This invention relates to a methodology for assessing the sensitivity of an HIV-1 sample to zidovudine and to diagnostic assays for use in such assessment.

The present invention relates to a method for assessing the sensitivity of an HIV-1 sample to zidovudine and to diagnostic assays for use in such assessment.
One group of viruses which has recently assumed a particular importance are the retroviruses. Retroviruses form a sub-group of RNA viruses which, in order to replicate, must first xe2x80x98reverse transcribexe2x80x99 the RNA of their genome into DNA (xe2x80x98transcriptionxe2x80x99 conventionally describes the synthesis of RNA from DNA). Once in the form of DNA, the viral genome is incorporated into the host cell genome, allowing it to take full advantage of the host cell""s transcription translation machinery for the purposes of replication. Once incorporated, the viral DNA is virtually indistinguishable from the host""s DNA and, in this state, the virus may persist for as long as the cell lives. As it is believed to be invulnerable to attack in this form, any treatment must be directed at another stage of the virus life cycle and would, have to be continued until all virus-infected cells have died.
A species of retrovirus has also been reproducibly isolated from patients with AIDS and is now named as human immunodeficiency virus (HIV-1) and is also known as human T-cell lymphotropic virus III (HTLV III), AIDS associated retrovirus (ARV), or lymphadenopathy associated virus (LAV).
This virus has been shown preferentially to infect and destroy T-cells bearing the OKT4 surface marker and is now generally accepted as the aetiologic agent of AIDS. The patient progressively loses his set of T-cells, upsetting the overall balance of the immune system, reducing his ability to combat other infections and pre-disposing him to opportunistic infections which frequently prove fatal. Thus, the usual cause of death is AIDS victims is by opportunistic infection, such as pneumonia or virally induced cancers, and not as a direct result of HIV infection.
The complete nucleotide sequence of the AIDS virus HIV-1 or as it was previously known HTLV-III has been elucidated (Ratner, L., et al. Nature, Vol. 313, p 277, 24 Jan. 1985).
Recently, HIV-I has also been recovered from other tissue types, including B-cells expressing the T4 marker, macrophages and non-blood associated tissue in the central nervous system. This infection of the central nervous system has been discovered in patients expressing classical AIDS symptoms and is associated with progressive demyelination, leading to wasting and such symptoms as encephalopathy, progressive dysarthria, ataxia and disorientation. Further conditions associated with HIV infection are the asymptomatic carrier state, progressive generalised lymphadenopathy (PGL) and AIDS-related complex (ARC). HIV-1 can also be present in other tissues or physiological fluids such as urine, plasma, blood, serum, semen, tears, saliva or cerebrospinal fluid.
3xe2x80x2-Azido-3xe2x80x2-deoxythymidine-(hereafter called xe2x80x9czidivudinexe2x80x9d) is used in the control of HIV infections including AIDS and ARC. Zidovudine is a thymidine analogue whose triphosphate form inhibits the replication of the human immunodeficiency virus (HIV) by competitive binding to viral reverse transcriptase (RT) and DNA chain termination after phosphorylation by cellular enzymes (Furman, P. A et al., Pric. Natl. Acad. Sci. USA, 1986, 83: 8333). It is an effective antiviral agent both in vitro and in vivo against a variety of retroviruses (Mitsuya H et al., Cancer Res., 1987, 47: 3140; Ruprecht R. M et al., Nature, 1986, 323: 476.) and has been demonstrated to improve the quality and length of life of patients with AIDS and advanced ARC (Fischl M. A et al., N. Engl. J. Med., 1987, 317: 185; Schmitt F. A. et al, N. Engl. J. Med 1988, 31 9: 1573; Greagh-Kirk T et al, J. Am. Med. Assoc., 1988, 260.: 3009) and also in asymptomatics with low CD4+ cell
As with any anti-infective agent, concern about the potential development of resistance has engendered extensive investigations evaluating factors which might potentially alter the sensitivity of retroviruses to zidovudine.
A study carried out to measure zidovudine sensitivity of HIV isolates from patients with AIDS or ARC after zidovudine treatment has in fact revealed that a number of isolates from patients treated for six months or more showed reduced sensitivity to zidovudine whereas isolates from untreated individuals and those treated for less than six months showed uniform sensitivity to the drug (Larder, B. A., Darby, G, and Richman, D. D., Science, Vol. 243, 1731, 31st Mar. 1989).
At present the way to determine the sensitivity of HIV-1 strains to xe2x80x9czidivudinexe2x80x9d) is to isolate HIV-1 from a patient""s peripheral blood lymphocytes. HIV-1 isolates can be made by co-cultivation of peripheral blood lymphocytes (PBL""s) with cells of the continuous line MT-2. (Harada, S., Koyanagt, Y., Yamamoto, N., Science 229, 563 (1985). This procedure can take anything from between four sad fourteen days before HIV-1 can be isolated. The diagnosis of resistant strains of HIV-1 relies firstly on the isolation of virus and then on sensitivity testing by a tissue culture method and so is consequently extremely slow.
The present inventors have discovered the basis for resistance of HIV-1 to zidovutne at the nucleic acid level. Five nucleotide substitutions have been identified in the HIV-1 genome which result in a change of four amino acids in the RT protein. This discovery has important implications for the detection of resistant HIV isolates because of the highly conserved nature of these nucleotide mutations in RT conferring resistance to zidovudine and opens the way to the routine detection of such resistant isolates.
It is possible to carry out a diagnostic assay for the screening of bodily samples from patients for an assessment of the sensitivity of HIV-I to zidovudine. Using the knowledge of the mutations identified as important in the development of highly resistant strains of HIV-1 such as assay can be developed.
An analysis of a group of resistant mutants was carried out by nucleotide sequencing which allowed the identification of mutations in the HIV RT gene that confer resistance to zidovudine. The complete RT coding region (1.7 kb) was obtained far each isolate using polymerase chain reaction (PCR) amplification of infected cell DNA. The nucleotide changes at the five positions in HIV-1 RT that confer resistance to zidovudine are illustrated in FIG. 1. Numbering of the nucleotides of the HIV-1 RT gene is as reported by Ratner et al (Ratner et al., Nature. 313, 277, (1985)).
It is demonstrated that these specific mutations confer zidovudine-resistance, as an infectious molecular HIV clone containing only these nucleotide changes is resistant to zidovudine. (See Example 4).
From analysis of clinical samples it appears that the sensitivity of HIV-1 to zidovudtne changes over a period of time. It appears that mutations may occur at any of one or more of the five identified sites as the time from the onset of treatment with zidovudtne advances and it is clear than as HIV-1 sample which carries all five mutations is highly resistant to zidovudine.
At this time it is not possible to predict any order of occurence of these mutations, although particular attention is being focussed on the two nucleotides of the wild-type DNA sequence (or its corresponding RNA) or to the two nucleotides of the mutant DNA sequence (or its corresponding RNA) set forth in FIG. 1 at the 2772- and 2773- positions.
Accordingly in a fast aspect of the invention there is provided a method for assessing the sensitivity of an HIV-1 sample to zidovudine, which comprises:
(i) isolating nucleic acid from the sample,
(ii) hybridising an oligonucleotide to the nucleic acid, the oligonucleotide being complementary to a region of the wild-type DNA sequence (or its corresponding RNA) or to a region of the mutant DNA sequence set forth in FIG. 1 (or its corresponding RNA) and terminating at the 3xe2x80x2-end with the nucleotide in the 2328-, 2338-, 2772-, 2773- or 2784-position,
(iii) attempting polymerization of the nucleic acid from the 3xe2x80x2-end of the oligonucleotide,
(iv) ascertaining whether or not an oligonucleotide primer extended product is present.
It is possible to use genomic DNA or RNA isolated from HIV-1 samples in this methodology. Suitable cells for supporting the growth of HIV-1 such as MT-2 cells, are firstly infected with as HIV-1 isolate and incubated for a period of time. The cells are recovered by centrifugation. DNA can thaw be isolated by digestion of the cells with proteinase K in the presence of EDTA and a detergent such as SDS, followed by extraction with phenol (see Example 1 for the methodology used by the inventors for the isolation of HIV-1 DNA).
Well-known extraction and purification procedures are available for the isolation of RNA from a sample. RNA can be isolated using the following methodology. Suitable cells are again infected and incubated for a period of time. The cells are recovered by centrifugation. The cells are resuspended in an RNA extraction buffer followed by digestion using a proteinase digestion buffer and digestion with proteinase K. Proteins are removed in the presence of a phenol/chloroform mixture. RNA can than be recovered following further centriguation steps. (Maniatis, T., et al, Molecular Coning, A Laboratory Manual, 2nd Edition, Cold Spring Harbor Laboratory Press, (1989)).
Although it is possible to use unamplified nucleic acid, due to the relative scarcity of nucleic acid in an HIV-1 sample it is preferable to amplify it. Nucleic acid may be selectively amplified using the technique of polymerase chain reaction (PCR), which is an in vitro method for producing large amounts of a specific nucleic acid fragment of defined length and sequence from small amounts of a template.
The PCR is comprised of standard reactants using Mg2+ concentration, oligonucleotide primers and temperature Cycling conditions for amplification of the RT Gene using the primers. The primers are chosen such that they will amplify the entire RT gene or a selected Sequence which incorporates nucleotides corresponding to a region of the wild-type DNA sequence of HIV-1 between the nucleotides at the 2328- and 2784- positions set forth in FIG. 1. Example 2 provides a description of PCR used to amplify target nucleic acid.
RNA cannot be amplified directly by PCR. Its corresponding cDNA must be first of all synthesised. Synthesis of cDNA is normally carried out by primed reverse transcription using oligo-dT primers. Advantageously, primers are chosen such that they will amplify the nucleic acid sequence for RT or a selected sequence which incorporates nucleotides corresponding to the region of RNA corresponding to the wild-type DNA sequence or to the region of the mutant DNA sequence set forth in FIG. 1 between the nucleotides 2328- and 2784-. This could be achieved by preparing an oligonucleotide primer which is complementary to a region of the RNA strand which is up-stream of the corresponding sequence of the wild-type DNA sequence between nucleotides 2328- and 2784-. cDNA prepared by this methodology (see Maniatis, T., et al., supra.) can then be used in the saint way as for the DNA already discussed.
The next stage of the methodology is to hybridise to the nucleic acid an oligonucleotide which is complementary to a region of the wild-type DNA sequence (or its corresponding RNA) or to a region of the mutant DNA sequence (or its corresponding RNA) set forth in FIG. 1 and terminating at the 3xe2x80x2-end with the nucleotide at the 2328-, 2338-, 2772-, 2773- or 2784- position.
Conditions and reagents are then provided to permit polymerisation of the nucleic acid from the 3xe2x80x2-end of the oligonucleotide primer. Such polymerisation reactions are well-known in the art.
If the oligonucleotide primer has at its 3xe2x80x2-end a nucleotide which is complementary to a mutant genotype, that is a genotype which has a nucleotide change at the 2328-, 2338-, 2772-, 2773- or 2784- position as set forth in FIG. 1 then polymerization of the nucleic acid sequence will only occur if the nucleic acid of the sample is the same as the mutant genotype. Polymerisation of a wild type nucleic acid sequence will not occur or at least not to a significant extant because of a mis-match of nucleotides at the 3xe2x80x2-end of the oligonucleotide primer and the nucleic acid sequence of the sample.
If the oligonucleotide primer has at its 3xe2x80x2-end a nucleotide which is complementary to the wild-type genotype, that is a genotype which has the wild-type nucleotide at the corresponding 2328-, 2338-, 2772-, 2773- or 2784- position as set forth in FIG. 1, then these will be polymerisation of a nucleic acid sequence which is wild-type at that position. There will be no polymerisation of a nucleic acid which has a mutant nucleotide at the 3xe2x80x2-position.
The preferred length of each oligonucleotide is 15-20 nucleotides. The oligonucleotide can be prepared according to methodology well known to the man skilled in the art (Koster, H., Drug Research, 30 p548 (1980); Koster, H., Tetrahedron Letters p1527 (1972); Caruthers, Tetrahedron Letters, p719, (1980); Tetrahedron Letters, p1859, (1981); Tetrahedron Letters 24, p.245, (1983); Gate. M., Nucleic Acid Research, 8, p1081, (1980)) and is generally prepared using an automated DNA synthesiser such as an Applied Biosystems 381A synthesiser.
It is convenient to determine the presence of an oligonucleotide primer extended product. The means for carrying out the detection is by using an appropriate label.
The label may be conveniently attached to the oligonucleotide primer or to some other molecule which will bind the primer extended polymerisation product.
The label may be for example an enzyme, radioisotope or fluorochrome. A preferred label may be biotin which could be subsequently detected using streptavidin conjugated to an enzyme such as peroxidase or alkaline phosphatase. The presence of an oligonucleotide primer extended polymerisation product can be detected for example by running the polymerisation reaction on an agarose gel and observing a specific DNA fragment labelled with ethidium bromide, or Southern blotted and autoradiographed to detect the presence or absence of bawds corresponding to polymerised product. If a predominant band is present which corresponds only to the labelled oligonucleotide then this indicates that polymerisation has not occurred. If bands are present of the correct predicted size, this would indicate that polymerisation has occurred.
For example, DNA isolated from patients"" lymphocytes as described herein is used as a template for PCR amplification using synthetic oligonucleotide primers which either match or mis-match with the amplified sequences. The feasibility of PCR in detecting such mutations has already been demonstrated. PCR using the Amplification Refractory Mutation system (xe2x80x9cARMSxe2x80x9d) (Newton, C. R., et al. Nucleic Acids Research, 17, p.2503; (1989)) Synthetic oligonucleotides are produced that anneal to the regions adjacent to and including the specific mutations such that the 3xe2x80x2 end of the oligonucleotide either matches or mismatches with a mutant or wild-type sequence. PCR is carried out which results in the identification of a DNA fragment (using gel electrophoresis) where a match has occurred or no fragment where a mismatch occurred.
For example, using the 2 oligonucleotides below as PCR primers:
5xe2x80x2-ATG TTT TTT GTC TGG TGT GGT-3xe2x80x2- (1) OR
5xe2x80x2-ATG TTT TTT GTC TGG TGT GAA-3xe2x80x2- (2) plus the common oligonucleotide primer:
xe2x80x9cBxe2x80x9d-5xe2x80x2- GGA TGG AAA GGA TCA CC-3xe2x80x2 it is possible to distinguish between sensitive and resistant virus. DNA is extracted from HIV-1 infected T-cells as described herein and subjected to xe2x80x9cARMSxe2x80x9d PCR analysis using these primers. If the virus is sensitive a 210 bp fragment is generated with oligonucleotide B+(1) but not with B+(2). BY contrast, if the virus is zidovudine resistant a 210 bp fragment is generated with B+(2) but not with B+(1).
The presence of a fragment is identified by using an oligonucleotide primer as described above, i.e. by attempting polymerisation using an oligonucleotide primer which may be labelled for the amplified DNA fragment under stringent conditions which only allow hybridisation of complementary DNA (the only difference is that differential hybridisation does not have to be performed as fragments of DNA amplified by the xe2x80x9cARMSxe2x80x9d method will be the same whether derived from mutant or wild-type DNA, so a common oligonucleotide can be used to detect the presence of these fragments. The sequence of such an oligonucleotide is derived from a DNA sequence within the DNA fragment that is conserved amongst HIV-1 strains).
The above PCR assay may be adapted to enable direct detection of mutations associated with zidovudine resistance is DNA from PBL samples from infected individuals that have not been cultured to obtain virus. As this material generally contains considerably less HIV-1 DNA than that in infected lymphoid cultures a xe2x80x9cdouble PCRxe2x80x9d (or nested set) protocol can be used (Simmonds, P., Balfe, P, Peutherer, J. F., Ludlam, C. A., Bishop, J. O. and Leigh Brown, A. J., J. Virol., 64, 864-872, (1990)) to boost the amount of target HIV-1 RT DNA signal in the samples. The double PCR overcomes the problem of limited amplification of a rare template sequence. Initially a fragment may be amplified from within the RT region which encompasses all the commonly observed mutations. A small amount of the pre-amplified material may be used in the second PCR with primer pans designed to allow discrimination of wild type and mutant residues.
A suitable test kit for use in an assay to determine the resistance status of an HIV-1 sample to zidovudine which makes use of a methodology according to the first aspect of the invention, comprises an oligonucleotide being complementary to a region of the wild-type DNA sequence (or its corresponding RNA) or to a region of the mutant DNA sequence set forth in FIG. 1 (or its corresponding RNA) and terminating at the 3xe2x80x2-end with the nucleotide in the 2328-, 2338-, 2772-, 2773- or 2784- position, other materials required for polymerisation of the nucleic acid from the 3xe2x80x2- end of the oligonucleotide and means for determining the presence of an oligonucleotide primer extended product. Such other materials include appropriate enzymes, buffer and washing solutions, and a label and a substrate for the label if necessary. If PCR is used to amplify nucleic acid then additional materials such as appropriate oligonucleotide primers which will amplify a region of the wild-type DNA sequence (or its corresponding RNA) or a region of the mutant DNA sequence set forth in FIG. 1 (or its corresponding RNA) containing one or more of the nucleotides at the 2328-, 2338-, 2772-, 2773- or 2784- position, appropriate enzymes and dNTP""s should be included.
In a second aspect of the invention there is provided a method for determining the sensitivity of as HIV-1 sample to zidovudine which comprises:
(i) isolating the nucleic acid from the sample,
(ii) hybridising the nucleic acid with an oligonucleotide being complementary to a region of the wild-type DNA sequence (or its corresponding RNA) or to a region of the mutant DNA sequence set forth in FIG. 1 (or its corresponding RNA) containing one or more of the nucleotides at the corresponding 2328-, 2338-, 2772-, 2773- and/or 2784- position,
(iii) ascertaining whether or not any of the resulting hybrids of the oligonucleotide and nucleic acid have complementary nucleotides at one of these positions.
Preferably the oligonucleotide is so designed to form a perfectly matched hybrid with its complement.
Nucleic acid (DNA or RNA) is isolated from a sample by the aforementioned methods as described for the first aspect of the invention.
Similarly, PCR may be used to amplify the RT DNA (or its corresponding RNA) or preferably to amplify a region of the RT DNA (or its corresponding RNA; which incorporates DNA (or its corresponding RNA; containing one or more of the nucleotides at the 2328-, 2338-, 2772-, 2775- and/or 2784- position (see Example 2).
In the second stage of this methodology the nucleic acid is then used to hybridise to oligonucleotides complementary to a region of the wild-type DNA sequence (or its corresponding (RNA) or to a region of the mutant DNA sequence set forth in FIG. 1 (or its corresponding RNA) containing one or more of the nucleotides at the aforementioned positions.
The oligonucleotide may be of any length depending on the number of nucleotide positions of interest which are being examined. If the oligonucleotide is designed to include a nucleotide at only one position of interest then this nucleotide is preferably at or close to the centre position of the oligonucleotide.
For example, referring to FIG. 1, one oligonucleotide probe for detection of the mutation at nucleotide 2328- would be complementary to the mutated RT gene sequence and would include at its nucleotide corresponding to nucleotide 2328- the nucleotide complementary to the mutated 2328- nucleotide. A second oligonucleotide probe for the wild type HIV-1 RT would include at its nucleotide corresponding to nucleotide 2328- the nucleotide complementary to the wild-type 2328- nucleotide. Oligonucleotide probes designed to detect one or more of the mutations referred to in FIG. 1 are used to detect a specific mutation or that there has been a mutation.
In order to ascertain whether or not the oligonucleotide and nucleic acid sequence have formed a matched hybrid, specific hybridisation conditions are set so that a hybrid is only formed when the nucleotide or nucleotides at one or more of the 2328-, 2338-, 2772-, 2773- and 2784- position is or are complementary to the corresponding nucleotide or nucleotides of the oligonucleotide which either permits hybridisation or no hybridisation. It is important to establish for example the temperature of the reaction and the concentration of salt solution before carrying out the hybridisation step to find conditions that are stringent enough to guarantee specificity (Maniatis, T., et al., Molecular Cloning, A Laboratory Manual, 2nd edition, Cold Spring Harbour Laboratory Press, (1989)). If the oligonucleotide probe has a DNA sequence which is complementary to a wild-type nucleic acid sequence at one or more of its nucleotides corresponding to the 2328-, 2338-, 2772-, 2773- or 2784- position of the DNA sequence of FIG. 1 then this oligonucleotide will hybridise perfectly to wild-type nucleic acid. If there is no hybridisation then this would suggest that the nucleic acid isolated from the sample contains one or more mutations.
If the oligonucleotide probe has a DNA sequence which is complementary to a mutant nucleic acid sequence at one or more of its nucleotides corresponding to the 2328-, 2338-, 2772-, 2773- or 2784- positions of the DNA sequence of FIG. 1 then this oligonucleotide will hybridise perfectly to mutant nucleic acid. If there is no hybridisation this would suggest that the nucleic acid isolated from the sample contains no such mutation or mutations. The oligonucleotide probes may be labelled as a means of detection as for the fast aspect of the invention.
The hybridisation and subsequent removal of non-hybridised nucleic acids are performed under stringent conditions which only allow hybridisation of the complementary DNA and not the oligonucleotide containing a mismatch (i.e, oligonucleotide specific hybridisation as described for the detection of sickle cell mutation using the xcex2-globin or HLA-DQxcex1 gene (Saikt, R. K., et al., Nature, 324, p163, (1986)), the activated Ras gene (Ver Laan-de, Vries, M., et al., Gene, 50, 313, (1986)) and xcex2-thalassaemia Wonq, C., et al., Nature, 330, p384, (1987)).
The hybridisation may be carried out by immobilisation of the RT nucleic acid sequence onto nitrocellulose, nylon or other solid matrix (eg. dot-blot). It is convenient to determine the presence of an hybrid by using the means of a label. For example, the chemically synthesised oligonucleotide probes can be suitably labelled using enzyme, radiosotope or fluorochrome. A preferred label may be biotin which could be subsequently detected using streptavidin conjugated to an enzyme such as peroxidase or alkaline phosphatase.
Alternatively the hybridisation may be carried out by immobilisation of the chemically synthesised oligonucleotides referred to above, which are unlabelled, onto a solid support referred to above and subsequent hybridisation by a labelled RT nucleic acid sequence as described previously.
In both situations described above for hybridisation suitable control reactions will be incorporated to determine that efficient hybridisation has occurred. (eg the hybridisation of oligonucleotides to a complementary oligonucleotide).
Results would be readily interpreted as the isolated nucleic acid would hybridise to either the wild type oligonucleotide or the mutant oligonucleotide.
A suitable test kit for use in an assay to determine the sensitivity of an HIV-1 sample to zidovudine which makes use of a methodology according to the second aspect of the invention comprises an oligonucleotide being complementary to a region of the wild-type DNA sequence (or its corresponding RNA) or to a region of the mutant DNA sequence set forth in FIG. 1 (or its corresponding RNA) containing one or more of the nucleotides at the corresponding 2328-, 2338-, 2772-, 2773- and/or 2784- position, other materials required to permit hybridisation. Such materials include appropriate buffers and washing solutions and a label and a substrate for the label if necessary. Normally the oligonucleotide would be labelled. If PCR is used to amplify nucleic acid prior to hybridisation then additional materials such as appropriate oligonucleotide primers which will amplify a region of the wild-type DNA sequence (or its corresponding RNA) or a region of the mutant DNA sequence set forth in FIG. 1 (or its corresponding RNA) containing one or more of the nucleotides at the 2328-, 2338-, 2772-, 2773- or 2784- position, appropriate enzymes and dNTP""s (deoxy nucleotide triphosphates) should be included.
In one alternate format of the assay, the dNTP""s in the amplification may or may not be coupled to a detector molecule such as a radiosotope, biotin, fluorochrome or enzyme.
It is also possible to detect zidovudine resistant mutations is the HIV-1 RT RNA isolated from clinical samples using an RNA amplification system. Using the methodology described by Guatelli et al. (Proc. Natl. Acad. Sci, (USA), 8/7, 1874-1878, (March 1990)) a target nucleic acid sequence can be replicated (amplified) exponentially in vitro under isothermal conditions by using three enzymatic activities essential to retroviral replication: reverse transcriptase, RNase H and a DNA-dependant RNA polymerase. Such a methodology may be employed followed by an hybridisation step to distinguish mutant from wild-type nucleotides as discussed previously.


A pressure swing adsorption system including a plurality of vessels having one or more layers of adsorbent material therein, a feed gas channel, a waste channel, and a product channel. The system also includes at least one parallel channel connected to each of the vessels via a respective conduit with a valve. At least one pressure measuring device i configured to measure a pressure within the parallel channel. And, a controller is provided that is configured to monitor the at least one pressure measured by the at least one pressure measuring device during a PSA cycle performed within the PSA system, in order to determine the performance of the cycle and monitor proper operation of the system.

1. Field of the Invention
The present invention generally relates to pressure swing adsorption systems. More specifically, the present invention relates to a monitoring and control system for pressure swing adsorption systems.
2. Discussion of the Background
Pressure swing adsorption (PSA) systems are used for the separation of one or more gases from a mixture of gases. A PSA apparatus usually includes multiple pressure vessels filled with a suitable adsorbent/adsorbents, with each vessel subsequently connected to two or more on-off valves that sequentially admit and expel gases at different pressures in order to affect the gas separation. The PSA cycle is defined by adjusting the time the vessel is open to the product channel relative to the time required to regenerate the adsorbent within each vessel. Given the cyclic nature of a PSA system, multiple vessels operating out of phase with each other is required to maintain constant product delivery. The regeneration stages often involve the exchange of gas between different vessels to perform pressure equalization and purge.
An important aspect of multiple vessel PSA systems is the implementation of pressure equalization to conserve pressure energy. The process of equalizing the pressures between two vessels, rather than expelling the pressure to the waste gas channel, improves the recovery of the lightly adsorbed component. Pressure equalization is performed when gas from a first pressure vessel, at a high pressure, is directed through an on-off valve into a section of pipe (referred to here as the "equalization channel"), fills the equalization channel and is then directed into a second vessel, at a lower pressure, through a second on-off valve. During this pressure equalization stage all remaining on-off valves that connect other vessels to the equalization channel are closed. The first vessel, which is providing gas, decreases in pressure, while the second vessel, which is receiving gas, increases in pressure until the two vessels reach a common final pressure.
The PSA system described in U.S. Pat. No. 6,699,307 to Lomax et al. discloses a seven vessel PSA system with three pressure equalizations. During the first pressure equalization stage, a vessel at high pressure, p1, is opened to the equalization channel at the same time a vessel at a lower intermediate pressure, p3, opens to the equalization channel. Gas flows through the equalization channel until the two vessels reach an intermediate pressure, p2, where p3<p2<p1. The second pressure equalization stage opens the vessel that decreased in pressure to p2 to the equalization channel at the same time another vessel at a lower intermediate pressure, p4, opens to the equalization channel. Gas flows through the equalization channel until the two vessels reach an intermediate pressure, p3, where p4<p3<p2. The third pressure equalization stage opens the vessel that decreased in pressure to p3 to the equalization channel at the same time another vessel at a lower intermediate pressure, p6, opens to the equalization channel. Gas flows through the equalization channel until the two vessels reach an intermediate pressure, p4, where p6<p4<p3. As pressure decreases in the vessel providing equalization gas, the capacity of the adsorbent to retain the impurities in the adsorbed phase decreases according to the equilibrium isotherm and the composition front of each impurity continues to move towards the discharge end where gas is being withdrawn. It is a desirable condition of pressure equalization to prevent the breakthrough of impurities into the equalization channel by providing enough adsorbent mass to take up the propagation of these composition fronts.
Purge is another important aspect of multiple vessel PSA systems to maintain purity of the product gas. If the purge is insufficient, then the impurities desorbed during the depressurization stage are not swept out of the void space, consequently polluting the product on the next production stage. However, if the purge is too great, then the volume of valuable product gas passed back through the vessel is in excess of that required to clean the void space of desorbed impurities at the desired purity level. Over purge results in an undesirable drop in product recovery.
In the PSA cycle described in U.S. Pat. No. 6,699,307 to Lomax et al., the vessel providing purge is progressively decreasing in pressure from some intermediate pressure, p4, to a final pressure, p5, where p4>p5. The purge stage requires the ratio of purge-to-feed gas to be sufficient to maintain product purity, which requires p5 to be manipulated in order to attain the required volume of gas passed out of the providing vessel. Although breakthrough of gas impurities during pressure equalization is undesirable, a small amount of breakthrough can happen during purge as pressure further decreases to achieve the desired purge-to-feed ratio. Therefore a time-varying composition that starts relatively clean and progressively increases in impurity levels is passed into a pipe connecting these vessels (referred to here as the "purge channel"). This gas, which has been passed into the purge channel, is expanded across a flow constriction device and then directed into the top of a second vessel that has undergone depressurization and is at the lowest pressure of the cycle. According to the equilibrium isotherm, the lowest pressure during the cycle will concentrate most of the impurities in the void space surrounding the adsorbent. The receive purge stage subsequently involves the sweeping of these impurities from the void space into the waste gas channel of the PSA system using gas directed from the provide purge vessel. In addition, the provide purge stream, enriched in the lightly adsorbed component, further assists desorption of the impurities by reducing their concentration surrounding the adsorbent in the void space.
The gas remaining in the purge channel at the end of the previous purge coupling is heavier in impurities than it was when the provide purge vessel first opened to the purge channel. Therefore, the section of the purge channel between the vessel providing and receiving purge must be flushed by pushing this initially impure gas into the receiving vessel until the flow of gas discharged from the provide purge vessel reaches the receiving vessel. The inventors have determined that if the distance between vessels providing and receiving purge is not held uniform, then the time-varying composition received into the receive purge vessel will also vary. The inventors have determined that his will result in one or several vessels in the system being out of balance with the others in terms of final axial composition through the vessel at the end of purge, potentially resulting in off-specification gas being sent to the product channel on the next production stage.
Comparing multi-vessel PSA systems that invoke, provide, and receive purge in the above manner shows several problems arise with this offset distance between vessels exchanging gas through the purge channel. For example, U.S. Pat. No. 3,986,849 to Fuderer et al. describes a ten vessel system that couples vessels providing and receiving purge at a distance of two vessels apart, with the exception of two of the vessels therein in which the purge channel distance jumps to eight vessels. U.S. Pat. No. 4,315,759 to Benkmann describes a nine vessel system where the distance between coupled purge vessels is two vessels apart, with the exception of two stages where this distance increases to seven vessels. U.S. Pat. No. 6,565,628 to Xu et al. describes a sixteen vessel system where the distance between coupled purge vessels is four vessels apart, with the exception of four stages where this distance extends to twelve vessels. The inventors have determined that such systems will result in one or more vessels being out of balance with the others in terms of final axial composition through the vessel at the end of purge, potentially resulting in off-specification gas being sent to the product channel on the next production stage.

PSA pressure measurement and control system


An improved cutting insert cartridge arrangement for quick and easy mounting of cutting inserts to and removal from a rotary cutting tool, comprising a cutting insert receiver for the cutting insert, the insert receiver itself being quickly and easily removed from the rotary cutting tool body. The cutting insert receiver may have an outer end portion with an opening therein for receiving a cutting insert, the outer end portion being configurable to apply a varying lateral grasping force against an inserted cutting insert. The cutting insert receiver may be frusto conical in shape to mate with a complementary frusto conical recess in the rotary cutting tool body, whereby securing the receiver in the recess serves to apply the lateral grasping force against an inserted cutting insert due to the camming action between the mating surfaces of the two frusto conical members. Alternatively, a movable holder for holding the insert receiver may be coupled to the cutting insert receiver and slidable axially relative thereto to configure the outer end portion to increase grasping holding force against an inserted cutting insert in a first axial position of the movable holder, and to diminish grasping holding force against an inserted cutting insert in a second axial position of the movable holder.

1. Field of the Invention
The present invention is related to the field of rotary cutting tools, and more particularly to a cutting insert holder which facilitates easy removal and replacement of the cutting elements or cutting inserts used with rotary cutting tools.
2. Brief Description of the Prior Art
Rotary cutting tools are well known in the art. Such cutting tools have long been utilized in many fields of endeavor, such as the material shaping field, stone and concrete grinding, road surfacing, mining, tunnel construction, etc. In addition to the large sized road construction, mining, and tunnel construction machines, such cutting tools are commonly used in relatively small sized tools such as milling machines, lathes, boring tools, planing tools, etc. Cutting tools for these uses generally have one or more cutting inserts mounted thereon such that the cutting insert is fixed relative to its mounting or rotational with respect to such mounting. The cutting tool causes the cutting insert to engage the workpiece to cut a predetermined amount of material therefrom. In such cutting tools, many are provided with means for adjusting the position of the cutting insert with respect to a nominal or "zero" plane. Where more than one cutting insert is utilized on the tool, it is desirable to have all of the cutting inserts precisely adjusted to the same position with respect to the zero plane. Such adjustment, of course, is also desired in cutting tools in which only a single cutting insert is provided.
In some prior art rotary cutting tools, the cutting inserts are mounted on the cutting surface of the tool by use of a bolt or the like extending through the center of the insert and into a protruding base portion of the rotary cutting tool.
It is often desired to change the physical size of the cutting insert depending upon the machine operation being performed. Cutting tools heretofore available have, in general, not been able to accept cutting inserts of more than one size.
In many of the heretofore available cutting tools, it has been a comparatively time-consuming task to make the necessary adjustment of the cutting insert or inserts toward and away from the zero plane, and/or comparatively complex cartridge arrangements for holding the cutting inserts have been utilized with the consequent increase in cost and decrease in reliability associated with larger numbers of components.
Also, in the past, replacement of damaged or dulled cutting inserts involved a major disassembly of a rotary cutting tool. Such disassembly procedure is time-consuming, inconvenient, generally costly, and can involve a substantial waste of machining operating time.
There are some notable exceptions to the aforementioned lack in the prior art of addressing the several problems in the field of rotary cutting tools. Specifically, U.S. Pat. No. 4,477,211 provides cutting insert cartridges that permit new cutting inserts for rotary cutting tools to be easily, quickly, and cheaply replaced or installed. In U.S. Pat. No. 4,828,436, a cartridge assembly for a cutting insert in a rotary cutting tool is provided offering a high degree of precision adjustment of the cutting insert. Both rotating and fixed cutting inserts are shown in the '436 patent to be utilized interchangeably, and the removal and replacement of a cutting element is shown to be easily and quickly accomplished. The present invention offers an even further improvement over the inventions according to these prior U.S. patents by providing an extremely easily operated cutting insert removal and replacement function, as well as providing the ability to remove and replace the cutting insert holding cartridge for exchange with another cutting insert holding cartridge which will accept a different size cutting insert, all while maintaining a very precise zero plane position for the cutting edge of each cutting insert.


A backlight module includes a bezel, a light source, a reflector, a diffuser and a heat dissipation channel. The bezel includes a bottom plate, a top plate disposed above and in parallel with the bottom plate, and an inclined lateral plate for connecting the bottom plate and the top plate. The light source is disposed over the bottom plate. The reflector is disposed under the light source and attached on the bottom plate and the inclined lateral plate. The diffuser is disposed on one part of the top plate and is positioned above the light source. In addition, the heat dissipation channel is formed between the diffuser and the top plate.

1. Field of the Invention
The invention relates in general to a backlight module and a liquid crystal display (LCD) formed therefrom, and more particularly to a backlight module having a heat dissipation channel formed between a diffuser and a top plate of a bezel.
2. Description of the Related Art
Because of the rapid advance of the technology of manufacturing the liquid crystal display (LCD) and the LCD has the advantages of light, thin, power-saving and radiationless properties, the LCDs are widely used in various electrical products, such as personal digital assistants (PDAs), notebook computers, digital cameras, digital camcorders, mobile telephones, computer monitors and liquid crystal televisions. However, because the LCD panel in the LCD is a display panel that cannot emit light itself, a backlight module is needed to provide light so that the display function can be achieved. The conventional backlight module includes a bezel, a reflector, several cold cathode fluorescent lamps (CCFLs), a diffuser and an optical film set. The bezel includes a bottom plate, a top plate and an inclined lateral plate for connecting the bottom plate to the top plate. The bottom plate, the top plate and the inclined lateral plate define a downward concave space. The reflector is positioned above the downward concave space and attached on the bottom plate of the bezel and one part of the inclined lateral plate. The CCFL for providing light is positioned in the downward concave space and disposed above the reflector. The diffuser is disposed on the bezel and positioned above the CCFL. The optical film set is disposed above the diffuser. In addition, the edge of the diffuser usually contacts one part of the top plate to seal the opening of the downward concave space.
However, the CCFL generates heat to cause high temperature while emitting light. Because the edge of the diffuser contacts one part of the top plate to seal the opening of the downward concave space, the heat generated by the CCFL in the downward concave space cannot be dissipated to the outside. More particularly, as the required brightness of the LCD is gradually increasing, the increased brightness of the CCFL inevitably generates more heat, and the internal environmental temperature of the LCD is thus increased. Consequently, the working environmental temperature of the CCFL is increased a lot, thereby deteriorating the light emitting quality of the CCFL and thus greatly influencing the operating quality of the backlight module. Similarly, the backlight module using light emitting diodes (LEDs) to provide light also encounters the above-mentioned problems.

Backlight module and liquid crystal display incorporating same


The invention relates to a Canola hybrid variety designated 6CN0122, essentially derived variants of that Canola hybrid variety, to the cells, seeds, plants, and plant parts of this Canola hybrid variety 6CN0122. The invention also relates to methods for producing a canola plant containing in its genetic material one or more traits introgressed into 6CN0122 through backcross conversion and/or transformation, and to the Canola seed, plant and plant part produced thereby. The invention also relates to uses of 6CN0122.

The goal of oilseed rape breeding, in particular Canola breeding is to combine various desirable traits in a single hybrid variety. The resulting hybrid variety is of high quality and possesses a relatively low level of erucic acid in the oil component and a relatively low level of glucosinolates in the meal component, so it can be termed "Canola" in accordance with the nomenclature used in plant science. Other desirable traits may include stable and high yield, resistance to pests or phytopathogenic microorganisms, tolerance to heat and drought, reducing time to crop maturity, reduction in pod shatter (shatter resistance) and pod drop, better agronomic quality, for example uniformity of plant characteristics as germination and stand establishment, growth rate, maturity, plant height, higher nutritional value, and growth rate. Canola is economically important due to the high quality vegetable oil produced from the harvested Canola seeds; therefore also an increased oil content may be of interest as a breeding goal. While breeding efforts to date have provided a number of useful Canola lines and hybrid varieties with beneficial traits, there remains a great need in the art for new Canola hybrid varieties and lines with further improved traits regarding their agronomic characteristics. Such plants would benefit farmers and consumers alike by improving overall crop yields and/or quality.


Goalie pants provided with a space within the pants in which the upper protective pad of the goalie can be received. This space enables the goalie to freely move without causing any bunching of the upper pad or the pants that may lead to a lack of comfort. A second innovative feature of the improved goalie pants resides in the provision of overlapping thigh and knee padding elements that can move between a retracted and an extended position. In the extended position, the thigh and the knee padding elements are arranged such that they provide a continuous protection of the thigh and the knee. The overlapping relationship between the knee and the thigh padding elements allow them to retract when the goalie is in a position such that other protective equipment (such as the pads covering the legs) interferes with the goalie pants. A third innovative feature resides in the provision of a groin padding element that is mounted on the outside of the pants and forms a flap that overlaps the thigh padding element. This structure allows the groin padding element to smoothly slide over the thigh padding element when the goalie kneels on the ice.

In known types of goalie pants, the configuration of the padding either provides poor flexibility, which limits the goaltender's ability, or poor protection against impacts, which may lead to severe injuries, due to the lack of protection. Both situations penalize the goaltender.
Thus, there is a need in the industry for goalie pants with improved comfort and protection.


A system, method and apparatus is provided for pulse width correction in a power driver. In an embodiment, an apparatus includes an operational amplifier having an input and an output. The input of the operational amplifier is coupled to receive an input pulse signal. The apparatus further includes an output stage having an input coupled to the output of the operational amplifier. The output stage also includes a current output configured to couple to a load and to a voltage sense output. The apparatus also includes a comparator having an inverting input coupled to the voltage sense output of the output stage, a non-inverting input configured to couple to an input signal, and an output. Also, the apparatus includes a timing circuit with an input coupled to the output of the comparator and an input coupled to the input signal. The timing circuit also has an output to supply the input pulse signal. The timing circuit measures a delay from a change in the input signal to a change in the output of the comparator. The timing circuit replicates the measured delay as a delay in a change to the input pulse signal.

When operating a dimmer or other pulse-width-dependent circuit, replicating the pulse width can become important. If a pulse width at an input varies significantly from the corresponding output pulse width, this can cause significant problems. For example, a pulse may not achieve an output signal, as slew rate limits may stop the output stage from turning on. Likewise, an intended effect of a certain pulse width may be limited or missed completely, due to changes in pulse width to provide an output.
Many applications use a pulsed power waveform to provide power to a component. For example, light emitting diodes (LEDs) can be driven with a pulsed waveform. Likewise, sound equipment such as sub-woofers may be driven with a pulsed waveform to provide power. Moreover, dimmer switches are often implemented with a pulse waveform as a power output to the component to be dimmed or controlled.
Thus, it may be useful to find a way to make the pulse-width of the output of a circuit close to identical to the input. In particular, it may be useful to measure an input pulse width, to allow for calculation of a delay to a pulse width output (e.g. a rising edge of an output pulse) or to measure a delay to the end of the input pulse (e.g. a falling edge of the input pulse). In such an instance, dynamic range may be improved, and a situation where the output never turns on may be avoided.

Time delay compensation and pulse width correction


A control system for a wind turbine is provided. The control system includes a local terminal for locally generating wind turbine control commands, a control arrangement for generating control signals for the wind turbine on the basis of wind turbine control commands, and a switching arrangement for switching between a remote mode of operation over a main communication network, and a local mode of operation over a local communication network between the local terminal and the control arrangement such that a message passed between the local terminal and the control arrangement does not travel beyond the local communication network in the wind turbine. A method of locally controlling a wind turbine, and a wind park including a number of wind turbines, wherein each wind turbine comprises such a control system are also provided.

For generating electricity from wind energy, many wind turbines can be arranged in a wind park and can feed their output into a utility grid. The wind turbines of a wind park can be controlled collectively or individually by a park pilot or other control means that issues appropriate commands or performance setpoints. Inside a wind turbine, a turbine controller receives these commands and uses them to control the relevant elements of the wind turbine. At intervals, a wind turbine may require local servicing, for example to perform a diagnostic sequence or a maintenance routine. To this end, it is necessary for an operator or service technician to "disconnect" the turbine controller from the park pilot so that it can be controlled locally. To this end, in a known approach, a local operator panel can be connected to the turbine controller, for example over an RS422 connection. The turbine controller can be placed in a local mode of operation by throwing a mechanical or electric switch from a "remote" position to a "local" position. The switch might physically interrupt or break the connection to the outside world to ensure that the wind turbine cannot be remotely controlled by the park pilot, or the turbine controller can logically ignore any control commands or setpoints originating from outside when the switch is in the "local" position. The RS422 connection between the local operator panel and the turbine controller is physically and logically separate from a main communication network between the park pilot and the turbine controller. Because the RS422 technology does not offer communication over long distances, the distinction between the local and remote modes of operation is clear in such a realisation.
In more modern networked wind parks, it is desirable to connect all elements that communicate with one another using network technology. During a maintenance procedure in a wind turbine, it is necessary to ensure that the operator has full control over that wind turbine in which he is located. However, in a fully networked system, it can be problematic to identify where an operator is located. In a networked wind park, this is a complicated issue, since control commands are effectively sent over a network. One outcome of this might be that a local control command intended for one wind turbine might be erroneously sent to another wind turbine located in the vicinity. For example, a control command broadcast as a data packet from an operator panel in one wind turbine might also erroneously be received by a control arrangement of another wind turbine, if that other control arrangement happens to have the same address as the control arrangement for which the packet was intended or an incorrect address was entered when sending the control command. Such duplicate addresses can only be avoided if great care is taken in the configuration, and errors cannot be ruled out completely.
Also, control commands issued by a park pilot or originating from a customer server might be picked up and carried out by the turbine controller of a wind turbine that should in fact be locally controlled by an operator. Such conflicts could result in damage to wind turbine components and might even present a safety risk for the operator.


A solar cell testing system includes a multifunctional testing light source, a measuring unit, and an arithmetic unit. The multifunctional testing light source is configured to be switched to output a simulated solar light to a solar cell or asynchronously output a plurality of narrowband lights to the solar cell. The measuring unit is coupled to the solar cell and measures the solar cell's response to the simulated solar light and response to the asynchronously outputted narrowband lights. The arithmetic unit is coupled to the multifunctional testing light source and the measuring unit; it determines the solar cell's conversion efficiency and spectral response based on the solar cell's response to the simulated solar light and response to the asynchronously outputted narrowband lights.

1. Technical Field
The invention relates to solar cells, and more particularly, to a solar cell testing system, a solar cell testing method, and a multifunctional testing light source.
2. Related Art
Existing minerals that may be used to generate electricity, such as crude oil and coal, are being exhausted. Furthermore, thermal power plants have been exacerbating global warming. As a result, it is critical for the human being to develop and promote alternative energy that is sustainable. Among all potential sources of sustainable alternative energy, solar energy is a kind that's relatively more popular.
Not only do suppliers try to enhance solar cells' conversion efficiency, but conversion efficiency is also used to evaluate the quality of solar cells. For example, a 0.2% difference in conversion efficiency may lead to a huge disparity in price.
Suppliers frequently use artificial light sources to simulate sun light defined as AM1.5G in order to determine solar cells' conversion efficiency. Specifically, these artificial light sources may simulate the situation that the sun light incidents from an angle 48.2 degrees away from the vertical angle (i.e. zenith angle). However, artificial light sources seldom can match the AM1.5G specification exactly. Inevitably, this causes the tolerance for errors to be relatively large. For example, as defined by the IEC60904-9 standard, as long as a light source has less than 25% deviation in energy within each and every predetermined light band, the light source may be certified as a class-A light source. Because of the loose requirement, several class-A AM1.5G light sources may have quite different spectra. For example, one of the light sources may have relatively more energy in the band of blue light, while another light source may have relatively more energy in the band of red light. These light sources may not be sufficient to enable the determination of whether a solar cell has a 0.2% deviation in conversion efficiency.
Regardless of whether a single class-A light source or a plurality of class-A light sources are used, when the testing result indicates that two solar cells have the same conversion efficiency, the two cells may still have different spectral responses on different light bands. For example, one of the solar cells may have relatively stronger response to blue light, and the other may have relatively stronger response to red light. If these two solar cells are connected in series, they will hinder each other's performance regardless of whether the series circuit is receiving light with relatively more energy in the blue or red band. In other words, because of the mismatch between the two solar cells, the series circuit may not have optimal performance in supplying photo current.
To avoid errors in classification, a solar-cell supplier may measure a solar cell's spectral response additionally, and then infer the solar cell's quantum efficiency (QE). However, conventional methods of measuring spectral response are not only slow but also costly. As a result, the methods are not popularly used on solar cell production lines.
Therefore, solar cell suppliers likely will be interested in artificial light sources that not only may simulate AM1.5G light more precisely but also have smaller inter-machine variation. These suppliers likely will also be interested in methods and testing systems that may measure a solar cell's spectral response at a high throughput and low costs.

Solar cell testing system, solar cell testing method, and multifunctional testing light source


A high electric field radiation detector includes a first and second electrode, a radiation detector layer and a soft polvmer layer. The soft polvmer detector layer located below the radiation detector layer and in contact with at least the first electrode.

Conventional selenium detectors include using an insulating detector top contact and using multi-layer inorganic blocking contact devices. However, neither approach yields photo-gain nor do they use a blocking layer on the bottom of the detector as an anti-crystallization layer. Use of anti-crystallization layers is reported in U.S. Pat. No. 7,649,177 which describes using an inorganic conductive arsenic doped selenium layer.
Conventional avalanche selenium detectors include vacuum tube readout devices and devices using a resistive interface layer based on cellulose. The disadvantage with the former is the need for a high vacuum in order for the pixel to be read out. The disadvantage with the latter is the process complexity associated with multiple blocking layers and lower large area reliability.
In conventional systems, soft polymer layers have been used as top blocking contacts to reduce leakage currents. However, soft polymer layers have, in conventional devices, contributed to charge buildup and lower reliability.
Conventional lateral amorphous-selenium (a-Se) metal-semiconductor-metal (MSM) photodetectors may be used in indirect conversion X-ray imaging applications due to their ease of fabrication and higher speeds when compared to direct conversion a-Se systems. Conventional indirect conversion X-ray imagers couple a visible light-emitting scintillator to an optical detector such as an amorphous-silicon photodiode. Lateral a-Se indirect conversion devices may be individual detectors integrated with a thin-film transistor (TFT) imaging array for use in indirect conversion X-ray imaging. A limitation with conventional lateral detectors is a significant increase in dark current with an increasing applied bias. High biases are desirable to provide a higher photogeneration efficiency and carrier mobility that results from increasing the electric field within the a-Se layer. High dark current leads to a smaller ratio between the photo and dark current at high biases and ultimately limits the minimum detectable light level affecting the dynamic range.
In conventional vertical a-Se X-ray detectors different strategies have been used to mitigate injection of charge into the bulk photodetector. For example, p- and n-like layers are used to block holes and electrons, respectively. However, there may be complexities associated with depositing low-leakage p- or n-like blocking layers. In another conventional design, a single insulating blocking contact near the positively biased electrode is used to block holes only. For detecting visible light photons, vertical a-Se devices may have disadvantages as light must pass through either the top or bottom contact and a blocking layer. As such, there may be a loss of an optical signal compared to lateral photoconductors unless specialized contact layers, like beryllium or transparent conductive oxides, are used.
It is, therefore, desirable to provide faster device or photodetector operation for emerging high speed X-ray imaging applications, higher image quality with amorphous selenium photoconductor imagers, ease of fabrication by using same manufacturing process, and low cost impact.
It is also desirable to provide a photodetector with high reliability, photogain, high responsivity, low dark current, and/or a high speed of operation.

Radiation detector system and method of manufacture


Various embodiments described above provide a user interface system that can expose end users and others to color management information in an easy-to-understand manner. In one or more embodiments, the user interface system can provide information that allows the user to easily ascertain whether a device, component or application is color managed, and the status of the device, component or application. Further, the user interface system can enable the user to access links that provide additional information and/or diagnostic help in the event a color management issue is identified.

Many end users desire true and high quality color fidelity of the content with which they interact in various scenarios. For example, a user may browse the Web to search for a particular shirt they wish to purchase. Once they find the shirt, they may print a product description, including a picture of the shirt, on a color printer. A reasonable user expectation in this instance is that the printed product description would bear a desirable color likeness to the actual color of the shirt.
Other reasonable user expectations include those that would expect color digital pictures to maintain the same color appearance when consumed on a different computing device, such as a home computer or other display device.
One of the major issues for consistency in color management is that color is very dependent on each component that is part of a workflow that processes images and other data with associated color. If one component in a workflow is not working properly, then the whole color management scheme can break down.


A method, system, and computer program product to test a semiconductor device are described. The system includes an input interface to receive a set of test patterns to test the semiconductor device and a user selection corresponding to a subset of the set of test patterns. The system also includes a processor to process the subset of the set of test patterns to output test data to the semiconductor device.

The present invention relates to testing of a semiconductor device, and more specifically, to automated selective testing of a semiconductor device.
When a semiconductor design such as for a wafer, module, application specific integrated circuit (ASIC), or very large scale integrated circuit (VLSI) is tested, the testing involves a set of commercially available test patterns specific to the product under test. The commercially available test pattern generator output is made platform specific by an on-site test pattern processor that may support several test system platforms, for example. While the test pattern generator provides an efficient source for comprehensive testing of the product, the processing of all the test patterns can become time-consuming. At various stages of development, quick feedback from testing is important to determine, for example, new patterns that must be tested to isolate any issues. Thus the time associated with the test pattern processor processing all the test patterns may present issues.

This patent is subject to a terminal disclaimer.

International Business Machines Corporation


A transmission side generates a first frame comprising a field for storing error correction coded information and a field for storing identification information representing error correction coded information, and generates a second frame comprising a field for storing non error correction coded information, a field for storing identification information representing non error correction coded information and a field for storing an error-detecting bit. A reception side detects whether or not a received frame has an error based on bit contents of the field storing the error-detecting bit of the received frame. If the received frame has an error, a frame type is detected based on the identification information. If the detected frame type is the first type the received frame is output to a process stage. If the detected frame type is the second type the received frame is abandoned.

This invention relates to a communication technology for transmitting error correction coded information effectively through a communication system which has not been designed to process the error correction coded information with minimized modification thereof.
With a conventional communication system which has not been designed to transmit the error correction coded information, a transmission side serves to add error-detecting information to each transmission frame. An addressed reception side receives the transmission frame as FIG. 9 shows (step 605), and inspects whether or not the received frame has an error (step 600) by using the error-detecting information added to the transmission frame. If it is determined that an error exists in the received frame (step 601), the frame is abandoned (step 602).
While if it is determined that no error exists in the received frame, inspection is executed for each channel type (step 603), and the process further proceeds to the next step (step 604), where it is determined whether or not communication has been completed (step 606). If the communication has been completed, the line is disconnected. If it is determined that the communication has not been completed, the process returns to the step 605.
In order to make up for the abandoned frame, re-transmission of the same frame is required through, for example, an ARQ system (See Vijay K. Bhargava, David Ahccoun, Robert Matyas, and Peter P. Nuspl, "Digital Communications by Satellite", Willey & Sons, Inc., 1983).
With the above system, deterioration of the channel quality may increase the error rate in the frame, and demand frequent frame re-transmission, thus degrading transmission efficiency. In order to prevent the above described degradation of the transmission efficiency, an art for error correction coding has been disclosed. This art is used to correct the error correctable within a capacity of the error correction code, and to keep the transmission efficiency from degrading.
However such system is required to be designed on an assumption that the information which has been previously error correction coded is transmitted so as to improve transmission efficiency through the error correction coding technology. The system which has not been designed to transmit the error correction coded information as described above is so constructed to abandon the received frame if an error is found from the error-detecting information added to the transmission frame. Accordingly although the error correction coded information is transmitted, its function cannot work well, thus failing to overcome degradation of the transmission efficiency.

Communication method and communication system using the same


Novel forms of mutant BAD polypeptides or fragments thereof having an amino acid substitution for serine-112 and/or serine-136 are provided along with their encoding polynucleotides. Also disclosed are methods for preparation of the mutant BAD polypeptides and methods for treating disease conditions involving decreased apoptosis.

(1) Field of the Invention
This invention relates generally to the regulation of apoptosis and to compositions therefor and, more particularly, to serine substituted mutants of BCL-X.sub.L /BCL-2 associated cell death regulator.
(2) Description of the Related Art
Programmed cell death, referred to as apoptosis, plays an indispensable role in the development and maintenance of homeostasis within all multicellular organisms (Raff, Nature 356:397-400, 1992 which is incorporated by reference). Genetic and molecular analysis from nematodes to humans has indicated that the apoptotic pathway of cellular suicide is highly conserved (Hengartner and Horvitz, Cell 76:1107-1114, 1994 which is incorporated by reference). In addition to being essential for normal development and maintenance, apoptosis is important in the defense against viral infection and in preventing the emergence of cancer.
Considerable progress has been made in identifying the molecules that regulate the apoptotic pathway at each level. Of note, both positive and negative regulators, often encoded within the same family of proteins, characterize the extracellular, cell surface and intracellular steps (Oltvai and Korsmeyer 1994 which is incorporated by reference).
One such family of proteins that constitutes an intracellular checkpoint of apoptosis is the BCL-2 family of proteins. The founding member of this family is the apoptosis-inhibiting protein encoded by the BCL-2 protooncogene which was initially isolated from a follicular lymphoma (Bakhshi et al. Cell 41:889-906, 1985; Tsujimoto et al, Science 229:1390-1393, 1985; Cleary and Sklar, Proc Natl Acad Sci USA 82:7439-7443, 1985 which are incorporated by reference). The BCL-2 protein is a 25 kD, integral membrane protein of the mitochondria. This factor extends survival in many different cell types by inhibiting apoptosis elicited by a variety of death-inducing stimuli (Korsmeyer, Blood 80:879-886, 1992 which is incorporated by reference).
The family of BCL-2-related proteins has been defined by sequence homology that is largely based upon conserved motifs termed BCL-homology regions. (Yin et al, Nature 369:321-323, 1994 which is incorporated by reference). BCL-homology regions 1 and 2 (BH1 and BH2 ) domains have been shown to be important in dimerization and in modulating apoptosis (Yin et al. Nature 369:321-20 323, 1994 which is incorporated by reference). A third homology region, BH3, has also been identified as important to dimerization as well as apoptosis (Boyd et al., Oncogene 11:1921-1928; Chittenden et al., Embo J 14:5589-5596, 1995 which are incorporated by reference) as has been a fourth homology region, BH4, near the amino terminal end of some family members (Farrow and Brown, Curr Opin Genet Dev 6:45-49, 1996 which is incorporated by reference).
Members of this family can heterodimerize and, in most cases, homodimerize as well. The ratio of death antagonists (BCL-2, BCL-X.sub.L, MCL-1 and A1 ) to agonists (BAX, BAK, BCL-X.sub.S and BAD) determines which homodimers or heterodimers are formed and the balance of these is believed to determine whether a cell will respond to an 35 apoptotic signal (Oltvai and Korsmeyer, Cell 79:189-192, 1994 which is incorporated by reference). Thus, dimerization between agonists and antagonists is competitive. For example, the death promoting molecule BAX forms homodimers that favor death whereas BAX will also form heterodimers with BCL-2 or BCL-X.sub.L (Oltvai et al. 1993 which is incorporated by reference) and the formation of these heterodimers results in inhibition of cell death.
BAD (BCL-X.sub.L /BCL-2 Associated Cell Death Regulator) is a death agonist (U.S. Pat. No. 5,622,852 which is incorporated in its entirety by reference), which is a very distant BCL2 family member in sequence homology, having only the BH1 and BH2 domains and lacking the BH3, BH4 and transmembrane anchoring domains. BAD apparently exerts its death promoting effects by heterodimerizing with BCL-2 or BCL-X.sub.L, death antagonists (Yang et al., 1995). Thus, BAD may function as an inducer of apoptosis by competing for the apoptosis repressors, BCL-2 and BCL-X.sub.L.
BAD does not homodimerize, lacks the typical signal/anchor segment suggesting that its free form may reside in the cytosol, has PEST sequences and a much shorter half-life. These parameters suggested BAD could prove to be more proximal at the BCL2 step perhaps linked to signal events. The BAD polypeptide might, therefore, function in a signal transduction role and provide a potential site for modulation of apoptosis.
The 14-3-3 family of proteins of which there are at least seven mammalian isoforms, are highly conserved and ubiquitously expressed. These proteins bind to and regulate a variety of proteins including a number of proteins involved in signal transduction. 14-3-3 binding has been shown to be sequence-specific to a phosphoserine containing motif (Muslin et al. Cell 84:889-896, 1996 which is incorporated by reference). This group identified two serine residues (Serine-259 and Serine-621) in Raf-1 each of which lies within a six amino acid motif and phosphorylation of these serines results in 14-3-3 protein binding at each of these two sites. Furthermore, this group identified a number of proteins that contained this motif and postulated that if appropriately phosphorylated, these other proteins might bind 14-3-3. One such protein was BAD and the motif identified surrounds Serine-136 of BAD. Nevertheless, this reference did not report on any tests to determine whether such binding indeed occurs. Furthermore, the physiologic role of any possible binding of a Serine-136 phosphorylated BAD to 14-3-3 was not considered by this group with only the general suggestion that 14-3-3 might interact with proteins to perform an essential chaperone function. Moreover, this group did not suggest any possible phosphorylation of any other of the Serine residues of BAD such as Serine-112.
Some disease conditions are believed to be related to the development of a defective down-regulation of apoptosis in the affected cells. For example, neoplasias may result, at least in part, from an apoptosis-resistant state in which cell proliferation signals inappropriately exceed cell death signals. Furthermore, some DNA viruses such as Epstein-Barr virus, African swine fever virus and adenovirus, parasitize the host cellular machinery to drive their own replication and at the same time modulate apoptosis to repress cell death and allow the target cell to reproduce the virus. Moreover, certain other disease conditions such as lymphoproliferative conditions, cancer including drug resistant cancer, arthritis, inflammation, autoimmune diseases and the like may result from a down regulation of cell death regulation. In such disease conditions it would be desirable to promote apoptotic mechanisms and one advantageous approach might involve treatment with a cell to modulate the effect of BAD to increase its binding to BCL-2 and/or BCL-X.sub.L and thereby diminish the expression of the death repressor activity of these death antagonists.
Conversely, in certain disease conditions it would be desirable to inhibit apoptosis such as in the treatment of immunodeficiency diseases, including AIDS, senescence, neurodegenerative disease, ischemic and reperfusion cell death, infertility, wound-healing, and the like. In the treatment of such diseases it would be desirable to modulate the effect of BAD to decrease its binding to BCL-2 and/or BCL-X.sub.L and thereby increase the death repressor activity of these death antagonists. Thus, it would be desirable identify new approaches that can alter the binding of BAD to BCL-2 family members and to utilize these as a basis for treatment modalities in advantageously modulating the apoptotic process in disease conditions involving either inappropriate repression or inappropriate acceleration of cell death.

Serine substituted mutants of BCL-X.sub.L /BCL-2 associated cell death regulator


A LIDAR measuring device and a method for determining the speed of particles in a measuring volume includes a narrowband continuous wave laser light source (1), which emits light which is coupled into a measuring branch (3) and a reference branch (4). The light coupled into the measuring branch (3) is at least partially emitted by a transmitting device in the direction of the measuring volume such that the emitted light is at least partially scattered and/or reflected by the particles in the measuring volume. A part of the scattered and/or reflected light is then received by a receiver device and is coherently superimposed with the light leaving the reference branch (4), and the resulting light beam is directed onto a detector (6) to generate a detector signal characteristic for the resulting light beam. Finally, the speed of the particles in the measuring volume is determined in an evaluation unit (11) by taking into account the detector signal.

The invention relates to a LIDAR measuring device as well as a method for determining the speed of particles in a measuring volume. With the help of the described device as well as the method, the measurement of a wind speed in a remote measuring volume is realized with a narrowband continuous wave laser light source. The light emitted by the continuous wave laser light source is coupled into a measuring branch and a reference branch, wherein at least a part of the light coupled into the measuring branch is at least partially emitted by a transmitting device in the direction of the measuring volume in such a way that the emitted light is at least partially scattered and/or reflected by the particles in the measuring volume such that at least one part of the scattered and/or reflected light is received by a receiver device. This scattered and/or reflected received light is then coherently superimposed with the light leaving the reference branch, and the resulting light beam is directed onto a detector to generate a detector signal characteristic for the resulting light beam. The speed of the particles in the measuring volume is determined in an evaluation unit by taking into account the detector signal.
In general, land-based measuring methods for determining the wind speed and the wind direction for different altitude ranges of the atmosphere, for example to monitor industrial pollutant sources, for weather forecasts, as well as for atmospheric and climate research have been known for many years. In this context, for example, so-called SODAR measuring systems are used for wind measurements, wherein they use the Doppler effect with soundwaves which are scattered back from the atmosphere. Due to the use of wind energy, which is increasingly gaining in importance in recent years, a new significant application area has opened up for such measuring methods to measure wind speed and direction in areas remote from the actual measuring device. In addition to the known SODAR systems, so-called LIDAR measuring systems in which light is used instead of sound and which are partially superimposed on the SODAR have been used for such measurements recently.
LIDAR (light detection and ranging) is a method, related to radar, for the optical measurement of distance and speed as well as the measurement of atmospheric parameters. LIDAR systems for the atmospheric measurement emit a laser beam and detect the light scattered back from the atmosphere. The distance away from the location of the scattering is calculated from the light travel time of the signals. In particular, clouds and dust particles in the air scatter the laser light and enable a high-resolution selection and distance measurement of clouds and aerosol layers.
Furthermore, it is possible to determine the wind speed prevailing at a location remote from the measuring device with the LIDAR measuring systems via the measurement of light which is scattered and/or reflected on particles moved by wind. This type of measurement can be used, in particular, to measure the prevailing wind speed upstream of a wind turbine up to a few hundred meters away and to adapt control parameters of the wind turbine based on the measured wind speed. On one hand, the most effective use of a wind turbine possible and, on the other hand, system overloads due to special wind events should hereby be assured. In this manner, emergency measures can be introduced in a timely manner, for example with extreme wind gusts, in order to extensively prevent damage to the wind turbine.
The known LIDAR measuring systems for determining wind speeds are based on the detection and evaluation of the Doppler frequency shift of the scattered light effected by the scattering of laser light on the particles moved with the wind in comparison to emitted light (cf.: C. Weitkamp, LIDAR-range-resolved optical remote sensing of the atmosphere, Springer 2005).
Typically, the Doppler frequency shift is determined interferometrically by means of superimposition of the scattered light received by the measuring device with light which is coupled into the measuring device by the laser light source by means of a second optical path. To this end, highly coherent laser light sources which emit light with coherence lengths of several hundred meters, in which the bandwidth of the frequency is in the sub-MHz range, are used with the known LIDAR measuring devices.
In order to ensure the required and/or desired spatial resolution, essentially two different procedures are known. A first technical variant provides for the use of continuous wave laser sources which are focused on to the respectably desired target area with the help of a suitable optical system, for example a lens or a telescope. A corresponding technical solution is described in WO 2005/1142531. In the event that the desired focus area should be changed, this is achieved with the help of mechanical elements which usually have, however, a comparatively complex design and are expensive. Moreover, such adjusting elements carry the risk of additional faults, primarily in long-term operation.
A second technical variant for achieving and changing the desired spatial resolution is based on the use of pulsed laser sources. In this case, the location determination takes place by means of a travel-time measurement of the laser pulses. In this manner, multiple sequential measuring regions can be measured by the measuring system with a pulse, the pulse width of which determines the spatial resolution which is, for example, 30 m for pulses with a width of 200 ns. In this case, the individual sequentially measured measuring regions can each represent subsections of the entire measuring volume to be tested.
However, the illumination of an individual measuring region by a pulse, said illumination only occurring for a brief time, results in poor signal-to-noise ratios. Furthermore, the frequency resolution and thus also the resolution of the wind speed is limited due to the short pulse widths.
Starting from the previously described measuring systems, WO 2014/072514 discloses a further technical solution for recording the wind speed in a remote spatial area, which achieves a change of the spatial resolution with alternative technical measures. It is essential for this technical solution that a narrowband light source is used, which is modulated with a defined phase pattern, instead of the laser light sources typically used. Firstly, a relatively low transmitting power is required due to the use of a continuous wave laser source as compared to pulsed LIDAR. In addition, the spatial resolution does not have to be balanced against the speed resolution with a pulse LIDAR, but rather both parameters can be selected independently of one another within wide limits. In comparison to focused continuous wave LIDAR (CW-LIDAR), this solution furthermore offers the advantage that the spatial resolution does not become coarser as the distance increases but instead is independent of distance.
An essential component of the described LIDAR measuring device is a modulator, which is based, for example, on the electro-optical effect in a suitable material and which ensures desired phase modulation of the frequency of the light emitted by a laser diode. This modulator represents a comparatively expensive component, which furthermore requires a suitable actuation as well as supply of energy, in relation to the measuring device.
A problem with the previously known LIDAR measuring systems is that a spatial resolution can only be assured either with comparatively extensive complexity and components somewhat susceptible to faults, or comparatively expensive opto-electric components are required. This makes the provision of reliable and simultaneously economical LIDAR measuring devices significantly more difficult, particularly for the use of wind energy. Furthermore, it is often not possible with the known LIDAR measuring devices to differentiate, in a satisfactory manner, a positive Doppler shift caused by different movements of the particles in the measuring region from a negative Doppler shift. Further measuring devices must often be used as a supplement to the LIDAR measuring device.


The present invention relates to a solenoid device such as a flow control valve and a displacement sensor. In a conventional solenoid device, it is not possible to get characteristic curve for easy control of the input voltage to an electromagnetic coil and the stroke of a plunger, or the stroke of a plunger and the frequency of a coil. Thus, it is difficult to control, land the stroke of the plunger is short. Therefore, in the present invention, the above stated disadvantages are solved by forming the end section of the plunger tapered, so that an electromagnetic valve having linear characteristic curve and longstroke plunger or a highly precise displacement sensor can be provided.

Conventionally, an electromagnetic valve, which is one type of solenoid devices, has a plunger which is movably provided in a center hole of an electromagnetic coil in the axial direction thereof. A valve body is provided at the front end of the plunger. There is shown a proportional control valve for controlling the amount of flow in FIG. 15.
A proportional control valve 900 has an electromagnetic coil 904, which covers the outer face of a plunger 902. There are provided yokes 906 and 908 around the electromagnetic coil to enclose the magnetic circuit. The plunger 902 is biased to the electromagnetic coil 904 by leaf springs 910 and 912. The force working on the plunger 912 is transmitted to a valve body 916 by a slide pin 914.
Upon passing the electric current through the electromagnetic coil 904, the magnetic force corresponding to the intensity of electric current, voltage or number of pulse biases the plunger 902 downward to press the valve body 916 which is connected to a diaphragm. The amount of flow at an exit 920 can be controlled under the governor theory.
An example of displacement sensors is disclosed as Japanese Patent Provisional Publication (Kokai) No. 61-172011. This displacement sensor has a coil and a diaphragm. A magnetizable body, which can be slidable in the coil, is attached to the diaphragm. The end face of the magnetizable body is arranged outside of the coil. The change of the reactance (or the frequency) of the coil caused by displacement of the magnetizable body which is connected to the diaphragm is measured as the amount (or pressure) of displacement of the diaphragm.

Displacement sensor with a movable element shaped to provide a linear response curve


An operator assembly for shifting a movable barrier between open and closed positions thereof, wherein the operator assembly can be configured to function with a variety of different barrier sizes and orientations. The operator assembly may include one or more interchangeable transmission components for adapting the operator for use with different gate sizes and installations. The operator assembly may also comprise a substantially linear drive train for permitting use with different barrier orientations.

Operator assemblies, such as gate operators, are typically used for opening and closing of movable barriers, such as gates for selectively permitting access to a driveway or a walkway. Gate operators may use a system of linkage arms to pivot a hinged gate about its hinges and move the gate between open and closed positions.
Gate operators typically have a motor with an output shaft offset from the linkage or operating arms connected to the gates. However, offsetting the motor may require two different models of gate operators to be made, one for operating gates hinged on their left sides and another for operating gates hinged on their right sides. Providing two different models of gate operators, each designed for a specific hinge orientation of the gate, is disadvantageous in that it may increase the complexity and cost of producing the two different gate operators. Furthermore, having gate operators configured for solely right or left hand hinged gates limits the versatility of the operators.
Gates may come in a variety of different sizes, and may range from smaller gates for walkways, larger gates for single width driveways, and even larger gates for dual width driveways. Different gate sizes may require different gate operators, with each gate operator having a gearing ratio designed exclusively for the specific size or range or sizes of the gates. For example, a larger gate may require more torque than a smaller gate and thus a lower gearing ratio. A larger gate may also require slower opening by the gate operator due to the longer length thereof, in order to maintain a speed for the end of the gate opposite the hinged end comparable to a smaller gate. Producing different gate operators each having a different gearing ratio configured specifically for a particular size or range of gate sizes is disadvantageous due to the multiple different gate operators required. Furthermore, the versatility of the gate operator having a specific gear ratio for a specific gate is limited to use with that gate.
The linkage or arm components of a gate operator may have different formations thereon. For example, in a screw-type gate operator a thread may be provided at one end of an arm for engagement with a threaded screw. The thread may be integrally formed on the arm, or the thread may be attached separately. Attaching a separate thread to the arm can be disadvantageous because the thread may separate from the arm during repeated use. Thus, it is desirable to provide an operator assembly having components securely held together.
Gate operators are typically configured to be electronically activated. For example, the gate operator may be wired to a control, or may receive radio or remote control signals for activation thereof. Occassionally, however, a user may wish to open the gate manually, i.e., without the operation of the motor. Manually opening of the gate can be disadvantageous because the motor may be coupled to the arm or linkage, and movement of the arm or linkage may harm the motor. In addition, the motor may restrict the ease at which the gate can be manually shifted. Thus, it is desirable to provide an operator that is adapted to permit either manual or automated operation.


The disclosure describes devices, systems, and methods for integrating load locks into a factory interface footprint space. A factory interface for an electronic device manufacturing system can include an interior volume defined by a bottom, a top and a plurality of sides, a first load lock disposed within the interior volume of the factory interface, and a first factory interface robot disposed within the interior volume of the factory interface, wherein the first factory interface robot is configured to transfer substrates between a first set of substrate carriers and the first load lock.

An electronic device manufacturing system can include one or more tools or components for transporting and manufacturing substrates. Such tools or components can include a factory interface connected to a load lock and/or transfer chamber. In some instances, the load lock is positioned between the transfer chamber and the factory interface. However, such a configuration can be inefficient due to the manufacturing system using a large operational footprint. For example, this configuration can have a long width and/or length and large sections of unused space. Accordingly, improved electronic device manufacturing systems, apparatus, and methods for transporting and manufacturing substrates with increased footprint efficiency are sought.

Systems for integrating load locks into a factory interface footprint space