The present invention relates to compounds being esters of 5-aminolevulinic acids or pharmaceutically acceptable salts thereof, including compounds of formula (I) R22Nxe2x80x94CH2COCH2xe2x80x94CH2COxe2x80x94OR1 (wherein R1 may represent alkyl optionally substituted by hydroxy, alkoxy, acyloxy, alkoxycarbonyloxy, amino, aryl, oxo or fluoro groups and optionally interrupted by oxygen, nitrogen, sulphur or phosphorus atoms; and R2 represents a hydrogen atom or a group R1, and both R2 groups may be the identical or different), and their use in diagnosis and photochemotherapy of disorders or abnormalities of external or internal surfaces of the body, and products and kits for performing the invention.

The present invention relates to derivatives of 5-aminolevulinic acid (ALA) and in particular to esters of ALA for use as photosensitizing agents in photochemotherapy or diagnosis.
Photochemotherapy, or photodynamic therapy (PDT) as it is also known, is a recently up-coming technique for the treatment of various abnormalities or disorders of the skin or other epithelial organs or mucosa, especially cancers or pre-cancerous lesions, as well as certain non-malignant lesions for example skin complaints such as psoriasis. Photochemotherapy involves the application of photosensitizing (photochemotherapeutic) agents to the affected area of the body, followed by exposure to photoactivating light in order to activate the photosensitizing agents and convert them into cytotoxic form, whereby the affected cells are killed or their proliferative potential diminished.
A range of photosensitizing agents are known, including notably the psoralens, the porphyrins, the chlorins and the phthalocyanins. Such drugs become toxic when exposed to light.
Photosensitizing drugs may exert their effects by a variety of mechanisms, directly or indirectly. Thus for example, certain photosensitizers become directly toxic when activated by light, whereas others act to generate toxic species, e.g. oxidising agents such as singlet oxygen or other oxygen-derived free radicals, which are extremely destructive to cellular material and biomolecules such as lipids, proteins and nucleic acids. Psoralens are an example of directly acting photosensitizers; upon exposure to light they form adducts and cross-links between the two strands of DNA molecules, thereby inhibiting DNA synthesis. The unfortunate risk with this therapy is that unwanted mutagenic and carcinogenic side effects may occur.
This disadvantage may be avoided by selecting photosensitizers with an alternative, indirect mode of action. For example porphyrins, which act indirectly by generation of toxic oxygen species, have no mutagenic side-effects and represent more favourable candidates for photochemotherapy. Porphyrins are naturally occurring precursors in the synthesis of heme. In particular, heme is produced when iron (Fe3+) is incorporated in protoporphyrin IX (Pp) by the action of the enzyme ferrochelatase. Pp is an extremely potent photosensitizer, whereas heme has no photosensitizing effect.
One such porphyrin-based drug, Photofrin, has recently been approved as a photosensitizer in the therapy of certain cancers. The main disadvantage is that since it must be administered parenterally, generally intravenously, cause photosensitization of the skin which may last for several weeks following i.v. injection. Photofrin consists of large oligomers of porphyrin and it does not readily penetrate the skin when applied topically. Similar problems exist with other porphyrin-based photosensitizers such as the so-called xe2x80x9chematoporphyrin derivativexe2x80x9d (Hpd) which has also been reported for use in cancer photochemotherapy (see for example S. Dougherty. J. Natl. Cancer Ins., 1974, 52; 1333; Kelly and Snell, J. Urol, 1976, 115: 150). Hpd is a complex mixture obtained by treating haematoporphyrin with acetic and sulphuric acids, after which the acetylated product is dissolved with alkali.
To overcome these problems, precursors of Pp have been investigated for photochemotherapeutic potential. In particular the Pp precursor 5-aminolevulinic acid (ALA) has been investigated as a photochemotherapeutic agent for certain skin cancers. ALA, which is formed from succinyl CoA and glycine in the first step of heme synthesis, is to a limited extent able to penetrate the skin and lead to a localised build-up of Pp; since the action of ferrochelatase (the metallating enzyme) is the rate limiting step in heme synthesis, an excess of ALA leads to accumulation of Pp, the photosensitizing agent. Thus, by applying ALA topically to skin tumours, and then after several hours exposing the tumours to light, a beneficial photochemotherapeutic effect may be obtained (see for example WO91/01727). Since the skin covering basilomas and squamous cell carcinomas is more readily penetrated by ALA than healthy skin, and since the concentration of ferrochelatase is low in skin tumours, it has been found that topical application of ALA leads to a selectively enhanced production of Pp in tumours.
However, whilst the use of ALA represents a significant advance in the art, photochemotherapy with ALA is not always entirely satisfactory. ALA is not able to penetrate all tumours and other tissues with sufficient efficacy to enable treatment of a wide range of tumours or other conditions and ALA also tends to be unstable in pharmaceutical formulations. A need therefore exists for improved photochemotherapeutic agents.
The present invention addresses this need and in particular aims to provide photochemotherapeutic agents which are better able to penetrate the tumour or other abnormality, and which have an enhanced photochemotherapeutic effect over those described in the prior art.
In one aspect, the present invention thus provides compounds being esters of 5-aminolevulinic acids or pharmaceutically acceptable salts thereof for use in photochemotherapy or diagnosis.
In the esters of the invention the 5-amino group may be substituted or unsubstituted, the latter case being the ALA esters.
More particularly, the compounds for use according to the invention are esters of 5-aminolevulinic acids with optionally substituted alkanols, ie. alkyl esters or substituted alkyl esters.
Database Xfire, entries 3060978, 5347132, 5499790, 5620924, 5633390, 5991317, and 6517740 (Beilstein); Cosmo Sogo Kenkyusho KK, Patent Abstracts of Japan, Vol. 16; No. 156 (C-0930), 16.4.1992; EP-A-316179 (Tokuyama Soda KK); GB-A-2058077 (Hudson et al.); and DE-A-2411382 (Boehringer Sohn Ingelheim) describe alkyl ester derivative of 5-aminolevulinic acid, and derivatives and salts thereof and processes for their preparation.
Alternatively viewed, the invention can therefore be seen to provide compounds of formula I,
R22Nxe2x80x94CH2COCH2xe2x80x94CH2COxe2x80x94OR1xe2x80x83xe2x80x83(I)
(wherein R1 may represent alkyl optionally substituted by hydroxy, alkoxy, acyloxy, alkoxycarbonyloxy, amino, aryl, oxo or fluoro groups and optionally interrupted by oxygen, nitrogen, sulphur or phosphorus atoms; and R2, each of which may be the same or different, represents a hydrogen atom or a group R1) and salts thereof for use in photochemotherapy or diagnosis.
The sustituted alkyl R1 groups may be mono or polysubstituted. Thus suitable R1 groups include for example unsubstituted alkyl, alkoxyalkyl, hydroxyalkoxyalkyl, polyhydroxyalkyl, hydroxy poly alkyleneoxyalkyl and the like. The term xe2x80x9cacylxe2x80x9d as used herein includes both carboxylate and carbonate groups, thus, acyloxy substituted alkyl groups include for example alkylcarbonyloxy alkyl. In such groups any alkylene moieties preferably have carbon atom contents defined for alkyl groups below. Preferred aryl groups include phenyl and monocyclic 5-7 membered heteroaromatics, especially phenyl and such groups may themselves optionally be substituted.
Representative substituted alkyl groups R1 include alkoxymethyl, alkoxyethyl and alkoxypropyl groups or acyloxymethyl, acyloxyethyl and acyloxypropyl groups eg. pivaloyloxymethyl.
Preferred compounds for use according to the invention, include those wherein R1 represents an unsubstituted alkyl group and/or each R2 represents a hydrogen atom.
As used herein, the term xe2x80x9calkylxe2x80x9d includes any long or short chain, straight-chained or branched aliphatic saturated or unsaturated hydrocarbon group. The unsaturated alkyl groups may be mono- or polyunsaturated and include both alkenyl and alkynyl groups. Such groups may contain up to 40 carbon atoms. However, alkyl groups containing up to 10 eg. 8, more preferably up to 6, and especially preferably up to 4 carbon atoms are preferred.
Particular mention may be made of ALA-methylester, ALA-ethylester, ALA-propylester, ALA-hexylester, ALA-heptylester and ALA-octylester and salts thereof, which represent preferred compounds for use according to the invention.
The compounds for use in the invention may be prepared using standard processes and procedures well-known in the art for derivatization of multi-functional compounds, and especially esterification. As known in the art, such esterification of compounds may involve protection and deprotection of appropriate groups such that only the required groups remain active and take part in the reaction under the conditions of the esterification. Thus for example the substituents of substituted alkanols used to prepare the esters may be protected during esterification. Similarly the NR22 group on the compound contributing this group to compounds of formula I may be protected during the reaction and deprotected thereafter. Such protection/deprotection procedures are well known in the art for the preparation of derivatives, and in particular, esters of well known amino-acids, see for example Mcomie in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, Plenum, 1973 and T. W. Greene in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, Wiley-Interscience, 1981.
In a further aspect, the present invention thus provides a process for preparing the compounds for use in the invention, comprising forming an ester of the carboxy group of a 5-aminolevulinic acid.
The invention can thus be seen to provide a process for preparing the compounds for use in the invention, comprising reacting a 5-aminolevulinic acid, or an esterifiable derivative thereof, with an alkanol or an ester-forming derivative thereof.
More particularly, this aspect of the invention provides a process for preparing compounds of formula I, which process comprises at least one of the following steps:
(a) reacting a compound of formula II
R22Nxe2x80x94CH2COCH2xe2x80x94CH2COxe2x80x94Xxe2x80x83xe2x80x83(II)
(wherein X represents a leaving group, for example a hydroxyl group, a halogen atom or alkoxy group or COX represents an acid anhydride group and R2 is as hereinbefore defined)
with a compound of formula III
R1xe2x80x94OHxe2x80x83xe2x80x83(III)
(wherein R1 is as hereinbefore defined); and
(b) converting a compound of formula I into a pharmaceutically acceptable salt thereof.
The reaction of step (a) may conveniently be carried out in a solvent or mixture of solvents such as water, acetone, diethylether, methylformamide, tetrahydrofuran etc. at temperatures up to the boiling point of the mixture, preferably at ambient temperatures. The conditions of the esterification reactions will depend of the alcohol used and the conditions may be chosen such that maximum yield of the ester is obtained. Since the esterification reactions are reversible equilibrium reactions, reaction conditions may be selected in such a way that maximum yield of the ester product is obtained. Such conditions may be obtained by selecting a solvent which is capable of removing the water formed in a typical esterification reaction by forming an azeotrope with water. Such solvents are exemplified by aromatic hydrocarbons or others capable of forming azeotropes with water, e.g. some chlorinated hydrocarbons such as chloroform. For the formation of the lower esters of 5-ALA the equilibrium reaction may be driven to the ester side by using a large excess of the alcohol. With other esters the equilibrium may be driven towards the ester product by using a large excess of the acid.
Esterification reactions are well-known in the art for example, as described by Saul Patai in xe2x80x9cThe chemistry of the carboxylic acids and estersxe2x80x9d, (Ch. 11, p. 505, Interscience 1969) and Houban Weyl, (Methoden der Organische Chemie, Band ES, xe2x80x9cCarbonsauren und carbonsauren-derivatexe2x80x9d, p. 504, Georg Thieme Verlag, 1985). The formation of derivatives of amino-acids are described in Band XI/2 of the same series, (Houben Weyl, Methoden der Organische Chemie, Band XI/2, xe2x80x9cStickstoffverbindungenxe2x80x9d, p. 269, Georg Thieme Verlag, 1958).
The reaction will conveniently be carried out in the presence of a catalyst, eg. an inorganic or organic acid or an acid binding agent such as a base.
The compounds used as starting materials are known from the literature, and in many cases commercially available, or may be obtained using methods known per se. ALA, for example, is available from Sigma or from Photocure, Oslo, Norway.
As mentioned above, the compounds for use according to the invention may take the form of pharmaceutically acceptable salts. Such salts preferably are acid addition salts with physiologically acceptable organic or inorganic acids. Suitable acids include, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic, fumaric and ascorbic acids. Procedures for salt formation are conventional in the art.
As mentioned above, the compounds for use according to the invention and their salts have valuable pharmacological properties, namely a photosensitizing agent which renders them useful as photochemotherapeutic agents.
Like ALA, the compounds exert their effects by enhancing production of Pp; upon delivery to the desired site of action hydrolytic enzymes such as esterases present in the target cells break down the esters into the parent ALA, which then enters the haem synthesis pathway and leads to a build-up of Pp. However, the compounds for use according to the invention have a number of advantages over ALA itself. Firstly, the novel compounds are better able to penetrate skin and other tissues as compared with ALA; the penetration is both deeper and faster. This is an important advantage, especially for topical administration. Secondly, the esters have surprisingly been found to be better enhancers of Pp production than ALA; Pp production levels following administration of the ALA esters are higher than with ALA alone. Thirdly, the compounds for use in the invention demonstrate improved selectivity for the target tissue to be treated, namely the Pp production-enhancing effect is localised to the desired target lesion and does not spread to the surrounding tissues. This is especially evident with tumours. Finally, the compounds appear to localise better to the target tissue upon administration. This is especially important for systemic application, since it means that undesirable photosensitization effects, as reported in the literature for other porphyrin-based photosensitizers, may be reduced or avoided.
A further aspect of the present invention accordingly provides a pharmaceutical composition comprising a compound as described hereinbefore, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutical carrier or excipient.
In a still further aspect, there is also provided the use of a compound as described hereinbefore, or a pharmaceutically acceptable salt thereof, for the preparation of a therapeutic agent for use in photochemotherapy, and especially for the treatment of disorders or abnormalities of external or internal surfaces of the body which are responsive to photochemotherapy.
The abnormalities and disorders which may be treated according to the present invention include any malignant, pre-malignant and non-malignant abnormalities or disorders responsive to photochemotherapy eg. tumours or other growths, skin disorders such as psoriasis or actinic keratoses, skin abrasions, and other diseases or infections eg. bacterial, viral or fungal infections, for example Herpes virus infections. The invention is particularly suited to the treatment of diseases, disorders or abnormalities where discrete lesions are formed to which the compositions may be directly applied (lesions is used here in a broad sense to include tumours and the like).
The internal and external body surfaces which may be treated according to the invention include the skin and all other epithelial and serosal surfaces, including for example mucosa, the linings of organs eg. the respiratory, gastro-intestinal and genito-urinary tracts, and glands with ducts which empty onto such surfaces (e.g. liver, hair follicles with sebaceous glands, mammary glands, salivary glands and seminal vesicles). In addition to the skin, such surfaces include for example the lining of the vagina, the endometrium and the urothelium. Such surfaces may also include cavities formed in the body following excision of diseased or cancerous tissue eg. brain cavities following the excision of tumours such as gliomas.
Exemplary surfaces thus include: (i) skin and conjunctiva; (ii) the lining of the mouth, pharynx, oesophagus, stomach, intestines and intestinal appendages, rectum, and anal canal; (iii) the lining of the nasal passages, nasal sinuses, nasopharynx, trachea, bronchi, and bronchioles; (iv) the lining of the ureters, urinary bladder, and urethra; (v) the lining of the vagina, uterine cervix, and uterus; (vi) the parietal and visceral pleura; (vii) the lining of the peritoneal and pelvic cavities, and the surface of the organs contained within those cavities; (viii) the dura mater and meninges; (ix) any tumors in solid tissues that can be made accessible to photoactivating light e.g. either directly, at time of surgery, or via an optical fibre inserted through a needle.
The compositions of the invention may be formulated in conventional manner with one or more physiologically acceptable carriers or excipients, according to techniques well known in the art. Compositions may be administered topically, orally or systemically. Topical compositions are preferred, and include gels, creams, ointments, sprays, lotions, salves, sticks, soaps, powders, pessaries, aerosols, drops and any of the other conventional pharmaceutical forms in the art.
Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions may be formulated with an aqueous or oily base and will, in general, also contain one or more emulsifying, dispersing, suspending, thickening or colouring agents. Powders may be formed with the aid of any suitable powder base. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing, solubilising or suspending agents. Aerosol sprays are conveniently delivered from pressurised packs, with the use of a suitable propellant.
Alternatively, the compositions may be provided in a form adapted for oral or parenteral administration, for example by intradermal, subcutaneous, intraperitoneal or intravenous injection. Alternative pharmaceutical forms thus include plain or coated tablets, capsules, suspensions and solutions containing the active component optionally together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, stearylalcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof.
The concentration of the compounds as described hereinbefore the invention in the compositions, depends upon the nature of the compound, the composition, mode of administration and the patient and may be varied or adjusted according to choice. Generally however, concentration ranges of 1 to 50% (w/w) are suitable. For therapeutic applications concentration ranges of 10 to 50% have been found to be suitable, eg. 15 to 30% (w/w).
Following administration to the surface, the area treated is exposed to light to achieve the photochemotherapeutic effect. The length of time following administration, at which the light exposure takes place will depend on the nature of the composition and the form of administration. This can generally be in the order of 0.5 to 48 hours, e.g. 1 to 10 hours.
The irradiation will in general be applied at a dose level of 40 to 200 Joules/cm2, for example at 100 Joules/cm2.
The wavelength of light used for irradiation may be selected to achieve a more efficaceous photochemo-therapeutic effect. Conventionally, when porphyrins are used in photochemotherapy they are irradiated with light at about the absorption maximum of the porphyrin. Thus, for example in the case of the prior art use of ALA in photochemotherapy of skin-cancer, wavelengths in the region 350-640 nm, preferably 610-635 nm were employed. However, by selecting a broad range of wavelengths for irradiation, extending beyond the absorption maximum of the porphyrin, the photosensitizing effect may be enhanced. Whilst not wishing to be bound by theory, this is thought to be due to the fact that when Pp, and other porphyrins, are exposed to light having wavelengths within its absorption spectrum, it is degraded into various photo-products including in particular photoprotoporphyrin (PPp). PPp is a chlorin and has a considerable photo-sensitizing effect; its absorption spectrum stretches out to longer wavelengths beyond the wavelengths at which Pp absorbs ie. up to almost 700 nm (Pp absorbs almost no light above 650 nm). Thus in conventional photochemotherapy, the wavelengths used do not excite PPp and hence do not obtain the benefit of its additional photosensitizing effect. Irradiation with wavelengths of light in the range 500-700 nm has been found to be particularly effective. It is particularly important to include the wavelengths 630 and 690 nm.
A further aspect of the invention thus provides a method of photochemotherapeutic treatment of disorders or abnormalities of external or internal surfaces of the body, comprising administering to the affected surfaces, a composition as hereinbefore defined, and exposing said surfaces to light, preferably to light in the wavelength region 300-800 nm, for example 500-700 nm.
Methods for irradiation of different areas of the body, eg. by lamps or lasers are well known in the art (see for example Van den Bergh, Chemistry in Britain, May 1986 p. 430-439).
The compounds for use in the invention may be formulated and/or administered with other photosensitizing agents, for example ALA or photofrin, or with other active components which may enhance the photochemotherapeutic effect. For example, chelating agents may beneficially be included in order to enhance accumulation of Pp; the chelation of iron by the chelating agents prevents its incorporation into Pp to form haem by the action of the enzyme ferrochelatase, thereby leading to a build-up of Pp. The photosensitizing effect is thus enhanced. Aminopolycarboxylic acid chelating agents are particularly suitable for use in this regard, including any of the chelants described in the literature for metal detoxification or for the chelation of paramagnetic metal ions in magnetic resonance imaging contrast agents. Particular mention may be made of EDTA, CDTA (cyclohexane diamine tetraacetic acid), DTPA and DOTA. EDTA is preferred. To achieve the ironchelating effect, desferrioxamine and other siderophores may also be used, e.g. in conjunction with aminopolycarboxylic acid chelating agents such as EDTA.
The chelating agent may conveniently be used at a concentration of 1 to 20% eg. 2 to 10% (w/w).
Additionally, it has been found that surfacepenetration assisting agents and especially dialkylsuphoxides such as dimethylsulphoxide (DMSO) may have a beneficial effect in enhancing the photochemotherapeutic effect. This is described in detail in our co-pending application No. PCT/GB94/01951, a copy of the specification of which is appended hereto.
The surface-penetration assisting agent may be any of the skin-penetration assisting agents described in the pharmaceutical literature e.g. HPE-101 (available from Hisamitsu), DMSO and other dialkylsulphoxides, in particular n-decylmethyl-sulphoxide (NDMS), dimethylsulphacetamide, dimethylformamide (DMFA), dimethylacetamide, glycols, various pyrrolidone derivatives (Woodford et al., J. Toxicol. Cut. and Ocular Toxicology, 1986, 5: 167-177), and Azone(copyright) (Stoughton et al., Drug Dpv. Ind. Pharm. 1983, 9: 725-744), or mixtures thereof.
DMSO however has a number of beneficial effects and is strongly preferred. Thus, in addition to the surface-penetration assisting effect (DMSO is particularly effective in enhancing the depth of penetration of the active agent into the tissue), DMSO has anti-histamine and anti-inflammatory activities. In addition, DMSO has been found to increase the activity of the enzymes ALA-synthase and ALA-dehydrogenase (the enzymes which, respectively, form and condense ALA to porphobilinogen) thereby enhancing the formation of the active form, Pp.
The surface penetration agent may conveniently be provided in a concentration range of 2 to 50% (w/w), eg about 10% (w/w).
According to the condition being treated, and the nature of the composition, the compounds for use in the invention may be co-administered with such other optional agents, for example in a single composition or they may be administered sequentially or separately. Indeed, in many cases a particularly beneficial photochemotherapeutic effect may be obtained by pretreatment with the surface-penetration assisting agent in a separate step, prior to administration of the compounds for use in the invention. Furthermore, in some situations a pre-treatment with the surface-penetration assisting agent, followed by administration of the photochemotherapeutic agent in conjunction with the surface-penetration assisting agent may be beneficial. When a surface-penetration assisting agent is used in pre-treatment this may be used at high concentrations, e.g. up to 100% (w/w). If such a pre-treatment step is employed, the photochemotherapeutic agent may subsequently be administered up to several hours following pre-treatment eg. at an interval of 5-60 minutes following pre-treatment.
Viewed from a further aspect, the invention thus provides a product comprising a compound as described hereinbefore or a pharmaceutically acceptable salt thereof, together with at least one surface-penetration assisting agent, and optionally one or more chelating agents as a combined preparation for simultaneous, separate or sequential use in treating disorders or abnormalities of external or internal surfaces of the body which are responsive to photochemotherapy.
Alternatively viewed, this aspect of the invention also provides a kit for use in photochemotherapy of disorders or abnormalities of external or internal surfaces of the body comprising:
a) a first container containing a compound as described hereinbefore invention or a pharmaceutically acceptable salt thereof,
b) a second container containing at least one surface penetration assisting agent; and optionally
c) one or more chelating agents contained either within said first container or in a third container.
Where the surface penetration agent is applied in a separate pre-treatment step, it may be applied in higher concentration, for example up to 100% (w/w).
It will be appreciated that the method of therapy using compounds of the invention inevitably involves the fluorescence of the disorder or abnormality to be treated. Whilst the intensity of this fluorescence may be used to eliminate abnormal cells, the localization of the fluorescence may be used to visualize the size, extent and situation of the abnormality or disorder. This is made possible through the surprising ability of ALA esters to preferentially localize to non-normal tissue.
The abnormality or disorder thus identified or confirmed at the site of investigation may then be treated through alternative therapeutic techniques e.g. surgical or chemical treatment, or by the method of therapy of the invention by continued build up of fluorescence or through further application of compounds of the invention at the appropriate site. It will be appreciated that diagnostic techniques may require lower levels of fluorescence for visualization than used in therapeutic treatments. Thus, generally, concentration ranges of 1 to 50% e.g. 1-5% (w/w) are suitable. Sites, methods and modes of administration have been considered before with regard to the therapeutic uses and are applicable also to diagnostic uses described here. The compounds for use in the invention may also be used for in vitro diagnostic techniques, for example for examination of the cells contained in body fluids. The higher fluoresence associated with non-normal tissue may conveniently be indicative of an abnormality or disorder. This method is highly sensitive and may be used for early detection of abnormalities or disorders, for example bladder or lung carcinoma by examination of the epithelial cells in urine or sputum samples, respectively. Other useful body fluids which may be used for diagnosis in addition to urine and sputum include blood, semen, tears, spinal fluid etc. Tissue samples or preparations may also be evaluated, for example biopsy tissue or bone marrow samples. The present invention thus extends to the use of compounds of the invention, or salts thereof for diagnosis according to the aforementioned methods for photochemotherapy, and products and kits for performing said diagnosis.
A further aspect of the invention relates to a method of in vitro diagnosis, of abnormalities or disorders by assaying a sample of body fluid or tissue of a patient, said method comprising at least the following steps:
i) admixing said body fluid or tissue with a compound as described hereinbefore,
ii) exposing said mixture to light,
iii) ascertaining the level of fluorescence, and
iv) comparing the level of fluorescence to control levels.

Esters of 5-aminolevulinic acid as photosensitizing agents in photochemotherapy


Methods for reducing cross-temperature dependent word line failures using a temperature dependent sensing scheme during a sensing operation are described. In some embodiments, during a read operation, the sensing conditions applied to memory cells within a memory array (e.g., the sensing time, source line voltage, or bit line voltage) may be set based on a temperature of the memory cells during sensing and a word line location of the memory cells to be sensed. In one example, the memory array may comprise a NAND memory array that includes a NAND string and the sensing time for sensing a memory cell of the NAND string and the source line voltage applied to a source line connected to a source end of the NAND string may be set based on the temperature of the memory cells during sensing and the word line location of the memory cells to be sensed.

Semiconductor memory is widely used in various electronic devices such as cellular telephones, digital cameras, personal digital assistants, medical electronics, mobile computing devices, and non-mobile computing devices. Semiconductor memory may comprise non-volatile memory or volatile memory. A non-volatile memory allows information to be stored and retained even when the non-volatile memory is not connected to a source of power (e.g., a battery). Examples of non-volatile memory include flash memory (e.g., NAND-type and NOR-type flash memory) and Electrically Erasable Programmable Read-Only Memory (EEPROM).
Both flash memory and EEPROM utilize floating-gate transistors. For each floating-gate transistor, a floating gate is positioned above and insulated from a channel region of the floating-gate transistor. The channel region is positioned between source and drain regions of the floating-gate transistor. A control gate is positioned above and insulated from the floating gate. The threshold voltage of the floating-gate transistor may be controlled by setting the amount of charge stored on the floating gate. The amount of charge on the floating gate is typically controlled using Fowler-Nordheim (F-N) tunneling or hot-electron injection. The ability to adjust the threshold voltage allows a floating-gate transistor to act as a non-volatile storage element or memory cell. In some cases, more than one data bit per memory cell (i.e., a multi-level or multi-state memory cell) may be provided by programming and reading multiple threshold voltages or threshold voltage ranges.
NAND flash memory structures typically arrange multiple floating-gate transistors in series with and between two select gates. The floating-gate transistors in series and the select gates may be referred to as a NAND string. In recent years, NAND flash memory has been scaled in order to reduce cost per bit. However, as process geometries shrink, many design and process challenges are presented. These challenges include increased variability in memory cell characteristics over temperature.

This patent is subject to a terminal disclaimer.

Word line dependent temperature compensation scheme during sensing to counteract cross-temperature effect


An actuator includes: a rotor assembly including an output shaft having a male screw portion and having a pin attached thereto, and a sleeve having a female screw portion and threadedly engaged with the male screw portion of the output shaft so as to convert a rotary motion of the sleeve into a linear motion of the output shaft; a stator assembly disposed around the rotor assembly; a housing attached to the stator assembly; a coil spring; and a spring holder having slits to guide the pin into an axial direction. In the actuator, the coil spring and the spring holder constitute a fail-safe mechanism and are contained inside the housing, and the coil spring is arranged at such a location that the output shaft is caused to move in a direction to achieve a fail-safe operation. Thus, the actuator incorporates a fail-safe mechanism as an integral unit.

1. Field of the Invention
The present invention relates to an actuator for a flow control valve to control flow in a fluid channel, and more particularly to an actuator integrally provided with a fail-safe function to mandatorily actuate a valve so as to provide a safe condition for a fluid channel when electric power supply is accidentally cut off for some reason.
2. Description of the Related Art
A flow control valve is conventionally used for gas flow control performed with a shutoff valve provided in a fluid channel of a gas supply equipment, and also for switching control of a refrigerant channel for air-conditioning. Such a flow control valve is driven by an actuator in which that the rotary motion of a motor shaft is converted into the linear motion of a valve by means of a pinion gear or a screw structure.
Recently, a permanent magnet (PM) type stepping motor, which achieves a high positioning accuracy by means of step input, is increasingly combined with a mechanism to convert a rotary motion into a linear motion so that it can be used as an actuator.
A flow control valve is used in, for example, a gas meter, which is equipped with a safety mechanism to prevent troubles. Such a safety mechanism has what is called a fail-safe function incorporated in a gas shutoff valve system, and operates such that a flow control valve is automatically shut so as to close a gas channel when power supply is stopped due to electric power failure or due to trouble of a control circuit.
FIG. 7 is a schematic structural view of a conventional gas shutoff valve system provided with such a fail-safe function (refer to, for example, Japanese Patent Application Laid-Open No. 2003-042324).
The gas shutoff valve system shown in FIG. 7 includes a valve seat 101, a valve plug 102 adapted to block the valve seat 101, a valve shaft 103 connected to the valve plug 102, a guide 104 to cause the valve shaft 103 to move linearly, a spring 105 to press the valve plug 102 toward the valve seat 101, a stepping motor 106 as a rotary device having coils 111 and a rotor 112 with an output shaft 107, a feed screw 108 as a feeding element formed on the output shaft 107, a moving block 109 engaging threadedly with the feed screw 108 so as to thrust the valve plug 102, a rotation stopper 110 to prohibit the moving block 109 from rotating, and a lid 113. When something abnormal occurs in gas supply, pulsing currents with respective phases different from each other are applied to the coils 111 so as to rotate the rotor 112, whereby the moving block 109 moves toward the lid 113, and the valve plug 102, urged by the spring 105, is caused to move together so as to block the valve seat 101 thus stopping gas from flowing through.
FIG. 8 is a schematic structural view of another conventional gas shutoff valve system (refer to, for example, Japanese Patent Application Laid-Open No. 2003-222259).
In the gas shutoff valve system shown in FIG. 8, when there is something abnormal detected in gas supply, pulsing currents with respective phases different from each other are applied to respective wires 122 of coils 121 thereby rotating a rotor 123, and then a moving block 124, which engages threadedly with a feed screw 127 fixedly connected to the rotor 123, and which has a groove engaging with a rib 126 for prohibition of rotation, is caused to linearly move in the axial direction due to the feed screw 127 rotating together with the rotor 123. A valve plug 128 is engagingly attached to the moving block 124, and when the moving block 124 moves toward a valve seat 130, a sealing pad 129 of the valve plug 128 is brought into contact with the valve seat 130. And, when the moving block 124 further moves toward the valve seat 130, a coil spring 131 is further contracted so that a spring retaining portion 131 of the moving block 124 is brought into contact with a cylinder portion 133 of a sealing pad holding member 132, and the sealing pad 129 sags and is contracted, which causes the repulsion of the moving block 124 to exceed the thrust of the feed screw 127 consequently stopping the rotation of the rotor 123. At this time, the valve plug 128 is firmly pressed against the valve seat 130 by force of the coil spring 131, and gas flow is shut off. If electric power is turned off in this state, the rotor 123 keeps its position due to holding torque, and the valve plug 128 is kept pressed against the valve seat 130 so as to keep the valve closed.
In the gas shutoff valve system shown in FIG. 7 as disclosed in the aforementioned Japanese Patent Application Laid-Open No. 2003-042324, the spring 105 to press the valve plug 102 against the valve seat 101 is provided in a gas channel 114, which makes the system complicated, and the spring 105 is difficult to replace, which results in deteriorated workability in maintenance.
In the gas shutoff valve system shown in FIG. 8 as disclosed in the aforementioned Japanese Patent Application Laid-Open No. 2003-222259, since the coil spring 131 is attached at the valve plug 128, the valve plug 128 is prohibited from downsizing. Also, the coil spring 131 must be prepared so as to fit to the configuration of each valve plug 128, which leads to an increased number of components.

Actuator integrally provided with fail-safe function


A hybrid drive system has an engine (11); a motor-generator (16); a transmission (12) for converting drive force inputted from at least one of the engine (11) and the motor-generator (16) and transmitting the converted drive force to a drive wheel (15); a first rotating shaft (41), a second rotating shaft (42) and a third rotating shaft (43) disposed mutually in parallel. The drive system includes a first gear wheel (21) disposed coaxially with the first rotating shaft (41); a first clutch (31) for engaging/disengaging the first gear wheel (21) with/from the first rotating shaft (41); a second gear wheel (22) disposed coaxially with the second rotating shaft (42); a second clutch (32) for engaging/disengaging the second gear wheel (22) with/from the second rotating shaft (42); a third gear wheel (23), engaging with the first gear wheel (21) or the second gear wheel (22) and disposed coaxially with the second rotating shaft (42) or the first rotating shaft (41); and a third clutch (33) for engaging/disengaging the third gear wheel (23) with/from the first rotating shaft (41) or the second rotating shaft (42). The motor-generator (16) is connected to the first rotating shaft (41). The engine (11) is connected to the third rotating shaft (43). The transmission (12) includes an input disc (12a) connected to the third rotating shaft; an output disc (12b) disposed coaxially with the input disc; and a power roller (12c) sandwiched in a tiltable fashion between the input disc and the output disc.

Practical application of hybrid electric vehicles (HEVs) equipped with an engine and an electric motor-generator (hereinafter, referred to as "MG") has advanced in recent years. One type of HEV is equipped with a toroidal continuous variable transmission (hereinafter, referred to as "T-CVT"). In a T-CVT, an input disc and an output disc are disposed coaxially, and therefore the transmission is short in the radial direction of the discs, but it is long in the axial direction. Therefore, it is difficult to install a T-CVT in a vehicle in which the power train system is disposed in a transverse direction. Consequently, power train systems have been proposed wherein mountability is improved by eliminating the forward/reverse switching mechanism and torque converter, and hence reducing the length of the transmission. For example, JP-A-2002-104000 discloses a drive system wherein an MG and a T-CVT are disposed in parallel, and the vehicle is driven in reverse by using the MG as a drive source.


A base station having at least one reception antenna generates a reception beam using a previous reception beam weight and a despread signal of a current reception signal, calculates an error value indicating a difference between the current reception signal and a desired reception signal, and calculates a current reception beam weight using the previous reception beam weight, the despread signal and the error value. The base station generates a reception beam weight step value using the error value and an output signal, calculates a difference between the previous reception beam weight and a product of the reception beam weight step value, the despread signal, and a conjugate value of the error value, as the current reception beam weight, and selects the reception beam weight step value such that the current reception beam weight becomes the optimal reception beam.

1. Field of the Invention
The present invention relates generally to an apparatus and method for receiving data in a mobile communication system using Adaptive Antenna Array (AAA) technology, and in particular, to an apparatus and method for receiving data using a reception beam weight generation scheme having an adaptive reception beam weight step.
2. Description of the Related Art
A next generation mobile communication system has evolved into a packet service communication system that transmits burst packet data to a plurality of mobile stations (MSs). The packet service communication system has been designed to transmit mass data. Such a packet service communication system has been developing for high-speed packet service. In this regard, the 3rd Generation Partnership Project (3GPP), a standardization organization for asynchronous communication technology, proposes High Speed Downlink Packet Access (HSDPA) to provide the high-speed packet service, while 3rd Generation Partnership Project 2 (3GPP2), a standardization organization for synchronous communication technology, proposes 1× Evolution Data Only/Voice (1× EV-DO/V) to provide the high-speed packet service. Both HSDPA and 1× EV-DO/V intend to provide high-speed packet service for smooth transmission of Web/Internet service. In order to provide the high-speed packet service, a peak throughput and an average throughput should be optimized for smooth transmission of packet data and circuit data, such as voice service data.
In order to support high-speed transmission of packet data, a communication system employing HSDPA (hereinafter referred to as an "HSDPA communication system") has newly introduced 3 types of data transmission techniques: Adaptive Modulation and Coding (AMC), Hybrid Automatic Retransmission Request (HARQ), and Fast Cell Selection (FCS). The HSDPA communication system increases a data rate using the AMC, HARQ, and FCS techniques.
Another communication system that increases a data rate, is a communication system using 1× EV-DO/V (hereinafter referred to as a "1× EV-DO/V communication system"). The 1× EV-DO/V communication system also increases a data rate to secure system performance. Aside from the new techniques such as AMC, HARQ, and FCS, a Multiple Antenna technique is another technique for operating within the limited assigned bandwidth, i.e., increasing a data rate. The Multiple Antenna technique overcomes the limitation of bandwidth resource in a frequency domain by utilizing a space domain.
A communication system is constructed such that a plurality of mobile stations communicate with each other via a base station (BS). When the base station performs high-speed data transmission to the mobile stations, a fading phenomenon occurs due to a characteristic of radio channels. In order to overcome the fading phenomenon, a Transmit Antenna Diversity technique, which is a type of the Multiple Antenna technique, has been proposed. The "Transmit Antenna Diversity" refers to a technique for transmitting signals using at least two transmission antennas, i.e., multiple antennas, to minimize a loss of transmission data due to a fading phenomenon, thereby increasing a data rate.
Generally, in a wireless channel environment in a mobile communication system, unlike in a wired channel environment, a transmission signal is distorted by a number of factors, such as multipath interference, shadowing, wave attenuation, time-varying noise, interference, etc. Fading caused by the multipath interference is closely related to the mobility of a reflector or a user (or a mobile station), and actually, a mixture of a transmission signal and an interference signal is received. Therefore, the received signal suffers from severe distortion during its actual transmission, thereby reducing performance of the entire mobile communication system.
The fading may result in distortion in amplitude and phase of the received signal, preventing high-speed data communication in the wireless channel environment. A substantial amount of research is being conducted in order to resolve the fading. Therefore, in order to transmit data at high speed, the mobile communication system must minimize a loss due to a characteristic of a mobile communication channel such as fading, and interference of an individual user. A diversity technique is used for preventing unstable communication due to the fading, and multiple antennas are used to implement a Space Diversity technique, which is a type of the diversity technique.
The Transmit Antenna Diversity is commonly used as a technique for efficiently resolving the fading phenomenon. The Transmit Antenna Diversity receives a plurality of transmission signals that have experienced independent fading phenomena in a wireless channel environment, thereby handling the distortion caused by the fading. The Transmit Antenna Diversity is classified into Time Diversity, Frequency Diversity, Multipath Diversity, and Space Diversity.
In order to perform high-speed data communication, a mobile communication system must be able to handle the fading phenomenon that severely affects communication performance. The fading phenomenon must be overcome because it may severely reduce an amplitude of a received signal.
In order to overcome the fading phenomenon, the above-described diversity techniques are used. For example, Code Division Multiple Access (CDMA) technology utilizes a Rake receiver that can achieve diversity performance using delay spread of the channel. The Rake receiver is a kind of a Receive Diversity technique for receiving multipath signals. However, the Receive Diversity used in the Rake receiver is disadvantageous in that it cannot achieve a desired diversity gain when delay spread of the channel is relatively small.
The Time Diversity technique efficiently copes with burst errors occurring in a wireless channel environment using interleaving and coding, and is generally used in a Doppler spread channel. Disadvantageously, however, the Time Diversity can hardly obtain the diversity effects in a low-speed Doppler spread channel.
The Space Diversity technique is generally used in a channel with a low delay spread such as an indoor channel and a pedestrian channel, which is a low-speed Doppler spread channel. The Space Diversity is a technique achieves a diversity gain using at least two antennas. In this technique, when a signal transmitted via one antenna is attenuated due to fading, a signal transmitted via another antenna is received, thereby acquiring a diversity gain. The Space Diversity is classified into Receive Antenna Diversity using a plurality of reception antennas and Transmit Antenna Diversity using a plurality of transmission antennas.
Receive-Adaptive Antenna Array (Rx-AAA), a kind of the Receive Antenna Diversity. In the Rx-AAA technique, by calculating a scalar product between a signal vector and an appropriate reception beam weight vector of a reception signal received via an antenna array comprised of a plurality of reception antennas, a signal received in a direction desired by a receiver is maximized in its level and a signal received in a direction not desired by the receiver is minimized in its level. The "reception beam weight" refers to a weight with which the receiver generates a reception beam in the Rx-AAA technique. As a result, the Rx-AAA technique amplifies only a desired reception signal to a maximum level, thereby maintaining a high-quality call and increasing the entire system capacity and service coverage.
Although the Rx-AAA can be applied to both a Frequency Division Multiple Access (FDMA) mobile communication system and a Time Division Multiple Access (TDMA) mobile communication system, it will be assumed herein that the Rx-AAA is applied to a communication system using CDMA (hereinafter referred to as a "CDMA communication system").
FIG. 1 is a block diagram illustrating a structure of a base station receiver in a conventional CDMA mobile communication system. Referring to FIG. 1, the base station receiver includes N reception antennas (Rx_ANT), i.e., a first reception antenna 111, a second reception antenna 121, . . . , and an Nth reception antenna 131, N radio frequency (RF) processors, i.e., a first RF processor 112, a second RF processor 122, . . . , and an Nth RF processor 132, being mapped to the corresponding reception antennas, N multipath searchers, i.e., a first multipath searcher 113, a second multipath searcher 123, . . . , and an Nth multipath searcher 133, being mapped to the corresponding RF processors, L fingers, i.e., a first finger 140-1, a second finger 140-2, . . . , and an Lth finger 140-L, for processing L multipath signals searched by the multipath searchers, a multipath combiner 150 for combining multipath signals output from the L fingers, a deinterleaver 160, and a decoder 170.
Signals transmitted by transmitters in a plurality of MSs are received at the N reception antennas over a multipath fading radio channel. The first reception antenna 111 outputs the received signal to the first RF processor 112. Each of the RF processors includes an amplifier, a frequency converter, a filter, and an analog-to-digital (A/D) converter, and is used to process an RF signal. The first RF processor 112 RF-processes a signal output from the first reception antenna 111 in order to convert the signal into a baseband digital signal, and outputs the baseband digital signal to the first multipath searcher 113. The first multipath searcher 113 separates L multipath components from a signal output from the first RF processor 112, and the separated L multipath components are output to the first finger 140-1 to the Lth finger 140-L, respectively. The first finger 140-1 to the Lth finger 140-L, being mapped to the L multiple paths on a one-to-one basis, process the L multipath components. Because the L multiple paths are considered for each of the signals received via the N reception antennas, signal processing must be performed on N×L signals. Among the N×L signals, signals on the same path are output to the same finger.
Similarly, the second reception antenna 121 outputs the received signal to the second RF processor 122. The second RF processor 122 RF-processes a signal output from the second reception antenna 121 to convert the signal into a baseband digital signal, and outputs the baseband digital signal to the second multipath searcher 123. The second multipath searcher 123 separates L multipath components from a signal output from the second RF processor 122, and the separated L multipath components are output to the first finger 140-1 to the Lth finger 140-L, respectively.
In the same manner, the Nth reception antenna 131 outputs the received signal to the Nth RF processor 132. The Nth RF processor 132 RF-processes a signal output from the Nth reception antenna 131 to convert the signal into a baseband digital signal, and outputs the baseband digital signal to the Nth multipath searcher 133. The Nth multipath searcher 133 separates L multipath components from a signal output from the Nth RF processor 132, and the separated L multipath components are output to the first finger 140-1 to the Lth finger 140-L, respectively.
Accordingly, among the L multipath signals for the signals received via the N reception antennas, the same multipath signals are input to the same fingers. For example, first multipath signals from the first reception antenna 111 to the Nth reception antenna 131 are input to the first finger 140-1. The Lth multipath signals from the first reception antenna 111 to the Nth reception antenna 131 are input to the Lth finger 140-L. The first finger 140-1 to the Lth finger 140-L are different only in signals input thereto and output therefrom, and are identical in structure and operation. Therefore, for simplicity, only the first finger 140-1 will be described herein below.
The first finger 140-1 includes N despreaders, i.e., a first despreader 141, a second despreader 142, . . . , and an Nth despreader 143, that are mapped to the N multipath searchers, a signal processor 144 for calculating a reception beam weight vector for generating a reception beam using signals received from the N despreaders, and a reception beam generator 145 for generating a reception beam using the reception beam weight vector calculated by the signal processor 144.
A first multipath signal output from the first multipath searcher 113 is input to the first despreader 141 The first despreader 141 despreads the first multipath signal output from the first multipath searcher 113 with a predetermined spreading code, and outputs the despread multipath signal to the signal processor 144 and the reception beam generator 145. The despreading process is called "temporal processing."
Similarly, a first multipath signal output from the second multipath searcher 123 is input to the second despreader 142. The second despreader 142 despreads the first multipath signal output from the second multipath searcher 123 with a predetermined spreading code, and outputs the despread multipath signal to the signal processor 144 and the reception beam generator 145. Accordingly, a first multipath signal output from the Nth multipath searcher 133 is input to the Nth despreader 143. The Nth despreader 143 despreads the first multipath signal output from the Nth multipath searcher 133 with a predetermined spreading code, and outputs the despread multipath signal to the signal processor 144 and the reception beam generator 145.
The signal processor 144 receives the signals output from the first despreader 141 to the Nth despreader 143, and calculates a reception beam weight set Wk for generating a reception beam. Here, a set of first multipath signals output from the first multipath searcher 113 to the Nth multipath searcher 133 will be defined as "Xk." The first multipath signal set Xk represents a set of first multipath signals received via the first reception antenna 111 to the Nth reception antenna 131 at a kth point, and the first multipath signals included in the first multipath signal set Xk are all vector signals. The reception beam weight set Wk represents a set of reception beam weights to be applied to the first multipath signals received via the first reception antenna 111 to the Nth reception antenna 131 at the kth point. The reception beam weights constituting the weight set Wk are all vector signals.
A set of signals determined by despreading all of the first multipath signals in the first multipath signal set Xk will be defined as yk. The despread signal set yk of the first multipath signals represents a set of signals determined by despreading the first multipath signals received via the first reception antenna 111 to the Nth reception antenna 131 at the kth point, and the despread signals included in the despread signal set yk of the first multipath signals are all vector signals. Herein, for the convenience of explanation, the term "set" will be omitted, and the underlined parameters represent sets of corresponding elements.
Each of the first despreaders 141 to the Nth despreaders 143 despreads the first multipath signal Xk with a predetermined despreading code, such that reception power of a desired reception signal is higher than reception power of an interference signal by a process gain. The despreading code is identical to the spreading code used in transmitters of the mobile stations.
As described above, the despread signal yk of the first multipath signal Xk is input to the signal processor 144. The signal processor 144 calculates a reception beam weight Wk with the despread signal yk of the first multipath signal Xk, and outputs the reception beam weight Wk to the reception beam generator 145. More specifically, the signal processor 144 calculates the reception beam weight Wk including a total of N reception beam weight vectors applied to the first multipath signal Xk output from the first reception antenna 111 to the Nth reception antenna 131, with the despread signals yk of a total of N first multipath signals output from the first reception antenna 111 to the Nth reception antenna 131. The reception beam generator 145 receives the despread signals yk of a total of the N first multipath signals Xk and a total of the N weight vectors Wk. Thereafter, the reception beam generator 145 generates a reception beam with a total of the N reception beam weight vectors Wk, calculates a scalar product of the despread signal yk of the first multipath signal Xk and the reception beam weight Wk corresponding to the reception beam, and outputs the result as an output zk of the first finger 140-1. The output zk of the first finger 140-1 can be expressed in Equation (1).zk=wkHyk  (1)
In Equation (1), H denotes a Hermitian operator, i.e., a conjugate-transpose. A set zk of output signals zk from L fingers in the base station receiver is finally input to the multipath combiner 150.
Although only the first finger 140-1 has been described, the other fingers (140-2 to 140-L) operate in the same way as the first finger 140-1. Accordingly, a description of the operating procedure for second finger 140-2 to the Lth finger 140-L will not be given herein.
The multipath combiner 150 combines the signals output from the first finger 140-1 to the Lth finger 140-L, and outputs the combined signal to the deinterleaver 160. The deinterleaver 160 deinterleaves the signal output from the multipath combiner 150 in a deinterleaving method corresponding to the interleaving method used in the transmitter, and outputs the deinterleaved signal to the decoder 170. The decoder 170 decodes the signal output from the deinterleaver 160 in a decoding method corresponding to the encoding method used in the transmitter, and outputs the decoded signal as final reception data.
The signal processor 144 calculates a reception beam weight Wk such that a Mean Square Error (MSE) of a signal received from a mobile station transmitter, desired to be received by a predetermined algorithm, becomes minimized. The reception beam generator 145 generates a reception beam using the reception beam weight Wk generated by the signal processor 144. The process of generating a reception beam such that MSE becomes minimized is called "spatial processing." Therefore, when Rx-AAA is used in a CDMA mobile communication system, temporal processing and spatial processing are simultaneously performed. The operation of simultaneously performing temporal processing and spatial processing is called "spatial-temporal processing."
The signal processor 144 receives multipath signals despread for each finger as described above, and calculates a reception beam weight capable of maximizing a gain of the Rx-AAA according to a predetermined algorithm. The signal processor 144 minimizes the MSE. Therefore, a study is actively being conducted on a reception beam weight calculation algorithm for adaptively minimizing the MSE. However, the reception beam weight calculation algorithm for adaptively minimizing the MSE is an algorithm for reducing errors on the basis of a reference signal, and this algorithm supports a Constant Modulus (CM) technique and a Decision-Directed (DD) technique as a blind technique, when there is no reference signal.
However, the algorithm for reducing errors on the basis of a reference signal is difficult to converge into a minimum MSE value desired by the system in an environment where a channel such as a fast fading channel suffers from a rapid change, or an environment in which a high-order modulation scheme such as 16-ary quadrature amplitude modulation (16QAM) is used. Even though it converges into a particular MSE value, the minimum MSE value is set to a relatively large value. When the minimum MSE value is set to a relatively large value, a gain occurring by the use of the Rx-AAA is reduced. Therefore, this algorithm is not suitable for a high-speed data communication system.
Further, the conventional reception beam weight calculation algorithm for beam generation uses a Time-Domain Gradient technique. The Time-Domain Gradient technique utilizes a fixed reception beam weight step in calculating the reception bean weight. When the reception beam weight is calculated using the fixed reception beam weight step, if a mobile station moves at relatively high speed, i.e., if a channel environment suffers abrupt change, the convergence rate (or convergence speed) is reduced. The reduction in convergence rate decreases a rate of convergence to the minimum MSE value desired in the system. Therefore, this algorithm is also not suitable for a high-speed data communication system.

Apparatus and method for receiving signals in a mobile communication system using adaptive antenna array technology


Method and system for dividing a data segment of unknown length into first and second halves, for example, for interleaving the first and second halves. Units of the data segment are written into first and second register files. With respect to the first register file, responsive to determining that the last unit of the data segment has been written into the first register file, units of the data segment in the first register file that are not units of the first half of the data segment are removed, wherein the first register file stores the first half of the data segment. With respect to the second register file, responsive to writing each unit of the data segment into the second register file, data currently stored in the second register file is adjusted to comprise a last half of the data so far written into the second register file, wherein, when the last unit of the data segment has been written into the second register file, and the data currently stored in the second register file has been adjusted, the data currently stored in the second register file comprises the second half of the data segment.

1. Technical Field
The present invention is directed generally to the data processing field, and, more particularly, toward a method and system for interleaving first and second halves of a data segment of unknown length.
2. Description of the Related Art
A need exists in the data processing field to split a segment of data in half and then interleave the two halves together. For example, in a disk drive, read/write channels have the need to handle even and odd bits in parallel and use independent circuits in order to meet timing and power goals. To allow for this parallel even and odd data operation, even and odd data interleaves in the data stream are often required in order to have independent and often proprietary codings applied. These codings are better applied at a slower clock rate on a data path pipeline that is multiple bits wide, for example, 32 bits wide, and a mechanism is needed to separate the even and odd interleaves in such a data path for the purpose of applying such a coding.
Consider a segment of data that consists of N bits that are divided into N/S symbols, wherein S is symbol size in number of bits and N/S is an integer that can be bounded by a maximum constant value. The segment size N is based on the particular application, and ideally S has a relationship with the data path that interfaces to the circuit. For example, if a data path is 10 bits wide, it is convenient to choose a symbol size S that is either equal to 10 or is an integer multiple of 10. Consider also the interleave granularity K, which determines how many continuous bits are taken at a time from each half in order to perform the interleave. K can be any integer factor of S except S itself. If S is 10 bits, for example, K can be 1, 2 or 5.
As an example, consider a data segment having a length N=20 bits and a symbol size S=10 bits. The data segment thus has N/S=2 symbols. If the 20 bits of the data segment are designated a, b, c, d, e, f, g, h, i, j, k, l, m, n, o, p, q, r, s, t; splitting the data segment into two halves provides the following two data segment halves:
First half: a, b, C, d, e, f, g, h, i, j
Second half: k, l, m, n, o, p, q, r, s, t.
If the two halves are interleaved using K=5, the data bits will be arranged as follows:
a, b, c, d, e, k, l, m, n, o, f, g, h, i, j, p, q, r, s, t.
If the two halves are interleaved using K=2, the data bits will be arranged as follows:
a, b, k, l, c, d, m, n, e, f, o, p, g, h, q, r, i, j, s, t.
If the two halves are interleaved using K=1, the data bits will be arranged as follows:
a, k, b, l, c, m, d, n, e, o, f, p, g, q, h, r, i, s, j, t.
Consider an application in which the data bits must be interleaved within a data path pipeline that continuously takes S bits in and S bits out, and in which multiple input data segments are received concatenated together and multiple output interleaved data segments are transmitted concatenated together with no gaps in the pipeline. Also consider that N can be a variable in units of S for each of the data segments that are received, and that the actual value of N is not known until an indication occurs indicating that a given input symbol is the last symbol of the input data segment. N can, however, be bounded by a maximum value to assist in sizing structures used in the interleaving procedure. In such an application, a mechanism is needed to interleave the first and second halves of a data segment based on the above constraints.

Method and system for interleaving first and second halves of a data segment of unknown length


In general, in one aspect, the disclosure describes a memory array including a plurality of memory cells arranged in rows and columns. Each memory cell includes a transistor having a floating body capable of storing a charge. A plurality of word lines and purge lines are interconnected to rows of memory cells. A plurality of bit lines are interconnected to columns of memory cells. Driving signals provided via the word lines, the purge lines, and the bit lines can cooperate to alter the charge of the floating body region in one or more of the memory cells.

Modern microprocessors integrate on-chip (on-die) cache memory as an efficient means of achieving high performance memory access. On-chip cache provides high-speed, temporary data storage that the microprocessor can access more quickly than off-chip memory. The trend in microprocessor performance improvement is to incorporate ever more cache memory and to configure the cache in multiple (hierarchical) levels (e.g., L1 and L2).
Traditionally, on-chip cache memory has been implemented using Static Random Access Memory (SRAM) because SRAM has very high access speed and low latency. But because each bit of SRAM typically requires six transistors (6T), the size of on chip caches have been limited in order to maintain reasonable die size and manufacturing cost.
One alternative to SRAM is Dynamic Random Access Memory (DRAM). DRAM has a simpler cell structure than SRAM, but requires regular access (refresh) to maintain the data in each storage cell. One common type of DRAM is a 1T-1C DRAM that uses a cell made from one transistor (e.g., a Metal-Oxide-Semiconductor Field Effect Transistor (MOSFET)) and one capacitor. The capacitor is used to store a data bit in the form of an electronic charge, and the transistor provides read and write access to the charge held in the capacitor. The transistor is often referred to as the "access" transistor or the "transfer device" of the DRAM cell. This cell is typically about one-tenth the size of a 6T SRAM cell. However, this type of DRAM may require special processing steps to make capacitors that can store enough charge to maintain reasonable refresh times (e.g., at least 25 fF). The special processing steps are not typically used in the fabrication of microprocessors. The capacitor may also limit the scalability of the traditional DRAM structure.


In converting image sensing data into image data, a plurality of image sensing data meeting a predetermined condition are processed as a group of image sensing data. An image reproduction parameter is obtained from this image sensing data group, and each image sensing data of the image sensing data group is converted into image data by using the image reproduction parameter. Accordingly, an image reproduction parameter for obtaining an optimum reproduced image can be accurately set from the image sensing data group. Also, since a reproduction luminance level (range) is determined from the image sensing data group, the correlation between the luminances of image planes is not lost. This allows an easy comparison of reproduced images and prevents the boundaries of luminances from becoming unnatural when the reproduced images are synthesized.

1. Field of the Invention
The present invention relates to an image processing apparatus and method and, more particularly, to an image processing apparatus and method of adjusting the hue of an input image signal.
The present invention also relates to an image reproducing method and apparatus and, more particularly, to an image reproducing method and apparatus for converting an image sensing signal obtained from an image sensing device, such as an image sensing tube or a CCD, into a visualizable image signal, e.g., an NTSC-RGB signal.
2. Description of the Related Art
In a television camera using an image sensing device such as a CCD, some image reproduction parameters are generally determined from image sensing data during image reproduction processing, in order to constantly obtain images which apparently give the same impression or to obtain as faithful reproduced images as possible regardless of deterioration with time of the image sensing device or a color filter and changes in an illuminating light source. The image sensing data is two-dimensional digital image data formed from an image signal obtained by photographing an object by using an image sensing device.
Examples of the image reproduction parameters are a color temperature and a reproduction luminance level. The image production parameters are used to correct the color temperature or set the reproduction luminance level.
More specifically, the correction of the color temperature is to adjust a so-called white balance so that an object which is supposed to look white looks white. Generally, this color temperature correction is performed on the basis of image sensing data. That is, data of an object which is supposed to look white is extracted from image sensing data, and a white balance coefficient as one image reproduction parameter is determined on the basis of the extracted data. In the white balance adjustment, a plurality of color component signals constituting an output image signal from an image sensing device are amplified in accordance with the white balance coefficient. Consequently, the signal levels of the color components constituting the image signal of the object which is supposed to look white are so adjusted as to be equal to each other.
The setting of the reproduction luminance level is done by calculating a luminance distribution from image sensing data and setting an optimum reproduction luminance level (range). The parameter is adjusted such that a reproduced image is obtained within this range, and the image is reproduced.
FIGS. 1 and 2 are block diagrams showing configurations for performing the color temperature correction.
Referring to FIG. 1, complementary color data (consisting of color component signals of magenta Ma, green Gr, Yellow Ye, and cyan Cy) obtained by an image sensing unit 1 is supplied to a complementary color-pure color converting unit 11. The complementary color data is converted into pure color data (consisting of color component signals of red R, green G, and blue B) in the converting unit 11. The white balance of the pure color data obtained by the complementary color-pure color converting unit 11 is adjusted by a white balance (WB) adjusting unit 12 in the subsequent stage, and the gamma of the data is corrected by a gamma correcting unit 4.
In the configuration shown in FIG. 1 as above, the WB adjusting unit 12 is arranged subsequently to the complementary color-pure color converting unit 11, and the color temperature correction is done by performing the white balance adjustment for the pure color data (R,G,B) after complementary colors are converted into pure colors. This configuration is advantageous in that the color temperature correction can be relatively easily performed because the gain of the pure color data (R,G,B) can be directly adjusted.
In the configuration shown in FIG. 2, on the other hand, a WB adjusting unit 2 adjusts the white balance of complementary color data (Ma,Gr,Ye,Cy) obtained by an image sensing unit 1. Thereafter, a complementary color-pure color converting unit 3 performs complementary color-pure color conversion to obtain pure color data (R,G,B). This configuration has the advantage that a luminance signal with a higher resolution than that obtained in the configuration shown in FIG. 1 can be easily obtained.
The method of adjusting the hue of an image by adjusting the white balance is effective when many objects which are supposed to look white exist in an image signal obtained from an image sensing device. However, no such object which is supposed to look white exists in an image signal or only a very few such objects exist in an image signal in specific instances. In these instances, therefore, it is in principle impossible to adjust the hue by adjusting the white balance. In such instances, the general approach is to average image sensing data of one image plane for each color component and adjust the white balance by using the average. However, a color indicated by the obtained average is not necessarily white (the color of a light source), and so the white balance cannot be accurately adjusted.
That is, the white balance coefficient cannot be accurately set if it is determined from image sensing data in order to obtain an optimum reproduced image.
Also, in the setting of the reproduction luminance level, if the reproduction luminance level (range) is determined for each image plane, the correlation between the luminances of a plurality of image planes is lost. This makes the comparison of reproduced images difficult, or the connection of luminances becomes unnatural when the reproduced images are synthesized.
For example, the above inconveniences are significant when an object which is to be originally, desirably photographed as one image plane is divisionally photographed because the photographing area is small and one image plane is formed by synthesizing image sensing data of the obtained image planes.
That is, in the method of obtaining an image production parameter for each image sensing data of one image plane, it is impossible to obtain a reproduced image which is used when information between a plurality of images is extracted by comparing and analyzing the images, such as when physical property information is obtained from luminance information. Also, if the reflectance of an object spatially, gradually changes, individual image sensing data obtained by divisionally photographing the object have different luminance levels (ranges). If images are reproduced by independently optimizing these image sensing data, the correlation between luminances originally corresponding to the respective image sensing areas is lost in the reproduced images. Accordingly, if one image is formed by synthesizing these images taken in the respective image sensing areas, an unnatural synthetic image in which the correlation between luminances is lost results.
The hue of an image is adjusted by adjusting the white balance as follows. An object which is supposed to look white under a certain photographing light source is photographed. The amplification factor of each of a plurality of color component signals constituting an image signal obtained from the image sensing device is so adjusted that the white object accurately looks white when the image signal is reproduced. That is, it can be considered that the white balance adjustment is performed to compensate for changes in the light source during photography.
Commonly, the white balance adjustment described above is a principal means for compensating for changes in the light source during photography. A white balance coefficient used in this white balance adjustment is obtained on the basis of information of the light source during photography.
Of a plurality of different image reproduction parameters used in image reproduction, some parameters are preferably obtained on the basis of information of the light source during photography, like the image reproduction parameter (white balance coefficient) used in the white balance adjustment. An example is a complementary color-pure color conversion matrix used to convert an image signal obtained by using a complementary color filter into a pure color signal.
The complementary color-pure color conversion matrix is determined by the spectral transmittance characteristic of a complementary color filter. Usually, the spectral transmittance characteristic of a complementary color filter is not ideal. The influence of this difference from the ideal characteristic changes in accordance with the characteristics of the light source during photography. That is, a complementary color-pure color conversion matrix optimally selected under a certain photographing light source gives an optimum complementary color-pure color conversion result under this light source. However, this matrix does not give suitable conversion results to all light sources.
When a photographing light source changes, therefore, it is desirable to change the complementary color-pure color conversion matrix in accordance with the light source. Also, the above two image reproduction parameters, i.e., the white balance coefficient and the complementary color-pure color conversion matrix, are related to each other under a certain photographing light source. Accordingly, it is undesirable to individually determine these parameters.
Generally, however, the complementary color-pure color conversion is performed by using a semi-fixed complementary color-pure color conversion matrix which is optimally set under a certain photographing light source. If the photographing light source changes, therefore, the influence of the difference of the spectral transmittance characteristic of a complementary color filter from the ideal characteristic increases. Also, a contradiction sometimes occurs between the white balance coefficient and the complementary color-pure color conversion matrix having the correlation. Consequently, no complementary color-pure color conversion can be properly performed, and this makes faithful reproduction of an image difficult.


A stop control unit carries out control, when a moving speed of a bucket in a direction toward target design topography is the same in both of a first specifying state in which a bucket weight specifying portion specifies a weight of the bucket as large and a second specifying state in which the bucket weight specifying portion specifies a weight of the bucket as small, such that the moving speed of the bucket in the direction toward the target design topography is reduced from a position more distant from the target design topography in the first specifying state than in the second specifying state.

A work vehicle such as a hydraulic excavator includes a work implement including a boom, an arm, and a bucket. In control of the work vehicle, automatic control in which a bucket is moved based on target design topography (design topography) which is an aimed shape of an excavation target has been known.
PTD 1 has proposed a scheme for automatic control of profile work in which soil abutting to a bucket is plowed and leveled by moving the cutting edge of the bucket along a reference surface and a surface corresponding to the flat reference surface is made.
Automatic control above includes also control for automatically stopping an operation of a work implement (stop control) other than profile control above. This stop control enables automatic stop of an operation of the work implement just before target design topography such that a cutting edge of a bucket does not dig into target design topography. Such stop control is disclosed, for example, in PTD 2.


Techniques for a machine learning event-driven radio resource management (ED-RRM) module which provides analysis of interference events in a network system are described. The network system reacts to the detection of interference in a network system and uses multiple input parameters to determine a type of device creating the interference, a predicted duration of the interference, and an ED-RRM decision on whether to activate the radio resource management (RRM) processes to alter the network transmission or block the RRM processes to conserve system resources for the network system.

As the number of networked devices transmitting signals on various frequencies continually increases, the likelihood of radio interference between the various devices also increases. Furthermore, many electronic devices that are not connected to networks can cause enough radio interference that the network connection between networked devices is disrupted. Many modern networked communication devices detect the radio interference and begin processes to decrease the effects of the interference, such as changing the channel/radio frequencies used by the connected networked device.
In many cases, the processes used to change the channel/radio frequencies are expensive for the device to perform in both computing resources needed to implement the processes and power to complete the processes in addition to being disruptive to ongoing communications in various subsystems in the network. In some cases, these processes are triggered automatically as soon as adverse interference conditions are detected which can lead to wasted resources and energy in the system as well as unnecessary communication disruption, especially in instances when the radio interference is passing or temporary.
To facilitate understanding, identical reference numerals have been used, where possible, to designate identical elements that are common to the figures. It is contemplated that elements disclosed in one embodiment may be beneficially used in other embodiments without specific recitation.

Event-driven radio resource management triggering


A protocol for replicating replicas in a sync community. Each replica maintains a knowledge that represents changes that the replica is aware of. Each replica does not typically maintain knowledge about other replicas. The protocol includes messages that include knowledge about changes on the various replicas. Using the knowledge, the replicas can enumerate changes and send the changes using asynchronous messages that do not need to be received in any particular order. The protocol enables filters to ensure that a valid replication is possible using a minimum knowledge argument. The protocol also enables replicas to partially replicate using filtered knowledge.

1. The Field of the Invention
The present invention generally relates to systems and methods for replicating data stores. More specifically, the present invention relates to a protocol for replicating data stores in a sync community.
2. Background and Relevant Art
Background
In today's world of digital information handling, individuals may store information or data in a variety of different devices and locations. Often the user stores the same information in more than one device and/or location. Obviously, the user would like all of the various data stores to have the same information without having to manually input the same changes to each data store. Replication is the process used to ensure that each data store has the same information.
For example, a user may maintain an electronic address book in a myriad of different devices or locations. The user may maintain the address book, for example, on a personal information manager stored on their desktop computer, on their laptop computer, in a personal digital assistant (PDA), in an on-line contacts manager, and the like. The user can modify the electronic address books in each location by, for example, adding a contact, deleting a contact, or changing contact information. One goal of replication is to ensure that the change made on a particular device is ultimately reflected in the data stores of the user's other devices.
Various problems with current replication methods include inefficient use of bandwidth by replicating items that are already replicated but appear to be unreplicated, replication reflection, replication loops where data in one replica is continually updated and replaced, having data that is replicated being perceived as in conflict, and the like.
Further, some methods of replication use synchronous protocols that require handshaking and message acknowledgement. Because these protocols require handshaking and acknowledgement, these protocols normally have a time-out parameter within which acknowledgements should be sent. As a result, the connection between replicating replicas should be active during an entire replication. In addition, some protocols require that changes be sent and received in a certain order. If the changes are sent out of order, changes that are chronologically less current may be used to replace more current items.
Current protocols may also require the replicas to suspend other operations until changes are received and applies. This is done because changes must be applied in the order that they are made. If other operations are not suspended, changes may be made that would then be replaced by chronologically less current changes. Current protocols also suffer from problems when changes are sent by one replica and not received by another. In some cases, the a replication anchor may be updated by the sending replica such that the sending replica believes that changes have been received by another replica when in fact they have not.
In a replicated system, simply ensuring that every replica in a sync community sees every action or change is not sufficient to ensure eventual consistency among the replicas in the sync community. The replicas should apply changes in a consistent order, resolve conflicts in a consistent manner.


A centrifuge has a bucket for receiving the product to be centrifuged, and a support which is configured to be inserted in the bucket and receive microtiter plates and the like. The support has substantial stability and comprises a generally planar base and four upstanding lateral walls which are integrally formed with the base and which are coupled together at their upper edges to form a substantially self-contained enclosure.

The present invention relates to a centrifuge comprising at least one bucket for receiving the product to be centrifuged and a support that can be inserted into the bucket and is designed to receive microtiter plates, wherein the support comprises a base and lateral walls extending upwards from the base. Furthermore, the invention relates to a support that is used, for example, in a centrifuge.
Centrifuges of the aforementioned type are known from practical experience, exist in many different embodiments and sizes and are used, for example, in the separation of mixtures of materials with the help of the centrifugal force acting on the product. Centrifuges are known, for example as sedimentation centrifuges. This group of centrifuges also includes the bucket centrifuges, in which buckets, which can rotate about a horizontal axis, are suspended on a vertical shaft and are supported perpendicular to the rotational axis by the centrifugal force.
In bucket centrifuges, supports are used frequently, which are designed for receiving microtiter plates and are inserted for centrifugation into a bucket.
Known centrifuges are frequently involved in an automation process in such a way that the buckets of the centrifuges are loaded and unloaded automatically by means of electronically controllable manipulators. Due to this a high sample throughput can be achieved.
Known supports for microtiter plates comprise a substantially rectangular base and two lateral walls extending vertically from this base on two opposite sides. Between these lateral walls one or more microtiter plates can be then be arranged, if necessary, on top of one another in a sandwich-like manner. The entire arrangement made of support and microtiter plate or microtiter plates can then be provided by means of a manipulator into a bucket of the centrifuge.
The known supports are problematic in several respects. Firstly, very frequently a deflection at least of the upper end of both the lateral walls occurs during a centrifugation. This can lead to the used support being unusable after a brief application, thus requiring it to be replaced by a new support. Furthermore, due to its low form stability the known support does not enable a safe positioning of microtiter plates in the support during the centrifugation. In particular, in the case of a multi-layer design of micro-plates in the support, an unintentional slipping of a lower microtiter plate already inserted into the support can prevent a precisely aligned positioning of several microtiter plates on top of one another by means of an automatic manipulator. Thus a high and reliable sample throughput is not possible in an automatically loadable and unloadable centrifuge.
Furthermore, the manageability of the support with and without inserted microtiter plates is reduced due to its lack of form stability. Particularly in an automatic handling and positioning of the support, it is possible that the supports are not grasped properly and therefore are no longer moveable and positionable in the intended manner.
Finally, there is poor access to the microtiter plates inserted in the support in the region of the existing lateral walls due to the narrowness of the support. This prevents a safe manipulation of the microtiter plates arranged in the support.
Therefore an object of the present invention is to provide a centrifuge and a support of the aforementioned type, according to which a high sample throughput is enabled in an automated operation reliably and using simple means with regard to design.

Centrifuge and a support for use in a centrifuge