An improved waveguide is disclosed. The waveguide utilizes a luminescent material disposed within or around its perimeter to introduce additional light into the waveguide. For example, the waveguide may include a plurality of planar layers having different refractive indexes. A luminescent material may be disposed along the outer edge of these layers. When light from within the waveguide strikes the luminescent material, it emits light, thereby adding to the light in the waveguide. Not only does the luminescent material introduce more light into the waveguide, it also introduces more light sources, thereby making it more difficult to introduce a probe without blocking at least a portion of the light destined for the image sensor. The luminescent material may be a phosphor.

Security is becoming increasingly important as the internet and electronic devices become more pervasive. For example, computers and even mobile telephones are equipped with biometrics to prevent access by unauthorized users.
Encryption is also used to prevent unauthorized access to devices and information. For example, data can be encrypted before being transmitted on the internet. Other techniques, such as security tokens, are also employed to limit access to devices.
In addition, many electronic systems require a unique digital identifier for authentication, key derivation and other purposes. These electronic systems are often manufactured using traditional manufacturing processes. Creating a unique digital identifier in this environment is often difficult and time consuming. Furthermore, to be effective, the unique digital identifier should be extremely different or nearly impossible to determine and copy.
One method of creating this unique digital identifier is through the use of waveguides. FIG. 1 shows a cross section of a printed circuit board 10 with a conventional planar waveguide 20. The printed circuit board 10 includes one or more light sources 11. These light sources 11 emit light that enters the waveguide 20 by means of angle mirror 26 cut into the waveguide 20. The light initially appears in both the inner core 21 and the outer cladding 22, but an absorptive layer of material 25 absorbs the light in the outer cladding 22. The printed circuit board 10 also includes an image sensor 12, such as a CCD image sensor. Light in the inner core 21 is not coupled to the image sensor 12, but inhomogeneities 27 in the inner core 21 scatter light into the outer cladding 22 where some fraction of this light is received by the image sensor 12. Thus, some portion of the light emitted from the light sources 11 reaches the image sensor 12. The light pattern created on the image sensor 12 is then converted to a digital value. Slight differences in the structure of the waveguide 20 affect the resulting light pattern, causing unique patterns to be reflected onto the image sensor 12. Thus, the light pattern represents the unique identifier.
As mentioned above, these waveguides 20 are traditionally constructed using an inner core 21 surrounded by an outer cladding 22. The outer cladding 22 is then covered by a reflective silver layer 24. The inner core 21 may have a higher refractive index (n) than the outer cladding 22. For example, the inner core 21 may have a refractive index of 1.59, while the outer cladding has a refractive index of 1.49. Light is reflected at the boundary between the inner core 21 and the outer cladding 22 or at the boundary between the outer cladding 22 and the silver layer 24.
As shown in FIG. 1, the incident angle of the light determines at which boundary the light is reflected. Higher incident angle light is reflected at the boundary between the inner core 21 and the outer cladding 22, while lower incident angle light is reflected at the silver layer 24. For example, using the refractive indices described above, light with an incident angle of 70° to 90° will remain trapped in the inner core 21. Light with a lower incident angle, such as 60° to 70°, are contained within both the inner core 21 and the outer cladding 22. Further, at incident angles less than roughly 60°, the light will exit the outer cladding 22 and may be reflected by the silver layer 24.
FIG. 2 shows a top view of the waveguide 20 of FIG. 1. Disposed under the waveguide 20 are a light source 11 and an image sensor 12. Light is emitted from the light source 11 and traverses the waveguide 10 to the image sensor 12. FIG. 2 also shows an intrusive probe 13 that has been inserted into the waveguide 10. If the probe 13 is not inserted into the direct path between the light source 11 and the image sensor 12, its affect on the reflected light pattern received by the image sensor 12 may be minimal. For example, there may be some small amount of light 15 reflected off the probe 13 that may affect the reflected pattern; however, most of the light in the waveguide 20 that is destined for the image sensor 12 is unaffected by the probe 13. If the probe 13 is not inserted in the direct light path, the shadow 14 cast by the probe 13 may have no affect on the reflected light pattern received by the image sensor 12.
However, ideally, the light pattern should be significantly affected by the insertion of an intrusive probe 13, regardless of the location of that insertion. Therefore, it would be beneficial if there were a waveguide where the reflected light pattern is more significantly affected by the insertion of a probe. Furthermore, it would be advantageous if this significant change in the reflected light pattern occurred regardless of the location of the insertion.


An anionic polymerization initiator comprising the reaction product of a functionalizing agent selected from the group consisting of substituted aldimines, ketimines and secondary amines and, an organolithium compound. Elastomeric polymers prepared with these initiators have functional sites incorporated at the initiator end of the polymer chain and provide vulcanizable rubber compounds exhibiting reduced hysteresis. Articles such as tires, produced with low hysteresis elastomeric polymers have lower rolling resistance. Methods are also provided for preparing the initiators, functionalized polymers and vulcanizable elastomeric compounds having reduced hysteresis.

In the art it is desirable to produce elastomeric compounds exhibiting reduced hysteresis. Such elastomers, when compounded to form articles such as tires, power belts and the like, will show an increase in rebound, a decreased rolling resistance and will have less heat build-up when mechanical stresses are applied.
Previous attempts at preparing reduced hysteresis products have included high temperature mixing of the filler-rubber mixtures in the presence of selectively-reactive promoters to promote compounding material reinforcement; surface oxidation of the compounding materials; chemical modifications to the terminal end of polymers using tetramethyldiaminobenzophenone (Michler's ketone), tin coupling agents and the like and, surface grafting thereon. All of these approaches have focused upon increased interaction between the elastomer and the compounding materials.
It has also been recognized that carbon black, employed as a reinforcing filler in rubber compounds, should be well dispersed throughout the rubber in order to improve various physical properties. One example of the recognition is provided in published European Pat. Appln. EP 0 316 255A2 which discloses a process for end capping polydienes by reacting a metal terminated polydiene with a capping agent such as a halogenated nitrile, a heterocyclic aromatic nitrogen containing compound or an alkyl benzoate. Additionally, the application discloses that both ends of the polydiene chains can be capped with polar groups by utilizing functionalized initiators, such as lithium amides.
The present invention provides novel initiators for anionic polymerization which become incorporated into the polymer chain providing a functional group which greatly improves the dispersability of carbon black throughout the elastomeric composition during compounding. As will be described hereinbelow, these initiators are a product of the reaction between certain types of nitrogen-containing organic compounds and organolithium compounds.
Organolithium polymerization initiators are also known in the art. U.S. Pat. No. 3,439,049, owned by the Assignee of record, discloses an organolithium initiator prepared from a halophenol in a hydrocarbon medium.
U.S. Pat. No. 4,015,061 is directed toward amino-functional initiators which polymerize diene monomers to form mono- or di-primary aryl amine-terminated diene polymers upon acid hydrolysis.

Methods for preparing functionalized polymer and elastomeric compounds having reduced hysteresis


A method and system is provided for triggering an advertisement for display via a computer network. One of a several part numbers is received from a user request. An advertisement to be displayed is triggered if (i) the user is associated with a pre-determined desired group corresponding to the triggered advertisement, and (ii) the user is not associated with a pre-determined no-show group corresponding to the triggered advertisement; and (iii) at least one of the received part numbers is included in the portion of part numbers. The triggering step further includes determining whether the triggered advertisement has exceeded a pre-determined maximum number of showings. An advertiser associated with the advertisement is notified of the triggered advertisement and the user. Further, responsive to the user request, stored information is searched for a part corresponding to at least one part number. Further, the user is classified by type within a vertical industry such as the airline industry.

A portion of the disclosure of this patent document contains material which is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent disclosure, as it appears in the Patent and Trademark Office patent files or records, but otherwise reserves all copyright right whatsoever.
1. Field of the Invention
The present invention relates to method and systems for displaying targeted advertising and listings to web site users. More specifically, it relates to the qualification of an advertisement""s display and the notification to the advertiser. Further, the invention relates to advertisements displayed based upon a unique part identification being queried, and the industry segment of the inquirer.
2. Background of the Invention
One of the major problems facing advertisers is directing their advertisement to the correct prospect at just the right time. The advent of the internet presents interesting possibilities for attempting to customize an advertisement. For example, U.S. Pat. No. 6,009,410, LeMole, concerns a method for presenting customized advertising to a user on the internet, where banner advertisements are selected from several different advertisers, and the customized page is determined from the user""s specific area of interest based on demographic data. Similarly, U.S. Pat. No. 5,933,811, Angles, and U.S. Pat. No. 5,948,061, Merriman, concern other methods for delivering customized or targeted advertisements over the internet. Angles selects a customized advertisement based on a consumer profile (cookie). Merriman also uses a cookie, wherein an advertisement server determines which of several advertisements to match to the user.
It is also now conventional to utilize an internet user""s activity such as searching to trigger a particular advertisement. See, for example, U.S. Pat. No. 5,937,392, Alberts.
It is also generally known to utilize the internet to search for a product. In one variation, a user can type in a product number, and a predesignated information source, such as an advertisement, is displayed to the user. See U.S. Pat. No. 5,918,214, Perkowski.
None of these conventional advertising methods envision a specialized user. More specifically, traditional internet advertising frequently does not advertise close to the point of purchase, concerning the particular product use of interest to users on a vertical portal or web site. (xe2x80x9cVerticalxe2x80x9d is used herein to designate a web site or portal or the like which is directed to a specific industry or type of user rather than an undifferentiated member of the general population.)
Thus, there remains a need for a display advertisement system which utilizes unique qualities of certain industries in order to qualify an advertisement.
It is therefore an object of the present invention to provide an improved method for determining and directing advertisements on the internet, via user qualification. It is an optional feature of the present invention that it notifies an advertiser whose advertisement was displayed to a particular user.
According to the invention, there is provided a method and system for providing an advertisement for display on a computer system. One of several part numbers is received from a user request. An advertisement to be displayed is triggered if (i) the user is associated with a pre-determined desired group corresponding to the triggered advertisement, and (ii) the user is not associated with a pre-determined no-show group corresponding to the triggered advertisement. The triggering step further includes determining whether the triggered advertisement has exceeded a pre-determined maximum number of showings. An advertiser associated with the advertisement is notified of the triggered advertisement and the user. Optionally, the notifying step is substantially simultaneous with the triggering step, or is subsequent to the triggering step. Further, responsive to the user request, stored information is searched for a part corresponding to at least one part number. Also, the triggered advertisement is transmitted to the user. Further, the user is classified by type within a vertical industry. Classification includes storing an indication from the user of one of several of subtypes for a vertical industry. For each of several advertisers, there are stored part numbers; for each of a portion of part numbers for at least one of the advertisers, there is stored the triggered advertisement; further, the advertisement is triggered if (iii) at least one of the received part numbers is included in the portion of part numbers. For each of the users including the user, the users are classified with a group corresponding to the triggered advertisement. Further, optionally, for a portion of a plurality of users including the user, the portion of users are classified with a group corresponding to a no-show group.
These and other objects, features and advantages of the present invention are readily apparent from the following drawings and detailed description.

Method and system for display advertisement qualification and notification


A method and a system provide access to a communications medium that is suitable for allowing use of a plurality of Home Phoneline Network Association (HPNA) v2 frames in a centralized manner. Each HPNA v2 frame is timed to allow an Inter-Frame Gap (IFG) portion having a duration that is substantially a duration defined by an HPNA v2 protocol specification for an IFG portion of an HPNA v2 frame. A plurality of frames are generated in the communications medium with at least one frame of the plurality of frames having timing to allow a Shortened Inter-Frame Gap (SIFG) portion and a contention-free portion. The SIFG portion is less than about 17 μsec in duration. Access to the communications medium is then provided for at least one station (STA) during the contention-free portion of a frame having timing to allow the SIFG portion.

This application claims priority to provisional U.S. Application Ser. No. 60/269,354, entitled "Enhanced Channel Access Mechanisms For A QoS-Driven HPNA Network," invented by Wei Lin and Matthew Sherman, filed Feb. 20, 2001, and provisional U.S. Application Ser. No. 60/269,861, entitled HPNA 3.0 channel access mechanism for compatibility with HPNA 2, invented by Matthew J. Sherman, filed Feb. 21, 2001, both of which are incorporated by reference herein. The present application is also related to U.S. patent application Ser. Nos. 10/042,165, 10/042,179, 10/042,166, and 10/042,143, each entitled "Enhanced Channel Access Mechanism For QoS-Driven HomePNA (HPNA 2.1), each filed on Dec. 19, 2001, and each incorporated by reference herein.

Enhanced channel access mechanisms for an HPNA network


Disclosed is a method of directing a cellular immune response against an HIV-infected cell in a mammal involving administering to the mammal an effective amount of therapeutic cells which express a membrane-bound, proteinaceous chimeric receptor comprising (a) an extracellular portion which includes a fragment of CD4 which is capable of specifically recognizing and binding the HIV-infected cell but which does not mediate HIV infection and (b) an intracellular portion which is capable of signalling the therapeutic cell to destroy the receptor-bound HIV-infected cell. Also disclosed is a second method of treating HIV in a mammal involving administering to the mammal an effective amount of therapeutic cells expressing a membrane-bound, proteinaceous chimeric receptor comprising an extracellular portion which includes a fragment of CD4 which is capable of specifically recognizing and binding the HIV-infected cell but which does not mediate HIV infection. Also disclosed are cells which express the chimeric receptors and DNA and vectors encoding the chimeric receptors.

The invention concerns functional chimeras between CD4 fragments and immune cell receptors which are capable of directing immune cells to lyse HIV-infected cells, but which do not render the immune cells susceptible to HIV infection. The invention therefore provides a novel and effective HIV therapeutic.
T cell recognition of antigen through the T cell receptor is the basis of a range of immunological phenomena. The T cells direct what is called cell-mediated immunity. This involves the destruction by cells of the immune system of foreign tissues or infected cells. A variety of T cells exist, including xe2x80x9chelperxe2x80x9d and xe2x80x9csuppressorxe2x80x9d cells, which modulate the immune response, and cytotoxic (or xe2x80x9ckillerxe2x80x9d) cells, which can kill abnormal cells directly.
A T cell that recognizes and binds a unique antigen displayed on the surface of another cell becomes activated; it can then multiply, and, if it is a cytotoxic cell, it can kill the bound cell. HIV and Immunopathogenesis
In 1984 HIV was shown to be the etiologic agent of AIDS. Since that time the definition of AIDS has been revised a number of times with regard to what criteria should be included in the diagnosis. However, despite the fluctuation in diagnostic parameters, the simple common denominator of AIDS is the infection with HIV and subsequent development of persistent constitutional symptoms and AIDS-defining diseases such as a secondary infections, neoplasms, and neurologic disease. Harrison""s Principles of Internal Medicine, 12th ed., McGraw Hill (1991).
HIV is a human retrovirus of the lentivirus group. The four recognized human retroviruses belong to two distinct groups: the human T lymphotropic (or leukemia) retroviruses, HTLV-1 and HTLV-2, and the human immunodeficiency viruses, HIV-1 and HIV-2. The former are transforming viruses whereas the latter are cytopathic viruses.
HIV-1 has been identified as the most common cause of AIDS throughout the world. Sequence homology between HIV-2 and HIV-1 is about 40% with HIV-2 being more closely related to some members of a group of simian immunodeficiency viruses (SIV). See Curran et al., Science 329:1357-1359 (1985); Weiss et al., Nature 324:572-575 (1986).
HIV has the usual retroviral genes (env, gag, and pol) as well as six extra genes involved in the replication and other biologic activities of the virus. As stated previously, the common denominator of AIDS is a profound immunosuppression, predominantly of cell-mediated immunity. This immune suppression leads to a variety of opportunistic diseases, particularly certain infections and neoplasms.
The main cause of the immune defect in AIDS has been identified as a quantitative and qualitative deficiency in the subset of thymus-derived (T) lymphocytes, the T4 population. This subset of cells is defined phenotypically by the presence of the CD4 surface molecule, which has been demonstrated to be the cellular receptor for HIV. Dalgleish et al., Nature 312:763 (1984). Although the T4 cell is the major cell type infected with HIV, essentially any human cell that expresses the CD4 molecule on its surface is capable of binding to and being infected with HIV.
Traditionally, CD4+ T cells have been assigned the role of helper/inducer, indicating their function in providing an activating signal to B cells, or inducing T lymphocytes bearing the reciprocal CD8 marker to become cytotoxic/suppressor cells. Reinherz and Schlossman, Cell 19:821-827 (1980); Goldstein et al., Immunol. Rev. 68:5-42 (1982).
HIV binds specifically and with high affinity, via a stretch of amino acids in the viral envelope (gp120), to a portion of the V1 region of the CD4 molecule located near its N-terminus. Following binding, the virus fuses with the target cell membrane and is internalized. Once internalized it uses the enzyme reverse transcriptase to transcribe its genomic RNA to DNA, which is integrated into the cellular DNA where it exists for the life of the cell as a xe2x80x9cprovirus.xe2x80x9d
The provirus may remain latent or be activated to transcribe MRNA and genomic RNA, leading to protein synthesis, assembly, new virion formation, and budding of virus from the cell surface. Although the precise mechanism by which the virus induces cell death has not been established, it is believed that the major mechanism is massive viral budding from the cell surface, leading to disruption of the plasma membrane and resulting osmotic disequilibrium.
During the course of the infection, the host organism develops antibodies against viral proteins, including the major envelope glycoproteins gp120 and gp41. Despite this humoral immunity, the disease progresses, resulting in a lethal immunosuppression characterized by multiple opportunistic infections, parasitemia, dementia, and death. The failure of the host anti-viral antibodies to arrest the progression of the disease represents one of the most vexing and alarming aspects of the infection, and augurs poorly for vaccination efforts based upon conventional approaches.
Two factors may play a role in the efficacy of the humoral response to immunodeficiency viruses. First, like other RNA viruses (and like retroviruses in particular), the immunodeficiency viruses show a high mutation rate in response to host immune surveillance. Second, the envelope glycoproteins themselves are heavily glycosylated molecules presenting few epitopes suitable for high affinity antibody binding. The poorly antigenic target which the viral envelope presents allows the host little opportunity for restricting viral infection by specific antibody production.
Cells infected by the HIV virus express the gp120 glycoprotein on their surface. Gp120 mediates fusion events among CD4+ cells via a reaction similar to that by which the virus enters the uninfected cells, leading to the formation of short-lived multinucleated giant cells. Syncytium formation is dependent on a direct interaction of the gp120 envelope glycoprotein with the CD4 protein. Dalgleish et al., supra; Klatzman et al., Nature 312:763 (1984); McDougal et al., Science 231:382 (1986); Sodroski et al., Nature 322:470 (1986); Lifson et al., Nature 323:725 (1986); Sodroski et al., Nature 321:412 (1986).
Evidence that the CD4-gp120 binding is responsible for viral infection of cells bearing the CD4 antigen includes the finding that a specific complex is formed between gp120 and CD4 (McDougal et al., supra). Other investigators have shown that the cell lines, which were non-infective for HIV, were converted to infectable cell lines following transfection and expression of the human CD4 cDNA gene. Maddon et al., Cell 46:333-348 (1986).
Therapeutic programs based on soluble CD4 as a passive agent to interfere with viral adsorption and syncytium-mediated cellular transmission have been proposed and successfully demonstrated in vitro by a number of groups (Deen et al., Nature 331:82-84 (1988); Fisher et al., Nature 331:76-78 (1988); Hussey et al., Nature 331:78-81 (1988); Smith et al., Science 238:1704-1707 (1987); Traunecker et al., Nature 331:84-86 (1988)); and CD4 immunoglobulin fusion proteins with extended half-lives and modest biological activity have subsequently been developed (Capon et al., Nature 337:525-531 (1989); Traunecker et al. Nature 339, 68-70 (1989); Byrn et al., Nature 344:667-670 (1990); Zettlmeissl et al., DNA Cell Biol. 9:347-353 (1990)). Although CD4 immunotoxin conjugates or fusion proteins show potent cytotoxicity for infected cells in vitro (Chaudhary et al., Nature 335:369-372 (1988); Till et al., Science 242:1166-1168 (1988)), the latency of the immunodeficiency syndrome makes it unlikely that any single-treatment therapy will be effective in eliminating viral burden, and the antigenicity of foreign fusion proteins is likely to limit their acceptability in treatments requiring repetitive dosing. Trials with monkeys affected with SIV have shown that soluble CD4, if administered to animals without marked CD4 cytopenia, can reduce SIV titer and improve in vitro measures of myeloid potential (Watanabe et al., Nature 337:267-270 (1989)). However a prompt viral reemergence was observed after treatment was discontinued, suggesting that lifelong administration might be necessary to prevent progressive immune system debilitation.
Cell surface expression of the most abundant form of the T cell antigen receptor (TCR) requires the coexpression of at least 6 distinct polypeptide chains (Weiss et al., J. Exp. Med. 160:1284-1299 (1984); Orloffhashi et al., Nature 316:606-609 (1985); Berkhout et al., J. Biol. Chem. 263:8528-8536 (1988); Sussman et al., Cell 52:85-95 (1988)), the xcex1/xcex2 antigen binding chains, the three polypeptides of the CD3 complex, and xcex6. If any of the chains are absent, stable expression of the remaining members of the complex does not ensue. xcex6 is the limiting polypeptide for surface expression of the complete complex (Sussman et al., Cell 52:85-95 (1988)) and is thought to mediate at least a fraction of the cellular activation programs triggered by receptor recognition of ligand (Weissman et al., EMBO J. 8:3651-3656 (1989); Frank et al., Science 249:174-177 (1990)). A 32 kDa type I integral membrane homodimer, xcex6 (zeta) has a 9 residue extracellular domain with no sites for N-linked glycan addition, and a 112 residue (mouse) or 113 residue (human) intracellular domain (Weissman et al., Science 238:1018-1020 (1988); Weissman et al., Proc. Natl. Acad. Sci. USA 85:9709-9713 (1988)). An isoform of xcex6 called xcex7 (eta) (Baniyash et al., J. Biol. Chem. 263:9874-9878 (1988); Orloff et al., J. Biol. Chem. 264:14812-14817 (1989)), which arises from an alternate mRNA splicing pathway (Jin et al., Proc. Natl. Acad. Sci. USA 87:3319-3233 (1990)), is present in reduced amounts in cells expressing the antigen receptor. xcex6xe2x88x92xcex7 heterodimers are thought to mediate the formation of inositol phosphates, as well as the receptor-initiated programmed cell death called apoptosis (Merxc4x87ep et al., Science 242:571-574 (1988); Merxc4x87ep et al., Science 246:1162-1165 (1989)).
Like xcex6 and xcex7, the Fc receptor-associated xcex3 (gamma) chain is expressed in cell surface complexes with additional polypeptides, some of which mediate ligand recognition, and others of which have undefined function. xcex3 bears a homodimeric structure and overall organization very similar to that of xcex6 and is a component of both the mast cell/basophil high affinity IgE receptor, Fcxcex5RI, which consists of at least three distinct polypeptide chains (Blank et al., Nature 337:187-189 (1989); Ra et al., Nature 241:752-754 (1989)), and one of the low affinity receptors for IgG, represented in mice by Fcxcex3RIIxcex1 (Ra et al., J. Biol. Chem. 264:15323-15327 (1989)), and in humans by the CD16 subtype expression by macrophages and natural killer cells, CD16TM (CD16 transmembrane) (Lanier et al., Nature 342:803-805 (1989); Anderson et al., Proc. Natl. Acad. Sci. USA 87:2274-2278 (1990)) and with a polypeptide of unidentified function (Anderson et al., Proc. Natl. Acad. Sci. USA 87:2274-2278 (1990)). Recently it has been reported that xcex3 is expressed by a mouse T cell line, CTL, in which it forms homodimers as well as xcex3xe2x88x92xcex6 and xcex3xe2x88x92xcex7 heterodimers (Orloff et al., Nature 347:189-191 (1990)).
The Fc receptors mediate phagocytosis of immune complexes, transcytosis, and antibody dependent cellular cytotoxicity (ADCC) (Ravetch and Kinet, Annu. Rev. Immunol. 9:457-492 (1991); Unkeless et al., Annu. Rev. Immunol 6:251-281 (1988); and Mellman, Curr. Opin. Immunol. 1:16-25 (1988)). Recently it has been shown that one of the murine low affinity Fc receptor isoforms, FcRxcex3IIIB1, mediates internalization of Ig-coated targets into clathrin coated pits, and that another low affinity receptor, FcRxcex3IIIA mediates ADCC through its association with one or more members of a small family of xe2x80x98trigger moleculesxe2x80x99 (Miettinen et al., Cell 58:317-327 (1989); and Hunziker and Mellman, J. Cell Biol. 109:3291-3302 (1989)). These trigger molecules, T cell receptor (TCR) xcex6 chain, TCR xcex7 chain, and Fc receptor xcex3 chain, interact with ligand recognition domains of different immune system receptors and can autonomously initiate cellular effector programs, including cytolysis, following aggregation (Samelson et al., Cell 43:223-231 (1985); Weissman et al., Science 239:1018-1020 (1988); Jin et al., Proc. Natl. Acad. Sci. USA 87:3319-3323 (1990); Blank et al., Nature 337:187-189 (1989); Lanier et al., Nature 342:803-805 (1989); Kurosaki and Ravetch, Nature 342:805-807 (1989); Hibbs et al., Science 246:1608-1611 (1989); Anderson et al., Proc. Natl. Acad. Sci USA 87:2274-2278 (1990); and Irving and Weiss, Cell 64: 891-901 (1991)).
In drawing parallels between the murine and human low affinity Fc receptor families, however, it has become clear that the human FcRxcex3IIA and C isoforms have no murine counterpart. In part because of this, their function has yet to be defined.
Because humoral agents based on CD4 alone may have limited utility in vivo, previous work explored the possibility of augmenting cellular immunity to HIV. Preparations of protein chimeras in which the extracellular domain of CD4 is fused to the transmembrane and/or intracellular domains of T cell receptor, IgG Fc receptor, or B cell receptor signal transducing elements have been identified (U.S. Ser. Nos. 07/847,566 and 07/665,961, hereby incorporated by reference). Cytolytic T cells expressing chimeras which include an extracellular CD4 domain show potent MHC-independent destruction of cellular targets expressing HIV envelope proteins. An extremely important and novel component of this approach has been the identification of single T cell receptor, Fc receptor, and B cell receptor chains whose aggregation suffices to initiate the cellular response. One particularly useful application of this approach has been the invention of chimeras between CD4 and xcex6, xcex7, or xcex3 that direct cytolytic T lymphocytes to recognize and kill cells expressing HIV gp120 (U.S. Ser. Nos. 07/847,566 and 07/665,961, hereby incorporated by reference).
In general, the invention features a method of directing a cellular immune response against an HIV-infected cell in a mammal. The method involves administering to the mammal an effective amount of therapeutic cells, the therapeutic cells expressing a membrane-bound, proteinaceous chimeric receptor comprising (a) an extracellular portion which includes a fragment of CD4 which is capable of specifically recognizing and binding the HIV-infected cell but which does not mediate HIV infection and (b) an intracellular portion which is capable of signalling the therapeutic cell to destroy the receptor-bound HIV-infected cell.
In a related aspect, the invention features a cell which expresses a proteinaceous membrane-bound chimeric receptor which comprises (a) an extracellular portion which includes a fragment of CD4 which is capable of specifically recognizing and binding the HIV-infected cell but which does not mediate HIV infection and (b) an intracellular portion which is capable of signalling the therapeutic cell to destroy the receptor-bound HIV-infected cell.
In a second aspect, the invention features a method of treating HIV in a mammal involving administering to the mammal an effective amount of therapeutic cells, the therapeutic cells expressing a membrane-bound, proteinaceous chimeric receptor comprising an extracellular portion which includes a fragment of CD4 which is capable of specifically recognizing and binding the HIV-infected cell but which does not mediate HIV infection.
In a related aspect, the invention features a cell which expresses a membrane-bound, proteinaceous chimeric receptor comprising an extracellular portion which includes a fragment of CD4 which is capable of specifically recognizing and binding the HIV-infected cell but which does not mediate HIV infection.
In preferred embodiments of both the first and second aspects, the CD4 fragment is amino acids 1-394 of CD4 or is amino acids 1-200 of CD4; the CD4 fragment is separated from the intracellular portion by the CD7 transmembrane domain shown in FIG. 26 or by the hinge, CH2, and CH3 domains of the human IgG1 molecule shown in FIG. 25; and the CD4 fragment is separated from the therapeutic cell by at least 48 angstroms (and preferably, by at least 72 angstroms). In preferred embodiments of the first aspect, the intracellular portion is the signal-transducing portion of a T cell receptor protein (for example, xcex6), a B cell receptor protein, or an Fc receptor protein; and the therapeutic cells are selected from the group consisting of: (a) T lymphocytes; (b) cytotoxic T lymphocytes; (c) natural killer cells; (d) neutrophils; (e) granulocytes; (f) macrophages; (g) mast cells; (h) HeLa cells; and (i) embryonic stem cells (ES).
In other related aspects, the invention features DNA encoding a chimeric receptor of the invention; and a vector including that chimeric receptor DNA.
Although the specific embodiment of the present invention is a chimera between CD4 and zeta, any receptor chain having a similar function to these molecules, e.g., in granulocytes or B lymphocytes, could be used for the purposes disclosed here. The distinguishing features of a desirable immune cell trigger molecule comprises the ability to be expressed autonomously (i.e., as a single chain), the ability to be fused to an extracellular CD4 domain such that the resultant chimera is present on the surface of a therapeutic cell, and the ability to initiate cellular effector programs upon aggregation secondary to encounter with a target ligand.
At present the most convenient method for delivery of the chimeras to immune system cells is through some form of genetic therapy. However reconstituting immune system cells with chimeric receptors by mixture of the cells with suitably solubilized purified chimeric protein would also result in the formation of an engineered cell population capable of responding to HIV-infected targets. Similar approaches have been used, for example, to introduce the CD4 molecule into erythrocytes for therapeutic purposes. In this case the engineered cell population would not be capable of self renewal.
The present invention relates to functional and simplified chimeras between CD4 fragments and T cell receptor, B cell receptor, and Fc receptor subunits which are capable of directing immune cells to recognize and lyse HIV-infected cells. The method for directing the cellular response in a mammal comprises administering an effective amount of therapeutic cells (for example, cytotoxic T lymphocytes) to the mammal, the cells being capable of recognizing and destroying the HIV-infected cell.
The invention also includes the chimeric receptor proteins which direct the cytotoxic T lymphocytes to recognize and lyse HIV-infected cells, the host cells transformed with a vector comprising the chimeric receptors, and antibodies directed against the chimeric receptors.
These and other non-limiting embodiments of the present invention will be apparent to those of skill from the following detailed description of the invention.
In the following detailed description, reference will be made to various methodologies known to those of skill in the art of molecular biology and immunology. Publications and other materials setting forth such known methodologies to which reference is made are incorporated herein by reference in their entireties as though set forth in full.
Standard reference works setting forth the general principles of recombinant DNA technology include Watson et al., Molecular Biology of the Gene, volumes I and II, the Benjamin/Cummings Publishing Company, Inc., publisher, Menlo Park, Calif. (1987); Darnell et al., Molecular Cell Biology, Scientific American Books, Inc., publisher, New York, N.Y. (1986); Lewin, Genes II, John Wiley and Sons, publishers, New York, N.Y. (1985); Old et al., Principles of Gene Manipulation: An Introduction to Genetic Engineering, 2nd ed., University of California Press, publisher, Berkeley, Calif. (1981); Maniatis et al., Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory, publisher, Cold Spring Harbor, N.Y. (1989); and Ausubel et al., Current Protocols in Molecular Biology, Wiley Press, New York, N.Y. (1989).
By xe2x80x9ccloningxe2x80x9d is meant the use of in vitro recombination techniques to insert a particular gene or other DNA sequence into a vector molecule.
By xe2x80x9ccDNAxe2x80x9d is meant complementary or copy DNA produced from an RNA template by the action of RNA-dependent DNA polymerase (reverse transcriptase). Thus a xe2x80x9ccDNA clonexe2x80x9d means a duplex DNA sequence complementary to an RNA molecule of interest, carried in a cloning vector.
By xe2x80x9ccDNA libraryxe2x80x9d is meant a collection of recombinant DNA molecules containing cDNA inserts which comprise DNA copies of mRNA being expressed by the cell at the time the cDNA library was made. Such a cDNA library may be prepared by methods known to those of skill, and described, for example, in Ausubel et al., supra and Maniatis et al., supra. Generally, RNA is first isolated from the cells of an organism from whose genome it is desired to clone a particular gene. Preferred for the purpose of the present invention are mammalian, and particularly human, lymphocytic cell lines. A presently preferred vector for this purpose is the vaccinia virus WR strain.
By xe2x80x9cvectorxe2x80x9d is meant a DNA molecule derived, e.g., from a plasmid, bacteriophage, or mammalian or insect virus, into which fragments of DNA may be inserted or cloned. A vector will contain one or more unique restriction sites and may be capable of autonomous replication in a defined host or vehicle organism such that the cloned sequence is reproducible. Thus, by xe2x80x9cDNA expression vectorxe2x80x9d is meant any autonomous element capable of directing the synthesis of a recombinant peptide. Such DNA expression vectors include bacterial plasmids and phages and mammalian and insect plasmids and viruses.
By xe2x80x9csubstantially purexe2x80x9d is meant a compound, e.g., a protein, a polypeptide, or an antibody, that is substantially free of the components that naturally accompany it. Generally, a compound is substantially pure when at least 60%, more preferably at least 75%, and most preferably at least 90% of the total material in a sample is the compound of interest. Purity can be measured by any appropriate method, e.g., column chromatography, polyacrylamide gel electrophoresis, or HPLC analysis. In the context of a nucleic acid, xe2x80x9csubstantially purexe2x80x9d means a nucleic acid sequence, segment, or fragment that is not immediately contiguous with (i.e., covalently linked to) both of the coding sequences with which it is immediately contiguous (i.e., one at the 5xe2x80x2 end and one at the 3xe2x80x2 end) in the naturally occurring genome of the organism from which the DNA of the invention is derived.
A xe2x80x9cfragmentxe2x80x9d of a molecule, such as any of the cDNA sequences of the present invention, is meant to refer to any contiguous nucleotide subset of the molecule. An xe2x80x9canalogxe2x80x9d of a molecule is meant to refer to a non-natural molecule substantially similar to either the entire molecule or a fragment thereof. A molecule is said to be xe2x80x9csubstantially similarxe2x80x9d to another molecule if the sequence of amino acids in both molecules is substantially the same. In particular, a xe2x80x9csubstantially similarxe2x80x9d amino acid sequence is one that exhibits at least 50%, preferably 85%, and most preferably 95% amino acid sequence identity to the natural or reference sequence and/or one that differs from the natural or reference amino acid sequence only by conservative amino acid substitutions. Substantially similar amino acid molecules will possess a similar biological activity. As used herein, a molecule is said to be a xe2x80x9cchemical derivativexe2x80x9d of another molecule when it contains chemical moieties not normally a part of the molecule. Such moieties may improve the molecule""s solubility, absorption, biological half life, etc. The moieties may alternatively decrease the toxicity of the molecule, eliminate or attenuate any undesirable side effect of the molecule, etc. Moieties capable of mediating such effects are disclosed, for example, in Remington""s Pharmaceutical Sciences, 16th ed., Mack Publishing Co., Easton, Pa. (1980).
A xe2x80x9cfunctional derivativexe2x80x9d of a receptor chimera gene of the present invention is meant to include xe2x80x9cfragmentsxe2x80x9d or xe2x80x9canaloguesxe2x80x9d of the gene, which are xe2x80x9csubstantially similarxe2x80x9d in nucleotide sequence. xe2x80x9cSubstantially similarxe2x80x9d nucleic acids encode substantially similar amino acid sequences (as defined above) and also may include any nucleic acid sequence capable of hybridizing to the natural or reference nucleic acid sequence under appropriate hybridization conditions (see, for example, Ausubel et al., Current Protocols in Molecular Biology, Wiley Press, New York, N.Y. (1989) for appropriate hybridization stringency conditions.) A xe2x80x9csubstantially similarxe2x80x9d chimeric receptor possesses similar activity to a xe2x80x9cwild-typexe2x80x9d T cell, B cell, or Fc receptor chimera. Most preferably, the derivative possesses 90%, more preferably, 70%, and preferably 40% of the wild-type receptor chimera""s activity. The activity of a functional chimeric receptor derivative includes specific binding (with its extracellular CD4 portion) to an HIV-infected cell and resultant destruction of that cell; in addition, the chimeric receptor does not render the receptor-bearing cell susceptible to HIV infection. Chimeric receptor activity may be tested using, e.g., any of the assays described herein.
A DNA sequence encoding the CD4 receptor chimera of the present invention, or its functional derivatives, may be recombined with vector DNA in accordance with conventional techniques, including blunt-ended or staggered-ended termini for ligation, restriction enzyme digestion to provide appropriate termini, filling in of cohesive ends as appropriate, alkaline phosphatase treatment to avoid undesirable joining, and ligation with appropriate ligases. Techniques for such manipulations are disclosed by Maniatis et al., supra, and are well known in the art.
A nucleic acid molecule, such as DNA, is said to be xe2x80x9ccapable of expressingxe2x80x9d a polypeptide if it contains nucleotide sequences which contain transcriptional and translational regulatory information, and such sequences are xe2x80x9coperably linkedxe2x80x9d to nucleotide sequences which encode the polypeptide. An operable linkage is a linkage in which the regulatory DNA sequences and the DNA sequence sought to be expressed are connected in such a way as to permit gene expression. The precise nature of the regulatory regions needed for gene expression may vary from organism to organism, but shall in general include a promoter region which, in prokaryotes, contains both the promoter (which directs the initiation of RNA transcription) as well as the DNA sequences which, when transcribed into RNA, will signal the initiation of protein synthesis. Such regions will normally include those 5xe2x80x2-non-coding sequences involved with initiation of transcription and translation, such as the TATA box, capping sequence, CAAT sequence, and the like.
If desired, the non-coding region 3xe2x80x2 to the gene sequence coding for the protein may be obtained by the above-described methods. This region may be retained for its transcriptional termination regulatory sequences, such as termination and polyadenylation. Thus, by retaining the 3xe2x80x2-region naturally contiguous to the DNA sequence coding for the protein, the transcriptional termination signals may be provided. Where the transcriptional termination signals are not satisfactorily functional in the expression host cell, then a 3xe2x80x2 region functional in the host cell may be substituted.
Two DNA sequences (such as a promoter region sequence and a CD4-receptor chimera encoding sequence) are said to be operably linked if the nature of the linkage between the two DNA sequences does not (1) result in the introduction of a frame-shift mutation, (2) interfere with the ability of the promoter region sequence to direct the transcription of the receptor chimera gene sequence, or (3) interfere with the ability of the receptor chimera gene sequence to be transcribed by the promoter region sequence. A promoter region would be operably linked to a DNA sequence if the promoter were capable of effecting transcription of that DNA sequence. Thus, to express the protein, transcriptional and translational signals recognized by an appropriate host are necessary.
The present invention encompasses the expression of a CD4-receptor chimera protein (or a functional derivative thereof) in either prokaryotic or eukaryotic cells, although eukaryotic (and, particularly, human lymphocyte) expression is preferred.
Antibodies according to the present invention may be prepared by any of a variety of methods. For example, cells expressing the CD4-receptor chimera protein, or a functional derivative thereof, can be administered to an animal in order to induce the production of sera containing polyclonal antibodies that are capable of binding the chimera.
In a preferred method, antibodies according to the present invention are monoclonal antibodies. Such monoclonal antibodies can be prepared using hybridoma technology (Kohler et al., Nature 256:495 (1975); Kohler et al., Eur. J. Immunol. 6:511 (1976); Kohler et al., Eur. J. Immunol. 6:292 (1976); Hammerling et al., In: Monoclonal Antibodies and T-Cell Hybridomas, Elsevier, N.Y., pp. 563-684 (1981)). In general, such procedures involve immunizing an animal with the CD4-receptor chimera antigen. The splenocytes of such animals are extracted and fused with a suitable myeloma cell line. Any suitable myeloma cell line may be employed in accordance with the present invention. After fusion, the resulting hybridoma cells are selectively maintained in HAT medium, and then cloned by limiting dilution as described by Wands et al. (Gastroenterology 80:225-232 (1981)). The hybridoma cells obtained through such a selection are then assayed to identify clones which secrete antibodies capable of binding the chimera.
Antibodies according to the present invention also may be polyclonal, or, preferably, region specific polyclonal antibodies.
Antibodies against the CD4-receptor chimera according to the present invention may be used to monitor the amount of chimeric receptor (or chimeric receptor-bearing cells) in a patient. Such antibodies are well suited for use in standard immunodiagnostic assays known in the art, including such immunometric or xe2x80x9csandwichxe2x80x9d assays as the forward sandwich, reverse sandwich, and simultaneous sandwich assays. The antibodies may be used in any number of combinations as may be determined by those of skill without undue experimentation to effect immunoassays of acceptable specificity, sensitivity, and accuracy.
Standard reference works setting forth general principles of immunology include Roitt, Essential Immunology, 6th ed., Blackwell Scientific Publications, publisher, Oxford (1988); Kimball, Introduction to Immunology, 2nd ed., Macmillan Publishing Co., publisher, New York (1986); Roitt et al., Immunology, Gower Medical Publishing Ltd., publisher, London, (1985); Campbell, xe2x80x9cMonoclonal Antibody Technology,xe2x80x9d in Burdon et al., eds., Laboratory Techniques in Biochemistry and Molecular Biology, volume 13, Elsevier, publisher, Amsterdam (1984); Klein, Immunology: The Science of Self-Nonself Discrimination, John Wiley and Sons, publisher, New York (1982); and Kennett et al., eds., Monoclonal Antibodies. Hybridoma: A New Dimension In Biological Analyses, Plenum Press, publisher, New York (1980).
By xe2x80x9cdetectingxe2x80x9d it is intended to include determining the presence or absence of a substance or quantifying the amount of a substance. The term thus refers to the use of the materials, compositions, and methods of the present invention for qualitative and quantitative determinations.
The antibodies and substantially purified antigen of the present invention are ideally suited for the preparation of a kit. Such a kit may comprise a carrier means being compartmentalized to receive in close confinement therewith one or more container means such as vials, tubes and the like, each of said container means comprising the separate elements of the assay to be used.
The types of assays which can be incorporated in kit form are many, and include, for example, competitive and non-competitive assays. Typical examples of assays which can utilize the antibodies of the invention are radioimmunoassays (RIA), enzyme immunoassays (EIA), enzyme-linked immunoadsorbent assays (ELISA), and immunometric, or sandwich, immunoassays.
By the term xe2x80x9cimmunometric assayxe2x80x9d or xe2x80x9csandwich immunoassay,xe2x80x9d it is meant to include simultaneous sandwich, forward sandwich, and reverse sandwich immunoassays. These terms are well understood by those skilled in the art. Those of skill will also appreciate that antibodies according to the present invention will be useful in other variations and forms of assays which are presently known or which may be developed in the future. These are intended to be included within the scope of the present invention.
By xe2x80x9cspecifically recognizes and bindsxe2x80x9d is meant that the antibody recognizes and binds the chimeric receptor polypeptide but does not substantially recognize and bind other unrelated molecules in a sample, e.g., a biological sample.
By xe2x80x9ctherapeutic cellxe2x80x9d is meant a cell which has been transformed by a CD4-receptor chimera of the invention so that it is capable of recognizing and destroying an HIV-infected cell; preferably such therapeutic cells are cells of the hematopoietic system.
By xe2x80x9cextracellularxe2x80x9d is meant having at least a portion of the molecule exposed at the cell surface. By xe2x80x9cintracellularxe2x80x9d is meant having at least a portion of the molecule exposed to the therapeutic cell""s cytoplasm. By xe2x80x9ctransmembranexe2x80x9d is meant having at least a portion of the molecule spanning the plasma membrane. An xe2x80x9cextracellular portionxe2x80x9d, an xe2x80x9cintracellular portionxe2x80x9d, and a xe2x80x9ctransmembrane portionxe2x80x9d, as used herein, may include flanking amino acid sequences which extend into adjoining cellular compartments.
By xe2x80x9coligomerizexe2x80x9d is meant to complex with other proteins to form dimers, trimers, tetramers, or other higher order oligomers. Such oligomers may be homo-oligomers or hetero-oligomers. An xe2x80x9coligomerizing portionxe2x80x9d is that region of a molecule which directs complex (i.e., oligomer) formation.
By xe2x80x9ccytolyticxe2x80x9d is meant to be capable of destroying a cell (e.g., an HIV-infected cell) or to be capable of destroying an infective agent (e.g., an HIV virus).
By xe2x80x9cimmunodeficiency virusxe2x80x9d is meant a retrovirus that, in wild-type form, is capable of infecting T4 cells of a primate host and possesses a viral morphogenesis and morphology characteristic of the lentivirus subfamily. The term includes, without limitation, all variants of HIV and SIV, including HIV-1, HIV-2, SIVmac, SIVagm, SIVmnd, SIVsmm, SIVman, SIVmand, and SIVcpz.
By xe2x80x9cMHC-independentxe2x80x9d is meant that the cellular cytolytic response does not require the presence of an MHC class II antigen on the surface of the targeted cell.
By a xe2x80x9cfunctional cytolytic signal-transducing derivativexe2x80x9d is meant a functional derivative (as defined above) which is capable of directing at least 40%, more preferably 70%, or most preferably at least 90% of the biological activity of the wild type molecule. As used herein, a xe2x80x9cfunctional cytolytic signal-transducing derivativexe2x80x9d may act by directly signaling the therapeutic cell to destroy a receptor-bound agent or cell (e.g., in the case of an intracellular chimeric receptor portion) or may act indirectly by promoting oligomerization with cytolytic signal transducing proteins of the therapeutic cell (e.g., in the case of a transmembrane domain). Such derivatives may be tested for efficacy, e.g., using the in vitro assays described herein.
By a xe2x80x9cfunctional HIV envelope-binding derivativexe2x80x9d is meant a functional derivative (as defined above) which is capable of binding any HIV envelope protein. Functional derivatives may be identified using, e.g., the in vitro assays described herein.
The transformed cells of the present invention are used for immunodeficiency virus therapy. Current methods of administering such transformed cells involve adoptive immunotherapy or cell-transfer therapy. These methods allow the return of the transformed immune-system cells to the bloodstream. Rosenberg, Sci. Am. 62 (May 1990); Rosenberg et al., N. Engl. J. Med. 323:570 (1990).
The pharmaceutical compositions of the invention may be administered to any animal which may experience the beneficial effects of the compounds of the invention. Foremost among such animals are humans, although the invention is not intended to be so limited.
The drawings will first be described.

Targeted cytolysis of HIV-infected cells by chimeric CD4 receptor-bearing cells


The invention relates to an energy-focusing and space-angle focusing reflector for time-of-flight mass spectrometers. The invention consists in producing an adjustable space-angle focusing system by means of an adjustably weaker field with curved equipotential lines at the end of the reflector instead of a fully homogeneous electrical reflection field.

The invention relates to an energy-focusing and space-angle focusing reflector for time-of-flight mass spectrometers.
Two-stage reflectors with grids are known from the work of B. A. Mamyrin, V. I. Karatzev and D. V. Shmikk (U.S. Pat. No. 4,072,862). These allow ions to be reflected with velocity focusing with an adjustable focal length (see FIG. 1). An initial, strong opposing field decelerates the ions while a second, well homogenized field reflects the ions to produce the velocity focusing. The focal length of the energy focusing can be adjusted by adjusting the field-strength ratio of the deceleration and reflection field. This reflector does not produce space-angle focusing.
Instead of two-stage reflectors, single-stage reflectors with only one grid in the input area can be used; these have a fixed, relatively short focal length for energy focusing and take up a large proportion of the total flight path of the time-of-flight mass spectrometer.
The work of R. Frey and E. W. Schlag (EP 0 208 894, U.S. Pat. No. 4,731,532) discloses grid-free, two-stage reflectors which provide space-angle focusing as well as a velocity focusing (FIG. 2). The space-angle focusing is produced by the grid-free deceleration field, which acts like an ion lens. However, the focal lengths of the velocity focusing and the space-angle focusing cannot be adjusted independently from each other; only a certain geometric arrangement is able to form an image on an ion detector from a slightly divergent ion beam emerging from a single source which is both velocity focused and space-angle focused.
The grid-free reflector is assembled from a number of metallic annular electrodes and a terminating electrode. The terminating electrode is usually in the form of a grid so that the spectrometer can also be operated in non-reflecting, linear mode with an ion detector placed behind the terminating electrode. The first two annular electrodes can have a relatively small internal diameter. A strong deceleration field is set up between them by applying a high potential difference. The equipotential lines which emerge from the space between, and pass through, the electrode apertures form the space-angle focusing ion lens. The other annular electrodes have the same internal diameter, the same distances between them and the same potential differences. They form a homogeneous reflection field which provides the energy focusing for ions of different energies due to the different penetration depths (and therefore different flight paths). The focal length of the energy focus is adjusted by the ratio of the field strengths in the deceleration and the reflection fieldxe2x80x94as with the grid reflector. The focus adjustment of the space-angle focusing, the focal length of which is not normally the same as that of the energy focusing, is therefore permanently coupled.
The invention consists in producing a weaker electrical field strength in the final section of the reflector field component. This creates the conditions for a field penetration of the somewhat stronger fields of the previous sections into the region of the weaker field and, due to the field penetration, slightly curved equipotential surfaces in the area of the last annular electrode. If the ions which are injected into this region are now brought to a stop before they are accelerated in the opposite direction, they are slightly deflected by the curved potential surfaces as they are reflected. Marginal beams which do not pass along the axis are deflected toward the axis and are therefore space-angle focused. The degree of deflection, and therefore the focal length of the space-angle focusing, can be adjusted by the degree to which the equipotential surfaces are curved. If the degree to which the equipotential surfaces are curved is predetermined and fixed, then the focal length of the space angle focusing can be adjusted by the total voltage at the reflector, i.e. by the penetration depth of the ions into the area of the increasingly curved equipotential surfaces.
The weaker field in the final section can be produced by lower potential differences with the same distance between the electrodes, by a larger distance between the last annular electrode and the terminating electrode at the same potential difference, by a combination of the two or by a dented terminating electrode. The dented terminating electrode pulls the curved equipotential surfaces as far as the terminating electrode. The dent does not have to be curved, a simple recess is sufficient.
The invention can be used in both single-stage and two-stage reflectors, with or without grids in each case.

Space-angle focusing reflector for time-of-flight mass spectrometers


A programmable system for providing a programmable ratio of output pulses to input pulses. The programmable system receives pulses from an electric power meter and outputs a programmable number of pulses representing a number of kilowatt hours consumed. Various electric power meter disk patterns can be processed by the programmable system. The programmable ratio can be applied via input pins and/or via an external memory.

The present invention is related to electrical power meters, and more particularly, to an integrated circuit that simplifies the mechanical portions of an electric power meter.
In an electric power meter, a mechanical gear train is driven by a meter disk. Various customers of electric power meters required that the gear train have various customized ratios between the number of meter disk rotations and the output of the gear train. As a result, various electrical power meters require different mechanical gear trains to provide the customized ratio. This increases the cost of electric power meters as well as the time required to manufacture electric power meters for a given customer.


A method and apparatus to optimize class of service under multiple VCs with mixed reliable transfer (RT) and continuous transfer (CT) modes have been disclosed where outstanding packets to be processed is through a Retransmission Mapper with a VOQ read pointer realignment that can quickly optimize network traffic with multiple VCs and mixed RT/CT modes.

Switches are widely used in systems. For example, the Serial Rapid Input Output (sRIO) Gen2 Switch may be used to meet wireless infrastructure customer's requirements for WCDMA/LTE Base Stations.
Quality Of Service (QOS) is an important issue in insuring that data that needs to arrive does so that the transmission does not suffer (e.g. video breaking up, voice dropping out, etc.) Switches are used to handle the data and quality of service is important across switch fabric. Certain traffic type may require reliable transfer without any packet loss through packet retransmission with low latency. Other traffic types can afford to be lossy but require fastest throughput. Under multiple Virtual Channels (VCs) with mixed Reliable Transfer/Continuous Transfer (RT/CT) modes, it may be difficult to handle packet retransmission for a VC in RT mode and discard the packets for a VC in CT mode. As a result, network traffic cannot be optimized especially when many packets are outstanding with large packet sizes. This presents a problem.

Method and apparatus to optimize class of service under multiple VCs with mixed reliable transfer and continuous transfer modes


The invention provides a method and apparatus for obtaining a selectable contrast image in an X-ray exposure. The method comprises applying a controlled high voltage to an X-ray tube in response to a controlled invertor-generated voltage; generating the controlled invertor-generated voltage; driving the invertor in response to a KV control signal; comparing a KV feedback signal with a KV reference signal for developing said KV control signal, and selecting any of a plurality of variable level reference signals as the KV reference signal. The apparatus comprises means for carrying out the foregoing method.

The invention is directed to the field of diagnostic X-ray imaging apparatus, and more particularly to a novel and improved method and apparatus for obtaining a selectable contrast image in a diagnostic X-ray exposure.
Diagnostic X-ray imaging apparatus has traditionally provided a program and technique, often presented on a chart, which allows a selection of three key factors prior to each exposure in an effort to optimize the levels of contrast in each exposure. These factors are (1) KVP - the peak kilovoltage (KV) applied to the X-ray tube during exposure; (2) MA - the milliamperes current forced through the X-ray tube in response to the selected KVP; and (3) time - the number of seconds, from on the order of tens of milliseconds up to on the order of ten seconds of duration of the exposure. More recently, the combined milliamperes and seconds are being combined in a term MAS, which refers to the multiplication product of the milliamperes times the seconds.
The KVP has two effects on the diagnostic value or exposure of the film. The peak KV value determines the penetrating power of the X-ray beam and also affects film-blackening. The MA or MAS determines the intensity of the beam, with total blackening of the film being directly proportional to the time of exposure.
A proper selection of these two (KVP and MAS) factors will produce an exposure of the film in varying levels of black and white contrast, forming an image of all parts of the body through which the X-rays have passed. That is, the various gradations of black and white exposure levels on the film will create a picture or image of the various body parts. This gradation may extend from an almost total black exposure for areas outside of the body part being imaged to a clear and virtually unexposed transparent film area for those body parts which are so dense that they totally absorb all X-rays that enter. In between the total black and clear or transparent areas, the gradations of film density provide diagnostic details in the form of variations of film density or black/white contrast levels.
In most X-ray generators heretofore, the KVP is determined by the voltage to the primary side of a high voltage generator circuit (allowing for voltage drops due to the regulation of the system). The earliest systems were single-phase, full-wave rectified, essentially giving a KVP waveform which converts a 60 Hz sine wave signal to two positive half-waves per cycle and transforms the voltage levels to the desired KVP voltage. Regardless of the KVP selected, the radiation exposure spectrum contained energies at all wavelengths from the lowest usable KV level (on the order of 30-40 KV) up to the KVP level selected by the operator. Hence as the KV level rises sinusoidally in these older systems, it first produces contrast on the exposure on the softer and less dense areas of the body part being imaged and continues to increase penetration into denser areas progressively. This relatively broad band of energy therefore permitted the X-ray film to display a relatively broad range of contrast for a given KVP setting. The greater the contrast of a film exposure, the easier it is, in theory, to visualize small density differences. As the KVP setting is increased, the range of contrast tends to be reduced, since it is the amount of relatively low level energy, produced by the lower KV levels, that determines the contrast range.
However, the foregoing single-phase system is highly inefficient by today's standards, and delivers an excessive amount of X-ray energy to the patient during the exposure. Later X-ray systems developed a three-phase technology designed to eliminate this waste of energy and excessive exposure. These three phase X-ray systems produced a waveform with very little energy at the lower kilovoltages, which greatly improve generator efficiency as compared to single phase. That is, instead of two sine waves per cycle, there were now six pulses interwoven in a mesh that eliminated much of the wasted energy in a single-phase system. However, the lowest KV level on any exposure was now only on the order of eighty percent of the peak KV value for the exposure. This resulted in a reduction of contrast in the exposure which was accepted as a trade-off for the higher efficiency. This means that smaller gradations of density are harder to identify in the exposed film, which may make diagnosis more difficult. Finally, with the development of high frequency X-ray generators, exposures are made at an almost constant kilovoltage level with very little "soft" radiation. In such systems, the efficiency is greatly improved by the use of high frequency switching which provides precise timing, precise duplication of exposures from one exposure to the next, and shortened exposure times. In high frequency generators, the kilovoltage at the generator is monitored and compared to a selectable, fixed reference voltage. Any resultant difference voltage is used to directly regulate the kilovoltage. As the reference voltage is changed by the operator, the kilovoltage changes correspondingly to a new level; that is, in a closed-loop type of system.
However, each improvement has further reduced the proportion of the lower KV levels to the selected KVP and therefore reduced the overall contrast of the image. However, because these changes have taken place over a long period of time, this gradual reduction in contrast has been generally accepted by diagnosticians.

Method and apparatus for obtaining a selectable contrast image in an X-ray film


A 3-dimensional motion picture display is achieved by raster scanning a beam of collimated light from each of a plurality of light sources into a viewing space. The system is essentially a time based ray tracer, and can thus simulate objects both behind, on, and in front of the physical locations of the light emanating from the sources.

Many methods have been proposed for displaying visual scenes in a realistic 3-dimensional form. Early forms of this art involve the wearing of glasses with a different color filter for each eye, or glasses with orthogonal polarizations for each eye. In both cases, the projection systems encoded two separate views accordingly, to be viewed separately by the individual eyes of a viewer.
Holography has been used in the 3-dimensional display of information, although applying these principles to moving pictures has proven difficult.
In accordance with the preferred embodiment of the present invention, a 3-dimensional motion picture display is achieved without special glasses on the viewers, and without reliance on holographic methods. Further, it actually displays a large multitude of scene angles, not just two, thereby giving full 3-dimensional effects as one moves around in the viewing space. The device generally projects this three dimensional image from a two dimensional screen.
The foregoing and additional features and advantages of the present invention will be more readily apparent from the following detailed description thereof, which proceeds with reference to the accompanying drawings.

Method and apparatus for 3-dimensional motion picture display


To efficiently process a parameterized query against a relational database in a streaming transaction processing system, the transaction stream is treated as a sequence of multi-record “chunks” and a single “quasi-batch” query is executed for each chunk. A specific table in the database holds the parameter values obtained from each transaction and the parameters are bound to the rest of the query by using a database join. Another embodiment uses a framework that automates the technique by accepting the parameterized query, identifying inputs and outputs, reading the stream for the parameter values and building the parameter table, converting the parameterized query into an equivalent query that contains a join against the parameter table, performing the equivalent query and inserting the resulting query values into the stream.

In many streaming transaction processing systems, it is necessary to execute queries that are driven by values in the streaming data against a conventional relational database. For example, in a typical streaming environment, a stream of records or objects that contain various data fields arrives continuously at the transaction processing system. In order to process a typical transaction, it is necessary to execute a conventional SQL query for each record in the stream where inputs to the SQL query are taken from selected field values in that record. Also, in many cases, the output values from the SQL query will be placed back into fields of that record so that the record can be further processed downstream of the SQL query lookup. For example, a billing processing system many receive a constant stream of records that are the result of metering equipment operating in the field. It is often necessary to lookup a rate or other value for each record based on the values in some of the fields in the record, such as type and quality of service, service duration, etc. Once the rate is determined it is written into a rate field in the record so that the record can be further processed as a unit.
One simple mechanism for executing such a query is to execute a parameterized SQL statement against the database as each new record is received. For example, assume that the transaction processing system receives a stream (stream) of records wherein each record (record) contains at least two fields, named field A and field B, each field containing values that are to be used in the query. Then, as discussed above, for each such record, it is necessary to retrieve a value from a field C that is stored in a relational database in a table where the retrieval is based on the values in fields A and B in the record. Such a query can be written as a join of two tables (tables t1 and t2) that are joined on the value of a third field D where the second table holds the parameter value for the field B. Such a query might be written in standard SQL language as:
SELECT t1.C FROM table1 t1 INNER JOIN table2 t2
                ON t1.D=t2.D        WHERE t1.A=@A AND t2.B=@B
This SELECT statement can then be used in a simple program that processes records in a stream by reading the values of fields A and B from each record, performing the query for that record, reading a field (C) from the query result and subsequently writing the contents of field C to the original record. The program can be described by the following "pseudo code":
FOR EACH record IN stream
                BEGIN                    READ A, B FROM record            EXECUTE query WITH @A=record.A AND @B=record.B            READ C FROM query            WRITE C TO record                        END
The biggest problem with this approach is that it is not efficient, particularly if the overhead cost of executing the query is small relative to the overhead cost of the query itself (including the RPC overhead, in particular). Furthermore, any work done by the database in the process of executing the query for one record is not leveraged when processing the same query for subsequent records (important examples of such work include sorting that occurs in merge joins, hash tables that are built to perform hash joins and index traversals to read a page in the case of nested loop joins).

Method and apparatus for efficiently processing queries in a streaming transaction processing system


A relatively low profile cash handling device or register for mounting on a support structure such as a table having a recess in its upper surface. The cash register includes an upper body portion on which the operation keys, the display portion and the printer are located and a lower drawer housing being located beneath and integral with the upper body portion, for covering and protecting both sides of the drawer and accommodating the drawer slidably movable therein, with the lower drawer housing including a lower section having a smaller width dimension relative to the front of the cash handling device than the width dimension of the upper body portion, and the lower drawer housing having an outwardly extending flange portion for contacting and being supported by the upper surface of the table so that the lower secetion and the drawer resides in the recess when mounted thereon. The upper body portion is integrally formed together with the lower drawer housing portion by means of synthetic resin.

1. Field of the Invention
The present invention relates to a cash handling device such as a cash register which is installed in various types of stores for totalizing the commodities transactions and a cash till which is installed in a bank.
2. Description of the Prior Art
Recently, stores whose interior design is unified, including the facilities and equipments to be installed therein, has been increasing. Typical examples are boutiques, coffee shops, etc. Therefore, a cash register which is to be installed in these stores requires designs tailored to the interior design of each store.
FIG. 1 for example, discloses, a perspective view of a cash register 1 in accordance with the known prior art. The cash register 1 comprises a body portion 7 including an upper casing 9 and a lower casing 10 that electronic circuits, etc. can be accommodated therein and a drawer housing portion 14 in which a drawer 12 of a cash box is housed. The body portion 7 is comprised of an operation portion 6 equipped with a key switch 11 on the surface 3 faced upwards and a protrusion 5 which protrudes upwards in FIG. 1 from the operation portion 6. A display portion 8 which can display transaction data is provided at the forward side of the protrusion 5, and a printer 4 which can issue a receipt and a journal is installed at the left side of the display portion 8'.
FIG. 2 is a sectionl view of a cash register taken along the sectional line II--II of FIG. 1. The body portion 7 and the drawer housing portion 14 of the cash register 1 are independently configured. More particularly, the drawer housing portion 14 is composed of a rectangular structure made of metal, and the body portion 7 is composed of an upper casing 9 and a lower casing 10, which are made of plastic resin, etc. The body portion 7 and the drawer housing portion 14 are fastened together by fitting bolts 15a and 15b in bosses 17a and 17b provided at the upper part of the money drawer housing portion 14 through through-holes 16a and 16b located at the bottom of the lower casing 10.
It is necessary for the printer 4 to accommodate a journal paper 19 and a receipt paper, each of which is a roll of paper. The printer 4 must also accommodate journal paper 20 which is printed out and wound by a printing mechanism 18. For this reason, the printer 4 is required to have a comparatively large capacity. A protrusion 5 which extends upwards from the operation portion 6 is installed in the cash register 1, thereby providing a space for the above journal paper 19 and 20'.
FIG. 3 is a simplified sectional view of the cash register 1 taken along the sectional line III--III in FIG. 1. In the cash register 1, the width W2 of the money drawer housing portion 14 is larger than that W1 of the body portion 7. Therefore, the cash register 1 is relatively large-sized.
In the cash register 1 of the above prior art, since the drawer housing portion 14 is made of metal, the weight thereof is also increased. Furthermore, the width W2 of the drawer housing portion 14 being larger than that W1 of the body portion 7, the outside profile of the cash register 1 may give customers an oppressive feeling.
Also, in the case of changing the design of this type of cash register 1, it is conventionally usual that the design of only the body portion 7 be changed. The design of the cash register 1 can not be completely changed. Therefore, it is difficult to change the design of the cash register to a novel one according to changes of the times. Moreover, since the drawer housing portion 14 and the body portion 7 are independently constructed, the number of component parts is increased, thereby causing the production cost to be accordingly increased.
Still further, since a protrusion 5 is provided in order to accommodate the printer 4 in the cash register 1 in the above prior art, the height of the cash register 1 becomes relatively high and the outside profile thereof is appears very large. And a design becomes uniform. Therefore, the cash register 1 like that shown in FIG. 1 may not match respective interior designs of some types of stores and may therefore cause a sense of incongruity.


A catalyst composition is provided which comprises at least one specified metal salt of a weak acid and a zinc salt of a weak acid or an iron salt of a weak acid. A process for preparing a N-halothio-sulfonamide-modified terpolymer of ethylene, an alpha olefin and a diene utilizing the catalyst is also provided. The catalyst is a selective catalyst in this process.

1. Field of the Invention
The present invention relates to a selective catalytic process for preparing N-halothio-sulfonamide modified terpolymers of ethylene-alpha olefin-diene, and catalyst compositions suitable for use in this process.
2. Description of Information Disclosures
Modified polymers of the type of interest herein, specifically rubbery polymers, are described in U.S. Pat. Nos. 3,915,907 and 3,970,133 (R. J. Hopper) incorporated herein by reference. The desirability and advantages of such polymers was additionally disclosed in articles authored and co-authored by R. J. Hopper (Rubber Chemistry and Technology, Vol. 49, p. 341-352 (1976) and International Conference on Advances in the Stabilization and Controlled Degradation of Polymers, Lucerne, Switzerland, May 23-25, 1984).
These references describe the reaction of various N-chlorothioamides, and particularly N-chlorothio-sulfonamides with various ethylene propylene diene monomer (EPDM) rubbers in solution (see, e.g., Examples I-XII of U.S. Pat. No. 3,915,907) as well as by mixing in a Banbury.RTM. type internal mixer (Examples XIII-XVI of U.S. Pat. No. 3,915,907). Furthermore, in Example XVII of the same reference, there is disclosed in a solution reaction the use of powdered anhydrous zinc chloride (this is referred to as a catalyst in Table I, footnote g and page 346 of the cited Rubber Chemistry and Technology article). The references contain no further disclosure concerning the effect of zinc chloride nor do they suggest the use of other catalytic agents.
U.S. Pat. No. 4,820,780 issued Apr. 11, 1989 discloses a method of preparing a N-chlorothio-sulfonamide-modified terpolymer of ethylene, alpha olefin containing from 3 to 6 carbon atoms and a diene in the presence of a saturated aliphatic carboxylic acid containing from 6 to 30 carbon atoms, such as stearic acid. Calcium carbonate may also be added to the reaction as a scavenger for the HCl by-product. It does not suggest the use of metal salts of weak acids as catalysts.
It would be desirable to improve the rate of reaction, the conversion and product quality produced by known processes to achieve commercially useful conditions. It would be particularly useful to improve the melt phase process so as to enhance the addition reaction while minimizing the crosslinking reaction.
It has now been found that certain catalyst compositions comprising zinc salts or iron salts of weak acid in combination with a metal salt of certain metals (other than zinc or iron) of weak acids (i.e., co-catalyst) are selective catalysts in the preparation of N-halothio-sulfonamide modified terpolymers of ethylene-alpha olefin-diene. By "selectivity", it is intended herein that the desired addition reaction is increased while the undesired crosslinking reaction, which leads to increased Mooney viscosity and to gelation, is minimized.
Mixtures or blends of low-unsaturation rubbery polymers, particularly EPDM, with highly unsaturated rubbery polymers are of practical importance because of the superior ozone resistance imparted to the blend by the low-unsaturation EPDM rubber. Unfortunately, the presence of the low-unsaturation rubber also affects the mechanical and hysteresis characteristics of the vulcanizates in an adverse manner, as evidenced by lower tensile strength and modulus values, and by higher dynamic heat build-up and permanent set. These undesirable responses are contributed to by the mutual incompatibility of the two types of rubber, the substantially slower cure rate of the low-unsaturation rubber, and the greater affinity of the typically polar curatives for the high-unsaturation rubber. As a result, the vulcanized blend is a heterogeneous dispersion of poorly cured and/or largely uncured low-unsaturation rubber in well cured high-unsaturation rubber. The resulting poorer mechanical and hysteresis properties severely limit, or preclude, the use of such blends in articles subjected to severe service requirements such as tires. A method for improving the physical and dynamic properties of such rubbery polymer vulcanized blends is of considerable commercial and practical importance.

Selective catalytic process for preparing N-halothiosulfonamide modified EPDM terpolymers


In one embodiment, a multi-stakeholder environment is controlled by first assigning a first domain to a first stakeholder and a second domain to a second stakeholder. Then a first access policy is defined for the first domain and access is restricted to the first domain for the second stakeholder according to the first access policy. In another embodiment, an access request is handled in a multi-stakeholder environment by first receiving parameters forwarded by hooks in system call functions in a kernel of the multi-stakeholder environment, wherein the parameters contain information about a first stakeholder requesting access to a domain corresponding to a second stakeholder. Then it is determined whether to allow the first stakeholder to access the domain based at least partially upon security settings corresponding to the domain.

1. Field of the Invention
The present invention relates to computer security. More specifically, the present invention relates to the building of trusted mobile platforms.
2. Description of the Related Art
Mobile devices such as mobile phones or personal data assistants often store sensitive data that could be damaging if it fell into the wrong hands. These data can come from the applications from multiple stakeholders, such as the manufacturer, network provider, and third party service providers. Additionally, the user of a mobile device can store personal data and download/install software from the Internet or from other potentially unreliable sources. Furthermore, malicious programs do not always require active installation by a user in order to gain access to sensitive information. For example, a malicious program may automatically (and surreptitiously) install itself on the mobile device upon download. Malicious programs can utilize this sensitive information for many different types of untoward behavior. For example, a recent mobile phone virus was found that can send out user address book or calling history to others without the user's permission.


An automatic-switching wireless communication system and method, comprising: a first device, and a second device. The first device verifies if said second device has paired with itself through using near end wireless communication. If an answer is positive, the second device connects with the first device by near end wireless communication and requests first device to activate remote end wireless communication. Then, second device searches to find a remote end wireless communication module of the first device. In case it is found, the first device is used as a wireless base station, such that the first device and the second device transmit data by remote end wireless communication, and the second device is connected to an outside network through the first device. If the second device is outside a range of the near end wireless communication of the first device, said remote end wireless communication module is closed automatically.

1. Field of the Invention
The present invention relates to a technology of wireless communication system, and in particular to an automatic-switching wireless communication system and method.
2. The Prior Arts
With the progress and development of Network technology, the wire network data transmission speed is increasing rapidly. Meanwhile, the emergence of wireless network has toppled the concept of conventional network that, for a network, communication can only be realized through a communication line, so the wireless network has brought convenience to the user, such that by connecting a mobile phone handset to the wireless network, the user can be connected to a computer while moving. As such, the mobile phone user can get on the network at any time, even while he is commuting or at work.
In transmitting data to another mobile phone handset, computer, or On-Board-Unit (OBU), an ordinary handset utilizes wireless network to transmit data. In general, the application of handset in wireless network can be classified into a near end wireless communication and a remote end wireless communication. The near end wireless communication includes: Bluetooth, Near Field Communication (NFC), wireless RF communication. While the remote end wireless communication includes WiFi. The near end wireless communication, such as Bluetooth or NFC is more power saving, yet its induction range is rather short of about 10 meters. Also, its transmission speed is slow. On the other hand, the induction range of WiFi is about 50 to 60 meters, but it is rather power consuming, such that its battery can not sustain long period of power-on of WiFi. For this reason, usually, a mobile phone handset powers on its Bluetooth function instead of continuously powering on WiFi. Only when it needs to transmit data thus requiring resetting of wireless network options, will it select the WiFi function. However, the actions involved in this process are tedious and complicated, thus it does not conform to time-effective requirement for the people of modern time.
Therefore, the design and performance of network wireless communication is not quite satisfactory, and it has much room for improvements.

Automatic-switching wireless communication system and method


A one-leaf or two-leaf sliding door, swinging/sliding door or pocket door, particularly for vehicles, has an electric, pneumatic or hydraulic drive. A nut is attached to the at least one door leaf and a spindle extends through the nut. A drive for moving the at least one door leaf is provided either to rotate the spindle directly or to linearly move the at least one door leaf. A freewheel is mounted on an end of the spindle, wherein the freewheel has a component which is stationary relative to but capable of rotating together with the spindle. A releasable brake or clutch is provided for preventing rotation of the freewheel component.

1. Field of the Invention
The invention is directed to one-leaf or two-leaf sliding doors, swinging doors or pocket doors with an electric, pneumatic or hydraulic drive, in particular for vehicles, wherein a spindle is provided, the leaf or leaves being connected therewith via a nut, wherein, in the case of two-leaf doors, the spindle is constructed symmetrically with respect to the center of the door, and wherein the door drive acts either rotatively on the spindle or linearly on one of the leaves.
2. Description of the Related Art
A swinging/sliding door with an electric drive is known, for example, from DE-C 36 30 229 which discloses a two-leaf door in which each leaf has an upper and a lower guide rail in which at least one roller engages in each instance. The vertically extending rotational axis of the rollers is swivelable about a vertically extending door post pipe, this swiveling movement causing the door to open outward.
Since the electric drive can carry current only when the door is actuated, a dead-center mechanism is required for locking the door so as to ensure that the closed door cannot be opened by manipulation.
As another consequence of this dead-center mechanism, the door is only locked when it has been moved completely into the final closing position, so that any failure of the drive or any obstacle preventing the door from being closed completely will allow the door to open, e.g., as a result of the vibrations of the moving vehicle. On the other hand, the dead-center mechanism must also be adjusted precisely which, under heavy-duty operating conditions and during large differences in temperature, is difficult and accordingly disadvantageous.
The use of the door post pipe which is associated with each door leaf and is located at the edge of the door opening in the region of the lateral closing edge is another great disadvantage. When the door is open, this door post pipe can be covered only with difficulty and, even then, not completely. In the process of closing the door, the door post pipe in the region of the lateral closing edge poses the most serious kind of risk, especially for children and older, frail persons seeking a handhold.
Problems also occur in alignment because the door post pipe must be fitted and aligned in the floor region as well as in the roof region. There is no need to demonstrate in particular such problems which occur in all three axial directions.
Swinging/sliding doors with a pneumatic or hydraulic drive in which the door leaves are guided in a swivelable manner by means of a slide so as to be longitudinally displaceable at a stationary circular supporting pipe have also been known from Austrian Patent document 188 323. The corresponding guide rails for the opening out movement and for longitudinal guidance are arranged on the vehicle side in the region of the upper edge and lower edge of the door. Suitable guide rollers are provided at the door leaf
The drive is effected via a cylinder-piston unit, and various lever mechanisms and scissor mechanisms have been suggested for reducing installation width. In the closed state, these doors are locked in the region of the lateral closing edge by a mechanism arranged in that location so that they remain closed while the vehicle is in motion in the event of a drop in pressure in the drive, but also because the normal operating pressure is not sufficient to prevent the door from opening in a reliable manner. It is not possible to achieve an operating pressure sufficient for this purpose in an economical manner due to the required wall thickness of the pipes and tubes.
The lock projecting beyond the free profile of the door at the height of the door handle in the region of the lateral closing edge poses a source of risk on a par with the door post pipe in the construction mentioned above.

One- or two-leaf sliding door, swinging door or pocket door