds it is important to maintain a low temperatures (120° C. to 145° C.) to avoid premature crosslinking which proves to be a problem at higher temperatures. However, low mixing temperatures result in a marked reduction in the mechanical efficiency of mixing that is essential for an optimum dispersion of the silica. The longer mixing time at a low temperature results in a significant reduction in mixing productivity which in turn increases expense. Another drawback of using low temperatures for mixing without extended mixing duration is that less completed silanization occurs which results in the release of ethanol in downstream operations giving rise to porosity from the extrudate and reduced extrusion rates.
Using a combination of two silane coupling agents in silica compounds has been suggested in the patent literature. U.S. Pat. No. 6,306,949 discloses the use of a combination of an organosilane disulfide and an organosilane tetrasulfide for silica compounds for enhanced processibility and improved compound properties. In such a process, the organosilane disulfide coupling agent is introduced during the non-productive stage of the mixing so that higher mixing temperatures can be used to mix the silica compounds to ensure a better dispersion of silica throughout the rubber compound. The organosilane tetrasulfide is introduced during the productive stage where the mixing temperature is low (100° C. to 120° C.) so that scorch of the compounds from premature crosslinking can be avoided. However, the very low temperature and short duration during the final pass of the mixing will not ensure sufficient silanization of the organosilane tertrasulfide in the silica compounds during compounding. Since the rate of silanization for tertrasulfide-type silane coupling agents is very low at a temperature lower than 120° C., ethanol is accordingly released during downstream operations, such as extrusions and curing.
U.S. Pat. No. 6,433,065 teaches the use of a small amount of a mercaptosilane coupling agent in combination with an allyl alkoxysilane for silica or silica/carbon black compounds in Banbury mixing. It is claimed that very high temperature mixing (170° C. to 185° C.) can be conducted without causing premature crosslinking of the compounds. U.S. Pat. No. 6,608,145 discloses the use of a small quantity of a organosilane tetrasulfide, bis(triethoxylsilylpropyl)tetrasulfide (TESPT) in combination with an allyl alkoxysilane. It is again claimed that very high temperatures (165° C. to 200° C.) could be used to mix silica or silica/carbon black compounds by Banbury mixing without causing premature crosslinking of the compounds. However, having a non-coupling silane (allyl alkoxysilane) in the silica compounds is not expected to enhance the interaction between silica and the polymeric chain, hence the performance of the silica compounds. U.S. Pat. No. 6,433,065 and U.S. Pat. No. 6,608,145 do not teach the use of mercaptosilane, singly or in combination with allyl alkoxysilane, for the preparation of silica masterbatches in a solvent system.
Different approaches are disclosed in the patent literature for the preparation of silica masterbatches. U.S. Pat. No. 5,985,953 reveals the preparation of emulsion styrene-butadiene rubber (e-SBR) based silica masterbatches. U.S. Pat. No. 6,433,064 discloses a rubber composition based on emulsion styrene-butadiene rubber and a two step process for making such a composition. U.S. Pat. No. 6,407,153, U.S. Pat. No. 6,420,456, and U.S. Pat. No. 6,323,260 describe processes by which silica particles are first treated with a compound containing amino and silane groups, followed by treatment with a silane compound containing a hydrophobic group. Similarly, U.S. Pat. No. 6,537,612 discloses a process through which the silica particles are treated with different chemical species to render the silica surface hydrophobic. The treated silica is then mixed with solution styrene-butadiene rubber or polybutadiene rubber cement to make elastomer masterbatches. However, an aqueous silica slurry is the starting material for the preparation of the silica masterbatch in all those approaches. Either the silica slurry is prepared by mixing water with silica or an aqueous silica slurry from the precipitated silica production process which is used directly in making silica masterbatches. Silica slurries are used in those approaches on the basis of the conventional thinking that because of the hydrophilic nature of silica, water would be the ideal medium for the treatment of the silica in the preparation of silica masterbatches.
It is well known to those skilled in the art that it is difficult for the silane coupling agents to react directly with silica in an aqueous medium. Hence, transfer agents are disclosed in U.S. Pat. No. 6,465,670 and French Patent 2,804,119 to increase the chance for the silane coupling agent to react with the silica surface. U.S. Pat. No. 6,407,153 and U.S. Pat. No. 6,420,456 disclose the use of amino silane with alkyl terminations before introducing silane coupling agents. In addition to being a more complex process, the introduction of other chemical species prior to silane coupling agents render some of the reactive sites on the silica surface unavailable for the silanization process.
U.S. Pat. No. 6,025,415 discloses a process through which silica powder could be rendered water-repellent and the dried water-repellent silica could be incorporated into solution elastomer cements in an organic solvent.
The size of the rubber crumb and the absence of fines in the rubber/water mixer from steam stripping operations are important parameters for successful down stream operations, such as dewatering using a shaker screen and an expeller and drying using an expander. U.S. Pat. No. 6,323,260 reveals that the speed of the agitation during the steam stripping operation needs to be reduced to ensure a relative large size of the crumb. However, reducing the speed of the agitation during the steam stripping operation also significantly reduce the efficiency of the steam stripping operation to remove organic solvents.


Methods and systems are disclosed that relate to the nondestructive erasure of data in a data storage system. An exemplary method includes providing a program that can generate instructions, which may be interpreted by the back end of the data storage system, to overwrite data on a disk drive.

A data storage system may be a significant asset. For example, a company may use a data storage system to store a large amount of information, some of which may be sensitive to the company and/or its customers. Similarly, a government organization or contractor may use a data storage system to store classified information. The user of a data storage system generally wants its data storage system to store its data reliably.
Nonetheless, there may be circumstances in which a user no longer wants to use its data storage system, or components thereof, to store its data. For instance, a user may want to upgrade disk drives within its data storage system. Similarly, a user may want to upgrade its storage system as a whole. The data on the old data storage system or components may then become a liability because its presence limits the extent to which the old system or components may be reused.
A user generally does not want its information to be available to others. Privacy and other legal or business concerns may obligate a user to ensure that access to its information is controlled. If the data storage system did not contain the user's information, a user may be able to sell or repurpose its data storage system without concern for the disclosure of its data. Similarly, if components of the data storage system did not contain the user's information, a user may be able to sell or repurpose the components without concern for the disclosure of data.
EMC Corp. has used a host-based kit—including a processor, a monitor, a keyboard, a communications link, and special software—to enable users of EMC's Clariion system to erase data contained thereon. A small number of these kits were built. Each kit weighs about 300 pounds and must be shipped to the site of the Clariion system prior to its use. Once on site, the kit requires special physical set-up and configuration of the target data storage system prior to the kit's use. The kit communicates with the front end of a Clariion system to erase data contained in the Clariion system. Thus, any instructions from the kit must be interpreted by both the front end and the back end of the system, before any persistent memory device is acted upon. Erasure time ranges from 2 to 72 hours depending on the data storage capacity of the entire system. EMC offers no certification of the erasure process done with the kit.
The inventors of the present invention recognized that a method or system for non-destructively erasing data in a data storage system that overcomes one or more of the limitations of the kit may have value. The inventors further recognized that a more flexible method or system for non-destructively erasing data in a data storage system would likely have the most value.

Methods and systems for enabling non-destructive erasure of data


Methods and apparatus for efficiently writing data to and reading data from multi-state memory cells. According to one aspect of the present invention, a memory system includes a first storage element, a data source, a first element, a second element, and a ripple clock. The data source provides a plurality of bits to be stored in the first storage element, and the first element receives a first bit from the data source, and also clocks the first bit into the second element. The first element then receives a second bit of the plurality of bits from the data source substantially while the first bit is being stored into the first storage element. The ripple clock enables access to the first element and the second element such that the first bit and the second bit may be pipelined.

1. Field of Invention
The present invention relates generally to mass digital data storage systems. More particularly, the present invention relates to systems and methods for reducing the overhead associated with multi-state storage systems.
2. Description of the Related Art
The use of non-volatile memory systems such as flash memory storage systems is increasing due to the compact physical size of such memory systems, and the ability for non-volatile memory to be repetitively reprogrammed. The compact physical size of flash memory storage systems facilitates the use of such storage systems in devices that are becoming increasingly prevalent. Devices which use flash memory storage systems include, but are not limited to, digital cameras, digital camcorders, digital music players, handheld personal computers, and global positioning devices. The ability to repetitively reprogram non-volatile memory included in flash memory storage systems enables flash memory storage systems to be used and reused.
Data that are streamed into a memory system are generally written into memory cells or, more generally, storage elements on a bit-by-bit basis and read out of the storage elements on a bit-by-bit basis. As will be understood by those skilled in the art, write operations are generally slow, e.g., take a relatively long time to perform. Often, some read operations may be time-consuming as well.
As will be appreciated by those skilled in the art, bits that are to be written into or read out of cells are typically buffered. Bits are generally buffered when a data bus has a width to and from memory that is substantially less than the number of bits which may be written to, read from, or operated on in parallel in the memory. Buffering bits also alleviates bandwidth and power consumption issues.
A master-slave register bit is generally needed for each bit that is to be buffered. Typically, each master-slave register bit requires up to approximately twenty-four transistors for implementation. One conventional master-slave register, or master-slave flip flop, is shown in FIG. 12. A master-slave register 1200 which includes a reset function is suitable for use in buffering a bit. For a non-volatile memory system, as for example a memory system that includes up to approximately 4000 cells or storage elements that may be operated on simultaneously, one or two bits may generally be stored in each cell. As such, when each of the 16,000 bits are to be buffered, 16,000 master-slave register bits may be required, which, in turn, generally requires a relatively high number of total transistors. Implementing a relatively high number of transistors which support master-slave register bits may occupy more physical space within a memory system than desired and therefore be more expensive.
In order to reduce the number of transistors needed to buffer bits in a memory device, single data latches may be implemented for use as buffers in lieu of master-slave latches or master-slave register bits. Each memory cell may operated simultaneously have one or more associated latches which are suitable for buffering both data that are to be stored in the memory cell and data that are to be read from the memory cell. The use of single data latches rather than master-slave latches may allow the number of transistors associated with buffering capabilities to be reduced by up to approximately fifty percent. However, while master-slave latches use a relatively simple clocking scheme to select individual master-slave latches to be accessed, the use of data latches generally require more complicated addressing schemes to access individual data latches. Such addressing schemes may, in some cases, require more transistors than are required to support master-slave latches or master-slave bits.
Since an addressing scheme which may utilize a relatively high number of transistors may not be efficient, ripple clocks are sometimes implemented to enable data latches to be accessed sequentially. That is, the single data latch associated with each memory cell may be accessed sequentially with respect to the data latches associated with other memory cells in a memory device. One example of data latches which are accessed by a ripple clock is shown in FIG. 13a. A system 1300 includes latches 1310 and master-slave registers or master-slave flip-flops 1314. Latches 1310 are data latches which are each associated with a memory cell, and are enabled by latch enable (LE) signals. Specifically, latch 1310a is enabled by an LEA signal, latch 1310b is enabled by a LEB signal which is an output of flip-flop 1314, and latch 1310c is enabled by a LEC signal which is an output of flip-flip 1314b. Flip-flops 1314 are generally controlled by a common clock (CK) signal.
In general, only one LE signal is asserted at any given time, and the asserted LE signal is effectively propagated by flip-flops 1314. The set of asserted LE signals effectively forms a ripple clock. As shown in a timing diagram 1350 of FIG. 13b, an LEA signal 1360a, an LEB signal 1360b, and an LEC signal 1360c are such that only one LE signal 1360 is asserted, e.g., at a high value, at any point in time to trigger latches 1310 of FIG. 13a.
A ripple clock that is implemented in a system such as system 1300 of FIG. 13a requires a master-slave latch or a flip-flop which generates the enable signal or signals for each set of latches to be accessed serially. As such, the use of ripple clocks and a single data latch for each memory cell may not reduce the number of transistors needed in an overall memory device.
Therefore, what is needed is a system and a method which enables bits to be written efficiently into and read efficiently from memory cells without requiring a relatively high number of components such as transistors. That is, what is desired is a system and a method for reducing the overhead associated with writing bits into and reading bits from a multi-state memory cell while enabling the writing and the reading to occur efficiently.
The present invention relates to a system and a method for efficiently writing data to and reading data from memory cells. According to one aspect of the present invention, a memory system includes a first storage element, a data source, a first element, a second element, and a ripple clock. The data source provides a plurality of bits to be stored in the first storage element, and the first element receives a first bit from the data source, and also clocks the first bit into the second element The first element then receives a second bit of the plurality of bits from the data source substantially while the first bit is being stored into the first storage element. The ripple clock enables access to the first element and the second element such that the first bit and the second bit may be pipelined.
In one embodiment, the ripple clock also allows substantially concurrent access to the first storage element and at least a second storage element included in the plurality of storage elements. In another embodiment, the first buffering element is a first latch and the second buffering element is a second latch.
The use of a plurality of buffering elements such as latches to pipeline data bits either into or out of a multi-state memory cell allows write and read operations, respectively, to occur more efficiently. As such, the overhead cost of multi-state storage may be reduced. By loading a bit into a second latch associated with a group of memory cells while a bit is being written from a first latch into the memory cell, the time associated with loading the bit into the second latch may effectively be masked. Hence, an overall write process may occur more efficiently.
According to another aspect of the present invention, a computing system includes a host that provides a first bit and a second bit, and a storage device that is in communication with the host. The storage device includes a first storage element which clocks the first bit into a second buffering element. The first buffering element receives the second bit from the host substantially while the first bit is being stored into the first storage element by the second buffering element. Finally, the storage device includes a ripple clock that enables access to the first buffering element and the second buffering element.
In accordance with still another aspect of the present invention, a method for storing a plurality of bits in a memory system that includes a storage element, a first buffering element, and a second buffering element involves receiving the plurality of bits, and providing a first bit included in the plurality of bits to the first buffering element. A write process is then initiated to write the first bit into the storage element, and a second bit included in the plurality of bits is provided to the second buffering element after the write process to write the first bit into the storage element is initiated. The write process to write the first bit into the storage element after the second bit is provided to the second buffering element is then completed.
These and other advantages of the present invention will become apparent upon reading the following detailed descriptions and studying the various figures of the drawings.

Efficient read, write methods for multi-state memory


A controller arrangement includes a controller, an actuator, and a measuring element. The measuring element captures a control variable with a predetermined sampling rate in consecutive sampling cycles and transmits it to the controller. The controller compares the control variable with a predetermined reference variable and determines how the control variable differs from the reference variable. The controller, in a first cycle, starts with a predetermined regulating variable and outputs it to the actuator, and subsequently determines how the control variable differs from the reference variable; in a second cycle, the controller varies the regulating variable based on the difference of the control variable from the reference variable in the first cycle, and outputs it to the actuator, and subsequently determines how the control variable differs from the reference variable; in a third cycle, the controller varies the regulating variable and outputs it to the actuator.

Generally, controllers are used to adjust a control variable (may also be referred to as controlled variable, process variable, actual value, measured value) to a reference variable (set point, set value). Depending on the parameter to be controlled (e.g., temperature, pressure, voltage, charge or in general any physical parameter) and the system to be controlled (room, fluid tank, etc.), a more or less complex structure of the regulator may be necessary. A controller typically has to consider system dynamics in order to reliably adjust the control variable to the reference variable and within a reasonable time.
In the field of control engineering, for example, so-called PID controllers (proportional-integral-derivative controllers) are known. A PID controller requires detailed knowledge of the behavior of the system/parameter to be controlled. The coefficients for the PID controller will be set according to this behavior. If the dynamics of the controlled system change, it may be necessary to change the coefficients of the PID controller.

Controller arrangement with adaptive adjusting of the regulating variable


The present invention is directed to a portable mirrored camouflage blind that incorporates a plurality of two-way mirrored panels positioned relative to each other side by side along a longitudinal edge, and flexible hinge means for flexibly connecting each of the plurality of two-way mirrored panels with an adjacent two-way mirrored panel whereby the plurality of two-way mirrored panels with the flexible hinge means form an accordion-like structure. Each of the plurality of two-way mirrored panels is optically constructed to produce undistorted reflections of objects located at near and far distances on an outer side of the plurality of two-way mirrored panels.

As in the past, hunters have consistently found themselves in certain types of terrain where there is little or no cover available in which to conceal themselves effectively. In certain wilderness areas and especially during the fall and winter seasons, the trees are not large enough to hang a portable tree stand, and the brush is too thin in which to hide. In such areas, hunters have often been forced to create camouflage barriers using materials from the immediate area. However, this can result in the hunters changing the local landscape. When hunters attempt to do so in areas favored by various animals indigenous to those wilderness areas (i.e., mature whitetails), such changes in the landscape are easily picked out by such wary animals. Thus, a problem exists in how hunters can effectively conceal themselves in any type of cover and blend in so as to be virtually invisible.
There exist today various types of camouflage clothing and portable blinds available on the market today. Among them are the camouflage devices disclosed in U.S. Pat. No. 4,506,467 to Strung, U.S. Pat. No. 4,773,437 to Glutting, U.S. Pat. No. 5,010,909 to Cleveland and U.S. Pat. No. 5,062,234 to Green. These and other types of camouflage are intended to effectively blend the hunter in with different types of cover provided that the camouflage pattern blends in and has the same pattern and colors as the immediate area. However, with devices such as those of Glutting, Cleveland and Green, there is nothing on the market today that effectively works in all types of cover and terrain without changing camouflage patterns. Rather, existing types of camouflage are limited in that they are typically designed to be most effective in only one type of terrain, and only nominally effective in a few others.
With devices such as that of Strung, the mirrored finish of the panels is designed to only reflect objects and colors in the terrain immediately adjacent the panels. The curved shape of those panels results in a distorted reflection of the immediate terrain, while the conical shape of the enclosure causes those distortions to vary in degree along its surface from top to bottom. These optical distortions have been found to scare and/or repulse wildlife from approaching. As a result, devices similar to that of Strung cannot produce true and effective camouflaging reflections of the terrain.
Camouflage devices such as those mentioned above that claim to be versatile and effective in various terrains may often require cumbersome amounts of equipment, and large amounts of time to set up initially. For example, the device of Strung alone requires that several flexible panels be connected to one another using channels on-site in order to form a conical enclosure. An overhead cover having a relatively rigid structure must then be placed on top of the conical enclosure. Even more, these camouflage devices supposedly adaptable to different types of terrain can require inordinate amounts of time to adapt them from one terrain type to another. Devices such as those of Glutting, Cleveland and Green would all require that their camouflage materials be removed from their mountings in order to adapt them from one camouflage pattern to another. Thus, a problem persists in that no camouflage device currently exists that will truly adapt to various types of terrain, while at the same time being easy to use and set up.
Existing types of camouflage devices also severely limit the ability of the hunter or some other user to see beyond the camouflage. Devices such as Glutting, Cleveland and Green only disclose the use of camouflage materials that are opaque, or at best translucent. The device of Strung provides no means for the user to effectively see out of the enclosure without compromising the camouflaging effects of the enclosure.
Some existing devices even require the user to limit his/her movement while using the device in order for it to be effective. Unnecessary or excess movement when using a conventional device may result in the user being seen despite being camouflaged, or at worst in the camouflage device's setup being destroyed. This is most evident in devices such as those of Strung and Cleveland where their enclosures have very restricted amounts of room available. Inherently, these restrictions severely limit the range of activities of the hunter or other users when using the device. Thus, a problem exists in that current camouflage devices strictly limit the freedom of movement of the user. This problem in turn compromises the overall usefulness of the device.