Chondrogenic differentiations is induced by administering a macrocyclic lactone to mammals to prevent or treat damage to cartilage.

This invention relates to a new use of macrolide compounds for inducing chondrogenic differentiation.
The inventors of this invention have surprisingly found that the macrolide compounds mentioned here-in-below has an inducing activity of chondrogenic differentiation.
Accordingly, this invention provides a new use of the macrolide compounds for inducing chondrogenic differentiation.
Further, this invention provides an agent for inducing chondrogenic differentiation, which comprises the macrolide compounds.
Still further, this invention provides a method for inducing chondrogenic differentiation, which comprises administering said macrolide compounds to mammals.
Still further, this invention provides a method for preventing or treating damages of cartilage, which comprises administering said macrolide compounds to mammals.
The term xe2x80x9cmacrolide compoundxe2x80x9d for use in accordance with the invention is the generic name of compounds with 12 members or more, which belong to macrocyclic lactones.
As a particular example of the macrolide compound, the tricyclic compound of the following formula (I) can be exemplified.
(wherein each of adjacent pairs of R1 and R2, R3 and R4 , and R5 and R6 independently
(a) are two adjacent hydrogen atoms, and R2 may optionally be an alkyl group, or
(b) forms another bond formed between the carbon atoms to which they are attached;
R7 is a hydrogen atom, a hydroxy group, a protected hydroxy group, or an alkoxy group, or an oxo group together with R1;
R8 and R9 are independently a hydrogen atom or a hydroxy group;
R10 is a hydrogen atom, an alkyl group, an alkyl group substituted by one or more hydroxy groups, an alkenyl group, an alkenyl group substituted by one or more hydroxy groups, or an alkyl group substituted by an oxo group;
X is an oxo group, a hydrogen atom and a hydroxy group, (a hydrogen atom and a hydrogen atom), or a group represented by the formula xe2x80x94CH2Oxe2x80x94;
Y is an oxo group, (a hydrogen atom and a hydroxy group), (a hydrogen atom and a hydrogen atom), or a group represented by the formula Nxe2x80x94NR11R12 or Nxe2x80x94OR13;
R11 and R12 are independently a hydrogen atom, an alkyl group, an aryl group or a tosyl group;
R13, R14, R15, R16, R17, R18, R19, R22 and R23 are independently a hydrogen atom or an alkyl group;
R24 is an optionally substituted ring system which may contain one or more heteroatoms;
n is an integer of 1 or 2; and
in addition to the above definitions, Y, R10 and R23, together with the carbon atoms to which they are attached, may represent a saturated or unsaturated 5- or 6-membered nitrogen, sulfur and/or oxygen containing heterocyclic ring optionally substituted by one or more groups selected from the group consisting of an alkyl, a hydroxy, an alkoxy, a benzyl, a group of the formula xe2x80x94CH2Se(C6H5), and an alkyl substituted by one or more hydroxy groups.
The definitions used in the above general formula (I) and the specific and preferred examples thereof are now explained and set forth in detail.
The term xe2x80x9clowerxe2x80x9d means, unless otherwise indicated, a group having 1 to 6 carbon atoms.
Preferable examples of the xe2x80x9calkyl groupsxe2x80x9d and an alkyl moiety of the xe2x80x9calkoxy groupxe2x80x9d include a straight or branched chain aliphatic hydrocarbon residue, for example, a lower alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, neopentyl and hexyl.
Preferable examples of the xe2x80x9calkenyl groupsxe2x80x9d include a straight or branched chain aliphatic hydrocarbon residue having one double-bond, for example, a lower alkenyl group such as vinyl, propenyl (e.g., allyl group), butenyl, methylpropenyl, pentenyl and hexenyl.
Preferable examples of the xe2x80x9caryl groupsxe2x80x9d include phenyl, tolyl, xylyl, cumenyl, mesityl and naphthyl.
Preferable protective groups in the xe2x80x9cprotected hydroxy groupsxe2x80x9d and the xe2x80x9cprotected aminoxe2x80x9d are 1-(lower alkylthio)-(lower) alkyl group such as a lower alkylthiomethyl group (e.g., methylthiomethyl, ethylthiomethyl, propylthiomethyl, isopropylthiomethyl, butylthiomethyl, isobutylthiomethyl, hexylthiomethyl, etc.), more preferably C1-C4 alkylthiomethyl group, most preferably methylthiomethyl group;
trisubstituted silyl group such as a tri(lower)alkylsilyl (e.g., trimethylsilyl, triethylsilyl, tributylsilyl, tert-butyldimethylsilyl, tri-tert-butylsilyl, etc.) or lower alkyl-diarylsilyl (e.g., methyldiphenylsilyl, ethyldiphenylsilyl, propyldiphenylsilyl, tert-butyldiphenyl-silyl, etc.), more preferably tri(C1-C4)alkylsilyl group and C1-C4 alkyldiphenylsilyl group, most preferably tert-butyldimethylsilyl group and tert-butyldiphenylsilyl group; and an acyl group such as an aliphatic, aromatic acyl group or an aliphatic acyl group substituted by an aromatic group, which are derived from a carboxylic acid, sulfonic acid or carbamic acid.
Examples of the aliphatic acyl groups include a lower alkanoyl group optionally having one or more suitable substituents such as carboxy, e.g., formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, carboxyacetyl, carboxypropionyl, carboxybutyryl, carboxyhexanoyl, etc.; a cyclo(lower)alkoxy(lower)alkanoyl group optionally having one or more suitable substituents such as lower alkyl, e.g., cyclopropyloxyacetyl, cyclobutyloxypropionyl, cycloheptyloxybutyryl, menthyloxyacetyl, menthyloxypropionyl, menthyloxybutyryl, menthyloxypentanoyl, menthyloxyhexanoyl, etc.; a camphorsulfonyl group; or a lower alkylcarbamoyl group having one or more suitable substituents such as carboxy or protected carboxy, for example, carboxy(lower)alkylcarbamoyl group (e.g., carboxymethylcarbamoyl, carboxyethylcarbamoyl, carboxypropylcarbamoyl, carboxybutylcarbamoyl, carboxypentylcarbamoyl, carboxyhexylcarbamoyl, etc.), tri(lower)alkylsilyl(lower)alkoxycarbonyl(lower)alkylcarbamoyl group (e.g., trimethylsilylmethoxycarbonylethylcarbamoyl, trimethylsilylethoxycarbonylpropylcarbamoyl, triethylsilylethoxycarbonylpropylcarbamoyl, tert-butyldimethylsilylethoxycarbonylpropylcarbamoyl, trimethylsilylpropoxycarbonylbutylcarbamoyl, etc.) and so on.
Examples of the aromatic acyl groups include an aroyl group optionally having one or more suitable substituents such as nitro, e.g., benzoyl, toluoyl, xyloyl, naphthoyl, nitrobenzoyl, dinitrobenzoyl, nitronaphthoyl, etc.; and an arenesulfonyl group optionally having one or more suitable substituents such as halogen, e.g., benzenesulfonyl, toluenesulfonyl, xylenesulfonyl, naphthalenesulfonyl, fluorobenzenesulfonyl, chlorobenzenesulfonyl, bromobenzenesulfonyl, iodobenzenesulfonyl, etc.
Examples of the aliphatic acyl groups substituted by an aromatic group include or(lower)alkanoyl group optionally having one or more suitable substituents such as lower alkoxy or trihalo(lower)alkyl, e.g., phenylacetyl, phenylpropionyl, phenylbutyryl, 2-trifluoromethyl-2-methoxy-2-phenylacetyl, 2-ethyl-2-trifluoromethyl-2-phenylacetyl, 2trifluoromethyl-2-propoxy-2-phenylacetyl, etc.
More preferable acyl groups among the aforesaid acyl groups are C1-C4 alkanoyl group optionally having carboxy, cyclo (C5-C6)alkoxy(C1-C4)alkanoyl group having two (C1-C4) alkyls at the cycloalkyl moiety, camphorsulfonyl group, carboxy-(C1-C4)alkylcarbamoyl group, tri(C1-C4)alkylsilyl(C1-C4)alkoxycarbonyl(C1-C4)alkylcarbamoyl group, benzoyl group optionally having one or two nitro groups, benzenesulfonyl group having halogen, or phenyl(C1-C4)alkanoyl group having C1-C4 alkoxy and trihalo(C1-C4)alkyl group. Among these, the most preferable ones are acetyl, carboxypropionyl, menthyloxyacetyl, camphorsulfonyl, benzoyl, nitrobenzoyl, dinitrobenzoyl, iodobenzenesulfonyl and 2-trifluoromethyl-2-methoxy-2-phenylacetyl.
Preferable examples of the xe2x80x9c5- or 6-membered nitrogen, sulfur and/or oxygen containing heterocyclic ringxe2x80x9d include a pyrrolyl group and a tetrahydrofuryl group.
R24 is an optionally substituted ring system which may contain one or more heteroatoms. Preferably R24 may be cyclo(C5-7)alkyl group optionally having suitable substituents, and the following ones can be exemplified.
(a) a 3,4-di-oxo-cyclohexyl group;
(b) a 3-R20-4-R21-cyclohexyl group,
xe2x80x83in which
R20 is hydroxy, an alkoxy group, an oxo group, or
a xe2x80x94OCH2OCH2CH2OCH3 group, and
R21 is hydroxy, xe2x80x94OCN, an alkoxy group, a heteroaryloxy which may be substituted by suitable substituents, 1- or 2-tetrazolyl, a xe2x80x94OCH2OCH2CH2OCH3 group, a protected hydroxy group, chloro, bromo, iodo, aminooxalyloxy, an azido group, p-tolyloxythiocarbonyloxy, or R25R26CHCOOxe2x80x94,
xe2x80x83in which
R25 is optionally protected hydroxy or protected amino, and
R26 R is hydrogen or methyl, or
R20 and R21 together form an oxygen atom in an epoxide ring; or
(c) cyclopentyl group substituted by methoxymethyl, optionally protected hydroxymethyl, acyloxymethyl
(in which the acyl moiety optionally contains either a dimethylamino group which may be quaternized, or a carboxy group which may be esterified), one or more amino and/or hydroxy groups which may be protected, or aminooxalyloxymethyl. A preferred example is a 2-formyl-cyclopentyl group.
xe2x80x9cA heteroaryl which may be substituted by suitable substituentsxe2x80x9d moiety of the xe2x80x9cheteroaryloxy which may be substituted by suitable substituentsxe2x80x9d may be the ones exemplified for R1 of the compound of the formula of EP-A-532,088, with preference given to 1-hydroxyethylindol -5-yl, the disclosure of which is incorporated herein by reference.
The tricyclic compounds (I) and its pharmaceutically acceptable salt for use in accordance with this invention are well known to have excellent immunosuppressive activity, antimicrobial activity and other pharmacological activities and, as such, be of value for the treatment or prevention of rejection reactions by transplantation of organs or tissues, graft-vs-host diseases, autoimmune diseases, and infectious diseases [EP-A-0184162, EP-A-0323042, EP-A-423714, EP-A-427680, EP-A-465426, EP-A-480623, EP-A-532088, EP-A-532089, EP-A-569337, EP-A-626385, WO89/05303, WO93/05058, WO96/31514, WO91/13889, WO91/19495, WO93/04680, WO93/5059, etc.], the disclosures of which are incorporated herein by reference.
Particularly, the compounds which are designated as FR900506 (=FK506), FR900520 (ascomycin), FR900523, and FR900525 are products produced by microorganisms of the genus Streptomyces, such as Streptomyces tsukubaensis No. 9993 [deposited with National Institute of Bioscience and Human Technology Agency of Industrial Science and Technology (formerly Fermentation Research Institute Agency of Industrial Science and Technology ), at 1-3, Higashi 1-chome, Tsukuba-shi, Ibaraki, Japan, date of deposit Oct. 5, 1984, accession number FERM BP-927] or Streptomyces hygroscopius subsp. yakushimaensis No. 7238 [deposited with National Institute of Bioscience and Human Technology Agency of Industrial Science and Technology (formerly Fermentation Research Institute Agency of Industrial Science and Technology ), at 1-3, Higashi 1-chome, Tsukuba-shi, Ibaraki, Japan, date of deposit Jan. 12, 1985, accession number FERM BP-928] [EP-A-0184162]. The FK506 (general name: tacrolimus) of the following chemical formula, in particular, is a representative compound.
The preferred examples of the tricyclic compounds (I) are the ones, wherein each of adjacent pairs of R3 and R4 or R5 and R6 independently form another bond formed between the carbon atoms to which they are attached;
each of R8 and R23 is independently a hydrogen atom;
R9 is a hydroxy group;
R10 is a methyl group, an ethyl group, a propyl group or an allyl group;
X is (a hydrogen atom and a hydrogen atom) or an oxo group;
Y is an oxo group;
each of R14, R15, R16, R17, R18, R19, and R22 is a methyl group;
R24 is a 3-R20-4-R21-cyclohexyl group,
xe2x80x83in which
R20 is hydroxy, an alkoxy group, an oxo group, or a xe2x80x94OCH2OCH2CH2OCH3 group, and
R21 is hydroxy, xe2x80x94OCN, an alkoxy group, a heteroaryloxy which may be substituted by suitable substituents, 1- or 2-tetrazolyl, a xe2x80x94OCH2OCH2CH2OCH3 group, a protected hydroxy group, chloro, bromo, iodo, aminooxalyloxy, an azido group, p-tolyloxythiocarbonyloxy, or R25R26CHCOOxe2x80x94,
xe2x80x83in which
R25 is optionally protected hydroxy or protected amino, and
R26 is hydrogen or methyl, or
R20 and R21 together form an oxygen atom in an epoxide ring; and
n is an integer of 1 or 2.
The most preferable tricyclic compounds(I) is, in addition to FK506, ascomycin derivatives such as halogenated-ascomycin (e.g., 33-epi-chloro-33-desoxyascomycin), which is disclosed in EP 427,680, example 66a.
The tricyclic compounds(I) has a similar basic structure, i.e., tricyclic macrolide structure, and at least one of the similar biological properties (for example, immunosupressive activity).
The tricyclic compounds(I) may be in a form of its salt, which includes conventional non-toxic and pharmaceutically acceptable salt such as the salt with inorganic or organic bases, specifically, an alkali metal salt such as sodium salt and potassium salt, an alkali earth metal salt such as calcium salt and magnesium salt, an ammonium salt and an amine salt such as triethylamine salt and N-benzyl-N-methylamine salt.
With respect to the macrolide compound used in the present invention, it is to be understood that there may be conformers and one or more stereoisomers such as optical and geometrical isomers due to asymmetric carbon atom(s) or double bond(s), and such conformers and isomers are also included within the scope of macrolide compound in the present invention. And further, the macrolide compounds can be in the form of a solvate, which is included within the scope of the present invention. The solvate preferably include a hydrate and an ethanolate.
The macrolide compounds usable in the present invention may be administered as pure compounds or mixtures of compounds or preferably, in a pharmaceutical vehicle or carrier.
The pharmaceutical compositions of this invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the macrolide compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external(topical), enteral, intravenous, intramuscular, or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable, carriers for tablets, pellets, capsules, eye drops, suppositories, solutions (saline, for example), emulsion, suspensions (olive oil, for example), ointment and any other form suitable for use. The carriers which can be used are water, glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesiumtrisilicate, talc, cornstarch, keratin, colloidal silica, potato starch, urea and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form, and in addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. The active object compound is included in the pharmaceutical composition in an effective amount sufficient to produce the desired effect upon the process or condition of the disease.
Mammals which may be treated using the method of the present invention include livestock mammals such as cows, horses, etc., domestic animals such as dogs, cats, rats, etc. and humans.
While the dosage of therapeutically effective amount of the macrolide compounds varies from and also depends upon the age and condition of each individual patient to be treated, a daily dose of about 0.0001-1000 mg, preferably, 0.001-500 mg and more preferably, 0.01-100 mg of the active ingredient is generally given for treating diseases, and an average single dose of about 0.001-0.01 mg, 0.2-0.5 mg, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 250 mg and 500 mg is generally administered. Daily doses for chronic administration in humans will be in the range of about 0.1-0.3 mg/kg/day.

Macrolide compounds for inducing chondrogenic differentiation


The manufacturing method provided by the present invention is a method for manufacturing core-shell particles that includes core particles and a shell, the constituent metal elements of the foregoing being different from each other. In the present invention, a quinone-containing core particle dispersion containing at least core particles consisting of a first metal, hydroquinone (HQ), benzoquinone (BQ), and a second metal compound including a second metal element for making up the shell is prepared, and a reduction treatment is performed on the quinone-containing core particle dispersion, through addition of a reducing agent, to form a shell including the second metal element as a main constituent element, on the surface of the core particles. A mass ratio: HQ/BQ ratio of added hydroquinone (HQ) and benzoquinone (BQ) is 0.1 to 120.

In recent years, core-shell particles have come to be used in various industrial fields, for instance from the viewpoint of imparting functionality and reducing costs. For example, AgPd core-shell particles, in which a Pd shell (covering portion) including palladium (Pd) as a main constituent metal element is formed on the surface of an Ag core including silver (Ag) as a main constituent metal element, are being developed in the field of for instance conductive pastes (also referred to as conductive pastes) and catalysts. Patent Literature 1 (Japanese Patent Application Publication No. H08-176605) discloses a method for manufacturing a palladium-coated silver powder wherein silver particles are formed through addition of a reducing agent to an aqueous solution of silver amine chloride, followed by covering of the silver particles with palladium.
To meet the demand for smaller electronic components and thinner electrodes in recent years, for instance, powder materials for conductive pastes, being paste-like (slurry-like) compositions for forming an electrode film or the like, that have metal particles constituting the main component of the powder material, and smaller particle sizes while exhibiting a sharp particle size distribution have been demanded. Therefore, in a case where core-shell particles including constituent metal elements in the form of a noble metal such as Ag or Pd or a base metal such as Ni are used as the main component of a powder material for conductive pastes, it is important to control the particle size of the core-shell particles down to a sub-micron region, while preserving a sharp particle size distribution.
When manufacturing this kind of core-shell particles in accordance with conventional methods, however, agglomeration and/or linking (necking) sometimes occurs between the produced core-shell particles (typically primary particles), with significant formation of secondary particles for instance in the form of agglomerates and/or linked (necked) masses of large particle size. In such secondary particles, multiple primary particles are adhered to each other via respective shells, the secondary particles becoming thus strong enough so as not be amenable to crushing. The particle size of the obtained secondary particles is as a result significantly larger than the particle size of the cores of the primary particles, and exhibits significant variability in particle size. Further, the higher the shell proportion is, the more readily the particles become linked to each other via shells, which makes inter-particle adhesion yet more difficult to suppress. For instance, it is difficult to suppress linking itself by a Pd shell in the art disclosed in Patent Literature 1.
It is deemed that, in order to suppress adhesion and agglomeration, it is preferable to form the shell (covering portion) upon thorough dispersion of a powder consisting of core particles in a predetermined solution for shell formation. In a case where the core particles are dispersed using a dispersant, however, the dispersant adsorbed on the core particle surface might hinder shell formation. Meanwhile, when a shell is formed on the core particle surface a further concern arises in that the function of the dispersant adsorbed on the core particle surface may be impaired as a result, which in turn may translate into poorer dispersibility.
Non Patent Literature 1 (ZHAO Bin, Naoki TOJIMA, Japanese Journal of Polymer Science and Technology, Vol. 46 (1989) No. 9, pp. 551) describes a technology for reducing the size of metal particles contained in a powder material. Non Patent Literature 1 discloses a technology wherein metal particles (for instance of Rh or Pd) are caused to precipitate in the presence of polyvinylpyrrolidone (PVP), to thereby generate metal ultramicroparticles the surface of which is protected by PVP. Non Patent Literature 2 (Abstracts of Annual Meeting of Japan Society for Molecular Science (2015), 2P077) and Non Patent Literature 3 (Nature nanotechnology, 6, 302 (2011) Supplementary information) disclose technologies in which PVP is used for manufacturing core-shell particles. For example, in Non Patent Literature 2, for instance, a solution resulting from dissolving silver nitrate and PVP is firstly prepared, whereupon Ag is caused to precipitate from the solution, to thereby generate Ag core particles. Palladium nitrate is then dissolved in a dispersion containing the Ag core particles, after which Pd is caused to precipitate to thereby form a Pd shell on the surface of the Ag core particles. Non Patent Literature 2 indicates that the average particle size of the AgPd core-shell particles obtained in accordance with such a procedure is about 5.0 nm.


There is provided a dispensing device for a welding rod dryer. The dispensing device may include a plurality of chambers configured to receive welding rod dryers; and a connection member provided in each of the plurality of chambers and configured to supply power to the welding dryers; and a door provided at an entrance of each of the plurality of chambers.

1. Field
Apparatuses consistent with exemplary embodiments relate to a dispensing device for a welding rod dryer, and more particularly, to a dispensing device for a welding rod dryer, in which the welding rod dryer can be maintained at a predetermined temperature in the state that the welding rod dryer receives a welding rod without being stored separately from the welding rod, and many welding operators can rapidly dispense welding rod dryers at a time without difficulty and inconveniences.
2. Description of the Related Art
Shielded metal arc welding (SMAW) is a technology first developed among arc welding technologies, and one of the technologies that have been most extensively used until now.
According to the SMAW, an arc is generated between an electrode rod formed by coating a core with a cladding material and a base material for the welding work. The SMAW has been extensively used to mainly perform a welding work for mild steel, low alloy steel, stainless steel, or cast iron. In addition, since the SMAW has no special limitation in the thickness of a structure to be welded or a welding posture of a welding operator, the SMAW has been widely employed in shipbuilding, bridge, construction, and petroleum refining industries.
A welding rod used in the SMAW is formed by coating a cladding material on an outer circumference of a metallic rod for generating an arc. If the cladding material of the welding rod is stripped or the welding rod becomes wet with moisture, the welding rod may not be operational, or the arc cannot be smoothly generated, so that a difficult situation in the use of the welding rod may frequently occur.
Therefore, when the welding rod is stored, there is required a special caution of preventing the cladding material from being stripped or preventing the welding rod from becoming wet with moisture.
Meanwhile, when storing the portable welding rod dryer, a welding rod remaining after the use thereof is separated from the welding rod dryer and put into a drying oven for the storage thereof, and the portable welding rod dryer is stacked and stored in a typical shelf.
Accordingly, in the case of heavy industry fields, delay time is significantly taken until many welding operators select and receive their respective welding rod dryers at a time. In other words, predetermined time is required to preheat the portable welding rod dryer, and the welding operation must significantly and inconveniently be delayed for the welding rod dryer for time ranging from several tens of minutes to several hours.
Accordingly, not only is too much time wasted, but also manpower of many welding operators is remarkably wasted. Further, since the welding rod stored in the drying oven must be drawn from the drying oven and received in the portable welding rod dryer again even though the heating of the portable welding rod dryer has been finished, procedures are remarkably complex and inconvenient.

DOOSAN HEAVY INDUSTRIES & CONSTRUCTION CO., LTD.


An improved method for the preparation of functionalized substituted bisphenol compound is provided. In particular, there is provided a method of making a functionalized substituted bisphenol compound of the formula: ##STR1## which comprises heating a mixture comprising a 2,6-dimethylphenol and levulinic acid in the presence of an effective amount of a macroreticular ion-exchange resin, optionally with removal of the water of reaction.

1. Field of the Invention
This invention relates to a process for making functionalized substituted bisphenol compounds using ion exchange resins. More particularly, this invention relates to the preparation of functionalized substituted bisphenol compounds from functionalized ketones or aldehydes with substituted phenols using macroreticular ion exchange resins. In an especially preferred embodiment, this invention relates to the synthesis of an acid functionalized bis-xylenol compound from levulinic acid and 2,6-dimethylphenol using a macroreticular ion exchange resin as catalyst
2. Description of the Prior Art
Condensation reactions, for example, the conversion of various phenols and functionalized ketones into functionalized bis-phenols, have been accomplished with mineral acids. For example, U.S. Pat. No. 3,567,686 describes in general terms the condensation of phenol with keto acids or keto esters such as levulinic acid to prepare bis-phenol compounds of ##STR2## the structure: COOR wherein A is a radical selected from the group consisting of hydrogen, methyl, and phenyl and R is an alkyl group containing one to eighteen carbon atoms, wherein the ester is prepared by reaction of the desired alcohol with the corresponding bis-phenol acid. The esters were described as useful in the polycarbonate resins.
The condensation of mono-alkyl substituted phenols wherein the alkyl group contains at least eight carbon atoms and keto-acids has been described in U.S. Pat. No. 3,954,808. At column 4, beginning at line 37, it is stated that the alkyl-substituted phenol preferably has at least ortho-position unsubstituted on the phenol ring. Acids such as sulphuric acid, p-toluenesulphonic acid, or a mixture of hydrochloric acid and glacial acetic acid were described as catalysts for the condensation reaction. Lactone structures from further condensation of the phenolic hydroxyl groups with the carbonyl-substituted carboxylic acid are also described.
Japanese publication JP62070338 (Tabayashi, et al.) refers to the preparation of functionalized bisphenols from phenols and keto-carboxylic acids using acid catalysis.
Japanese publication JP61186346 (Itsuda, et al.) refers to the preparation of 4,4-bis(4-hydroxyphenyl)pentanoic acid from phenol and levulinic acid using mineral acid catalysis.
Condensation reactions for the production of bis-phenols using ion exchange resins is fairly old and can be found in U.S. Pat. Nos. 3,049,568, 3,049,569 and 3,153,001 (Apel, et al) and 3,221,061 (Grover), among other references. Generally, the bis-phenol described is bis-phenol, a basic building block for polycarbonate resins. The use of ion exchange catalysts for the preparation of bis-xylenols containing acid moieties is unknown.
Due to the costs and efforts associated with the conversion and subsequent purification of bis-xylenols containing acid moieties prepared using mineral acids to catalyze the condensation reactions, it is apparent that a need exists for improved methods for the preparation of these materials.

Method for making bis-xylenols containing acid moieties


The present invention provides an automatic control device of foldable tent connecting to several roof strut sets wherein, said control device is of a central standing base containing a sliding hub, a spring and a tappet roller at inside. Cooperating to an extra force exerting on the central standing base to press it down relative to the roof strut sets, the sliding hub brings the tappet roller continuously to go down and up, by means of the special design between the spring and all the pushing lugs and hook slots of the tappet roller, positioning the sliding hub with the locking pin of the central standing base can be carried out, so that the tent can be opened and kept in open configuration automatically; when repeatedly press down the central standing base relative to the roof strut sets, the tent can be closed.

1. Field of the Invention
The present invention relates to a tent or an awning, and more particularly to an automatic control device of the roof staying mechanism on the same.
2. Description of Prior Art
The tents or awnings are leisure apparatuses in various styles standing outdoors, such as used in climbing, fishing, or picnicking outdoor leisure action. In accordance with the profile shapes of the conventional arts, they can be divided into ridge, igloo, framed, bell and so on; according to the folding or unfolding way, they are classified into conventional frame folding tent and umbrella folding tent in the manual operation framework.
Regarding to the umbrella folding tent, the framework and folding or unfolding operation are just like to the umbrella. The typical structure of it, as shown in FIG. 1, is typically to locate a static hub 10 at the center top for connecting with all the roof strut sets 40 in radial, therein said roof strut set 40 is comprised of several segments (three in the commonest) connected each other by pivoting connectors for facilitating to folding, and awning is fixed on the top sides of all the roof strut sets 40 flatly by fixing the rim of said awning on the outer ends of said roof strut sets 40 respectively, so as to construct an open-able tent. A main pole is located at the bottom side of said static hub 10 for fitting on a sliding hub 20 movingly; said sliding hub 20 is used for connecting one ends of all aid-strut rods 30 in radial coordinately, the another ends of said aid-strut rods 30 are respectively connected on the trunks of the first segments of said roof strut sets 40 pivotally. A spring 50 is positioned between said static hub 10 and said sliding hub 20, and it is in compression state as the tent is in folded configuration; as tending to open the tent, the restoring force of the spring 50 can make all the roof strut sets 40 automatically spread up.
In accordance with the above-described structure of umbrella-style foldable tent, there are following shortcomings existing:                1. said tent is opened via the aid-strut rod 30′ configuration, but the level aid-strut rods 30 are unable to push up the roof strut sets 40 directly, so it needs that user pulls down the sliding hub 20 along the trunk of the main pole, therefore adding a violent operation is inconvenient for use.        2. Building up all the aid-strut rods 30 and the main pole makes the volume of the control device of the roof staying mechanism increase greatly.

Automatic control device of foldable tent


The process for coding the current block comprises a step of selecting the predicted block from among candidate blocks, the selection being dependent on a difference DBdrx,dry between the co-located block of the current image block lying in an image of type B and the block of a reference image, the latter block being designated by the motion vector with components drx, dry which is allocated to co-located block and which is colinear with the motion vector Vp allocated to the current block and designating the candidate block. The process relates to data compression, the transmission of digital images using the video coding standard comprising a direct prediction mode, for example the h263, MPEG4 or h261 standard.

In data compression standards, for example of MPEG type, the images to be coded are generally images of intra and inter type and in the latter case, with predictive coding, of type P or with bidirectional predictive coding of type B. The term image is taken here within its broad sense and also encompasses the video object planes of which the image is composed, better known by the name VOP, standing for Video Object Plane.
Conventionally, the motion estimator contained in a coder is, firstly, invoked so as to extract the motion field of the type P image. Subsequently, after the coding of this P image, the motion estimator is called upon again for each of the B images, for the conventional forward, backward and bidirectional prediction modes. On completion of the various motion estimations of each of the B images, the coding is performed by choosing the best mode from among all the modes available, including the "temporal direct" mode, according to the criterion in force in the coder. This "temporal direct" mode, explained for example in paragraph 22.214.171.124. of the ISO/IEC 14496-2 standard, uses the motion vectors of the co-located macroblock in the most recently decoded type P image to perform the bidirectional prediction of the current macroblock in the type B image. The co-located macroblock is the macroblock lying at the same location, that is to say having the same vertical and horizontal index as the current macroblock of the P image.
FIG. 1 represents the motion prediction utilizing the direct mode.
Four successive images are represented in the order of display, that is to say before reordering, a first reference image of type I or P, a second and third image of type B and a fourth reference image of type P.
The prediction for the current macroblock MBp of the fourth image of type P, referenced 1, is the macroblock referenced 2 of the first image of type I or P. The corresponding motion vector MVp is referenced 3.
The co-located macroblock corresponding to the macroblock MBp for the second image, is referenced 4. The direct type prediction, for this macroblock belonging to the B image, gives a first macroblock MBfw in the first image and a second macroblock MBbck in the last image, these macroblocks referenced 5 and 6 respectively correspond to the forward motion vector MVF and to the backward motion vector MVB referenced 7 and 8 in the figure.
Although the motion vectors are generally allocated, in the MPEG standard, to macroblocks, the process can be applied to simple image blocks and therefore, hereinafter, no distinction will be made between image blocks and macroblocks.
By way of example, the traditional approach used during motion estimation making it possible to extract the vector of a block of a P image can be based on the technique of block matching, in a search windown, by minimizing the sum of the absolute value of the inter-image differences as follows:
                              SAD                      dx            ,            dy                    P                =                  (                                    ∑                              i                ,                                  j                  =                  0                                                            i                ,                                  j                  =                  L                                                                                                                                                    P                    cur                                                                          (                                          i                      ,                      j                                        )                                                  -                                                      IP                    prev                                                                          (                                                                  i                        +                        dx                                            ,                                              j                        +                        dy                                                              )                                                                                              )                                                  SAD                      Dx            ,            Dy                    P                =                              Min                                      (                              SAD                                  dx                  ,                  dy                                P                            )                                            dx            ,                          dy              =                              -                N                                                          dx            ,                          dy              =              N                                          with:
i, j: row and column indices of the pixels contained in the block of size L*L,
Pcur(i,j): block of a current image of type P,
IPprev(i,j): block of a previous (from the temporal point of view) image of type I or P,
SADdx,dyP: sum of the absolute value of the differences (the acronym standing for Sum of Absolute Differences) between the luminance values of the pixels of a block of a current image of type P and of a block displaced by dx, dy of a previous image of type I or P.
SADDx,DyP: minimum value of SADdx,dyP over the set of image blocks in a search window of dimension 2N+1, 2N+1 and corresponding to a displacement Dx, Dy
As far as the co-located block of the B image is concerned, said block is predicted according to the direct mode with the aid of the vectors MVF and MVB such that:
            MBprd      drc        =          (                                    MB            bck                    +                      MB            fw                          2            )        ,half-sum of the blocks MBbck and MBfw, pixelwise, with:
MBbck=Pnext(xbck,ybck) in backward prediction mode.
Pnext(xbck,ybck) signifies the prediction block belonging to the next P image, from the temporal point of view, whose position corresponds to that of the co-located block displaced by the vector with components xbck, ybck.
MBfw=IPprev(xfor,yfor) in forward prediction mode.
IPprev(xfor,yfor) signifies the prediction block belonging to the previous I/P image, whose position corresponds to that of the co-located block displaced by the vector with components xfor, yfor.
xbck, ybck, components of the vector MVB which are derived from the components of the vector MVp of the co-located block MBp.
xfor, yfor, components of the vector MVF which are derived from the components of the vector MVp of the co-located block MBp.
The motion vectors MVB and MVF allocated to the co-located block, are the vectors colinear with the motion vector MVp, pointing respectively into the next image of type P and into the previous image of type I or P, from which the co-located block originates.MBprddrc is the prediction block of the B image in direct mode, calculated on the basis of the forward and backward prediction blocks.
In such an approach, the motion estimation and the choice of the mode of prediction of the blocks MB of the P images are carried out independently of the content of the previous, from the temporal point of view, B images. The coding, that is to say the data compression, is consequently not optimal for these images of bidirectional type.

Motion estimation or P-type images using direct mode prediction


The present invention relates to a cooling module retentioner, which includes a fixing base and a flexible frame. The fixing base surrounds a heat-generating electronic component at a center and allows the placement of a cooling module therein, and a rising corner column is disposed at each of four corners thereof and each corner column has a snap hole; the flexible frame is composed of two M-like retention brackets whose bottom sides are mounted with a retention hook respectively for the corresponding snap hole, a lever is pivotally disposed at a lower center location thereof and pertains to a metal rod whose one end is integrally bent to form a protruded portion. The production process requires no mold so as to simplify the production process and reduce the production cost.

A cooling module structure mainly includes a heat sink and a cooling fan. The heat sink has two heat contact surfaces, in which the first heat contact surface is a heat conduction surface between heat-generating electronic components and a bottom surface of the heat sink, and the second heat contact surface is a thermal convection surface between cooling fins of the heat sink and the cooling fan. To elaborate the maximum efficacy of heat conduction, the heat conduction surface between the bottom of the heat sink and the heat-generating electronic components shall be tightly bonded. Otherwise, no matter how high the efficacy of the cooling module is, once there is any gap between the bottom surface of the heat sink and the heat-generating electronic components, the cooling efficacy will be greatly alleviated.
The function of the retentioner is to firmly fasten the cooling module above the heat-generating electronic components on the one hand and to be closely sandwiched by the bottom surface of the heat sink and the heat-generating electronic components to make the most of the heat conduction efficacy.
A conventional cooling module retentioner structure is illustrated in Taiwan Patent Publication No. M246991 entitled "Fixing device of heat sink" and Taiwan Patent Publication No. M258557 entitled "Heat sink retentioner" respectively. Not only are those retentioners disclosed by the two patents complex structurally, but also all components must be manufactured through their own molding and then assembled together. The costs for equipment, material and human labor are extremely high.
Above all, as heat-generating electronic components are made by different vendors or specifications, the cooling module retentioners thereof are usually not interchangeable. In view of different packaging techniques adopted by heat-generating electronic components, the requirements for holding pressure of retentioners also vary. If a retentioner with the inconsistent specification is inadequately applied, the heat-generating electronic components is often damaged while mounting the cooling module. In other words, if a conventional retentioner intends to comply with the requirements of heat-generating electronic components with different specifications, the retentioners matching therewith shall be separately molded and manufactured, thereby simply increasing the complexity and difficulty of production and assembly process.

Sunonwealth Electric Machine Industry Co., Ltd.


A computer readable medium storing executable code to generate an identity-based encryption key includes executable code to specify a master key, receive an identity-based string and execute a function that processes the master key and the identity-based string to produce a seed. The seed is then used to produce an identity-based encryption key interoperable with a deployed public key cryptosystem.

Conceptually, public keys behave a lot like telephone numbers—if I want to call you, I need your telephone number. I don't need my own number to make calls (I can use a pay phone, for example); I need a number to receive calls. In a fashion that is analogous to a telephone number, I need your public key to encrypt something so that it is secret to you.
Unlike telephone numbers, public keys are far too big for people to remember. Even elliptic curve keys, which are much shorter than the traditional ones are far too large for a person to remember. A 160-bit key is over 40 digits long (exactly 40 if one uses hexadecimal). So memorizing someone's key the way one memorizes a phone number is completely out of the question.
Consequently, we need to have blobs of data that say that a name such as firstname.lastname@example.com belongs to some key. There is also value in digitally signing the data so that the receiver has some assurance that the association is accurate. These blobs are certificates.
Like any data management problem, certificate management is harder than people would like. This is why in 1984 Adi Shamir suggested the idea of coming up with a crypto scheme in which any string can be a public key See, A. Shamir, Identity-based Cryptosystems and Signature Schemes, Proceedings of CRYPTO '84, LNCS 196, pages 47-53, Springer-Verlag, 1984. Thus, there is no need to associate a name with a public key, because they're effectively the same. This is Identity-Based Encryption (IBE).
While we typically think of IBE systems converting names into public keys, it should be possible to make any arbitrary bit-string, ID ε {0,1}*, a determinant of a public key in an IBE system. Thus, a name, an email address, or even a binary object such as a picture or sound can be considered equivalent to a public key. Thus, an IBE system can be thought of as a function of the form Ki=IBE(IDi) that produces keys from arbitrary bit strings that we call identities, without loss of generality.
An IBE system contains four basic components in its construction:                1. System Setup: IBE systems rely upon a trusted central authority that manages the parameters with which keys are created. This authority is called the Private Key Generator or PKG. The PKG creates its parameters, including a master secret Kpkg from which private keys are created.        2. Encryption: When Bob wishes to encrypt a message to Alice, he encrypts the message to her by computing or obtaining the public key, PAlice, and then encrypting a plaintext message M with PAlice to obtain ciphertext C.        3. Key Extraction: When Alice wishes to decrypt the message C that was encrypted to her name, she authenticates herself to the PKG and obtains the secret key SAlice that she uses to decrypt messages.        4. Decryption: When Alice has C and SAlice, she decrypts C to obtain the plaintext message M.No matter the specific parameters or requirements of the system, these functional aspects are always present in IBE systems as their defining components.
All of the existing IBE systems have their own limitations. One system signs but does not encrypt. Another system needs care to avoid an adaptive chosen ciphertext attack. While other systems have proofs of security, there is a notoriously poor relationship between proofs of security and actual system security. Security proofs can show where a system is safe, but not protect against new assumptions that an adversary can bring to bear against the system nor against uses of a system that its creators did not think of which may be outside of the scope of the original threat model. Still other subtle problems have shown up on other systems, such as the ability for colluding users to determine the PKG's master key.
With the exception of Shamir's system, IBE systems rely on new public-key cryptosystems, most often Weil pairing. Consequently, they are not compatible with existing systems that use RSA (the Rivest-Shamir-Adleman algorithm), Elgamal, or DSA (Digital Signature Algorithm). This limits their practical application, since there are many existing systems built upon these cryptosystems. Also, experience and comfort with the security of these established systems is high. A key advantage that Shamir's system has over all those that follow it is that it was based on established public key cryptography, and thus (had it been successful in being both a signing and encrypting system) is interoperable with non-IBE systems. Had Shamir s system been successful at encrypting, an RSA-based IBE system would likely be the dominant IBE system today, if for no other reason than its interoperability with deployed systems. This is an important observation—if one can construct an IBE system that uses traditional, integer-based, public key cryptography, the barriers to adoption of IBE systems might be lowered. The value that IBE has can be fully realized if it can be made to work with these established systems. Working with established systems has the advantage of relying on twenty years of mathematical and operational familiarity associated with these traditional public-key cryptosystems.
Previous IBE systems have as a desirable property that they support off-line generation of keys. That is to say, one receives key-generation parameters from the PKG once, and can then generate an arbitrary number of public keys. Off-line generation is ideal in an off-line environment. If communication with the PKG is slow, expensive, or unreliable, then off-line generation is a huge advantage to its users. They need only one interaction with a given PKG to be able to do all needed work with that server.
This advantage becomes less significant as communication with a PKG becomes cheaper, easier, and faster. On some level, off-line key generation is nothing more than a key server that is an algorithm instead of a database. This is an advantage when databases are static and expensive, but not when databases are cheap and fast. In an environment where the contents of the database are dynamically changing, a database change is not only an algorithm change, but an algorithm change that must be propagated to all clients of the PKG.
Oftentimes, the strengths of a system are also its weaknesses. This is also true with off-line generation. Off-line generation makes key generation easy not only for legitimate users of the system but for illegitimate ones as well. An issue that PKIs must consider in their design is that of a Directory Harvest Attack, in which senders of unwanted advertisements or outright fraudulent confidence games use the directory as a way to discover information paths into the system. Off-line generation of keys allows spammers and other attackers to pre-generate email attacks in their own system or create a distributed system for encrypted attacks. These attacks are not an issue in off-line systems. Off-line generation has the disadvantage that there is complete transparency in the directory, since the directory is an algorithm. Anyone with that algorithm has all possible entries in the directory and their public keys, and this can be exploited in side-channel attacks that are not attacks on the cryptographic system per se, but the way the system is used.
Off-line generation has as an additional disadvantage of increased revocation problems. A conventional PKI must be able to re-issue certificates and handle revisions in the PKI. An off-line IBE system must not only handle revocation of the certificates themselves but a revocation of the algorithmic parameters that comprise its own PKI. No IBE system has even considered this real-world problem.
In view of the foregoing, it would be desirable to develop an improved IBE system that overcomes the shortcomings associated with prior art IBE systems.

Apparatus and method for identity-based encryption within a conventional public-key infrastructure


The embodiments of the invention provide a metal capping process for a BEOL interconnect with air gaps. More specifically an apparatus is provided comprising metal lines within a first dielectric. Metal caps are over the metal lines, wherein the metal caps contact the metal lines. In addition, air gaps are between the metal lines, wherein the air gaps are between the metal caps. A second dielectric is also provided over the bottom portion of a first dielectric, wherein a top portion of the second dielectric is over the metal caps, and wherein top portions of the first dielectric and bottom portions of the second dielectric comprise sides of the air gap. The apparatus further includes dielectric caps over the metal lines, wherein the dielectric caps contact the metal caps.

1. Field of the Invention
The embodiments of the invention provide a metal capping process for a back end of line (BEOL) interconnect with air gaps.
2. Description of the Related Art
Metallization patterns on integrated circuits can be formed by depositing a dielectric layer, patterning the dielectric layer by photolithography and reactive ion etching (RIE) to form a groove or trench, and depositing a metal layer that fills the trench in the dielectric layer. The metal layer typically not only fills the trenches but also covers the entire semiconductor wafer. Therefore, the excess metal is removed using either chemical-mechanical planarization (CMP) or an etch back process so that only the metal in the trenches remains.
This process, called the "damascene process," forms conductors in-laid in the dielectric layer. The term "damascene" is derived from the name of a centuries-old process used to fabricate a type of in-laid metal jewelry first seen in the city of Damascus. In the context of integrated circuits, damascene means formation of a patterned layer imbedded on and in another layer such that the top surfaces of the two layers are coplanar. Planarity is essential to the formation of fine-pitch interconnect levels because lithographic definition of fine features is achieved using high-resolution steppers having small depths of focus. The "dual damascene" process, in which conductive lines and stud via metal contacts are formed simultaneously, is described in U.S. Pat. No. 4,789,648 issued to Chow.
As wire widths in integrated circuits continue to shrink, the electrical conductivity of the wiring material becomes increasingly more important. The material of choice since the integrated circuit art began, aluminum, is becoming less attractive than other materials, such as gold, copper, and silver, which are better conductors. In addition to processing superior electrical conductivity, these materials are more resistant than aluminum to electromigration, a property that increases in importance as wire cross-sectional areas decrease and applied current densities increase. In particular, copper is seen as an attractive replacement for aluminum because copper offers low cost, ease of processing, lower susceptibility to electromigration, and lower resistivity.
Metal caps on copper lines are the only way to improve the electromigration life time significantly. However, the selective metal cap deposition is often difficult and not manufacturable. A manufacturably feasible way to deposit metal caps on copper lines is needed.

Metal capping process for BEOL interconnect with air gaps

International Business Machines Corporation


A freefall-type windlass includes appropriate gearing for moving the windlass spool in a retrieve direction to wrap anchor cable thereabout or to permit the anchor to drop by gravity thereby unwrapping the anchor cable from the spool. A governor gear is incorporated into the windlass to restrict the rate at which the spool can rotate when the anchor is being paid out thereby avoiding entanglement of the anchor cable and malfunctioning of the windlass.

1. Field of the Invention
The present invention relates generally to windlasses and in particular to a windlass which is motor driven to raise an anchor or other heavy object while allowing the object to freefall in a controlled manner through use of a governor on the cable spool of the windlass.
2. Description of the Relevant Art
Recreational boats, as well as other crafts of similar size, frequently include power operated windlasses or anchor winches capable of automatically dropping, locking, or raising an anchor. Sometimes, the motor is reversible to raise the anchor or lower the anchor in a controlled manner, but many times the anchor is lowered through gravity so that the anchor freefalls through the water to its destination.
As will be appreciated, when an anchor and its cable is allowed to drop by gravity at a relatively fast speed, the cable will sometimes overrun the spool on which it is wrapped throwing the cable off the spool. When this happens, the cable can become entangled with itself leading to a malfunction of the windlass and a great deal of trouble in untangling the cable.
It would therefore be desirable to control the movement of the cable spool even in a freefall windlass so that the cable does not become entangled with itself and possibly the spool to thereby avoid malfunctioning of the windlass. It is to provide a system for controlling a freefall windlass that the present invention has been developed.


A system and method for presenting advanced editorial content items to subscribers in a distribution network. The method comprises presenting an electronic program guide comprised of data representing program availability on a broadcast distribution network and a selectable editorial content control to present an editorial content index page. An editorial content index page is presented on a display device within the context of the electric program guide in response to selecting the editorial content control, the editorial content index page comprising one or more links or pointers, such as hyperlinks, to editorial content items. A user selects a pointer to an editorial content item from the set of pointers and the editorial content item is presented on the display device.

The invention disclosed herein relates generally to rich media content delivery systems. More particularly, the present invention relates to a system and method for providing editorial content comprising rich media through television navigation controls and electronic program guides.
Various audio/video navigation and electronic program guide systems are known to those skilled in the art. These systems typically provide some degree of interactive functionality whereby advanced navigation features are made available to a user of such a system. For example, electronic program guides are provided whereby a user may explore programming available at a variety of future times. Likewise, advanced information may be provided to users as they navigate among the channels that comprise the available programming.
Currently deployed or developed cable systems provide functionality that allows for brief textual descriptions to be accessed through the use of an input device. These brief textual descriptions typically comprise a summary of the program, rating, start and end times, and other miscellaneous programming data. These current systems, however, do not provide access to rich media editorial content items. Furthermore, these brief textual descriptions do not provide for interactive functionality or contemplate executing interactive code to better interface with the user.
There is thus a need for a system and method whereby a variety of editorial content items comprised of rich media may be viewed within a set of television navigation controls or an electronic program guide.

System and method for displaying editorial content through television navigation controls and electronic program guides


A one-way clutch has an inner race, an outer race and a plurality of locking elements that are disposed between the races and that move with respect to one of the races when the clutch is overrunning. The clutch includes at least one end bearing for maintaining concentricity of the races that also adjusts the supply of lubricant inside the one-way clutch hydrodynamically. Several configurations and combinations for the end bearing are disclosed.

This invention relates generally to one-way clutches and more particularly to lubrication of one-way clutches that have at least one end bearing for positioning the inner and outer races of the one-way clutch concentrically with respect to each other and maintaining radial spacing between the races in a precise manner.
U.S. Pat. No. 5,042,628 granted to Gregory J. Malecha for a Radial Spacer and Retainer for Roller One-way Clutch discloses a one-way clutch that has an end bearing in the form of a spacer ring. The spacer ring has an inner surface that is supported on a shoulder of the inner race and an outer surface that is supported on a shoulder of the outer race to radially space the inner race and the outer race for precision accommodation of a caged one-way roller clutch sub-assembly in an operating space between the races. The patent specification does not deal with lubrication of the one-way clutch. However, it is well known that there is relative movement between the rollers or other locking elements and one race when the one-way clutch overruns. Consequently it is also well known that is a need to provide a layer of lubrication between the surfaces of the locking elements and the race that moves relative to the locking elements during the overrunning mode of operation.
U.S. Pat. No. 4,961,486 granted to Yoshio Kinoshita et al for a Retainer Plate of a One-way Clutch Assembly Oct. 9, 1990 discloses a one-way sprag clutch that has end bearings on each side for establishing and maintaining concentricity of the inner and outer races with respect to each other. Lubricant is supplied to the interior of the one-way clutch through a radial supply port that extends through the inner race. The end bearings engage retainer plates fastened to the outer race. These retainer plates have radial passages for directing the lubricant that is discharged through gaps at the inner and outer peripheries of the end bearings to lubricate elements outside the end bearings.
U.S. Pat. No. 4,913,271 granted to Yoshio Kinoshita et al for a On-Way Clutch Apr. 3, 1990 also discloses a one-way sprag clutch that has end bearings on each side for maintaining concentricity and a radial supply port that extends through the inner race for supplying lubricant to the interior of the one-way clutch that is discharged through gaps at the inner and outer peripheries of the end bearings. These end bearings are formed with a recessed lubricating oil supply area for expediting the introduction of discharged lubricating oil for lubricating the one-way clutch between exterior surfaces of the end bearings and surfaces sliding relative to these exterior surfaces. Several patterns of recessed lubricant supply areas are disclosed.


A method for the in vivo bioconversion of cyclic carotenes having a β-ionone ring to the corresponding aryl carotene is provided. Gram negative host cells expressing a heterologous, codon-optimized gene encoding a carotene desaturase are grown in the presence of a suitable cyclic carotene substrate to effect the production of aromatic carotenoids.

Carotenoids are pigments that are ubiquitous throughout nature and synthesized by all photosynthetic organisms, and in some heterotrophic growing bacteria and fungi. Carotenoids provide color for flowers, vegetables, insects, fish, and birds. Colors range from yellow to red with variations of brown and purple. As precursors of vitamin A, carotenoids are fundamental components in our diet and they play an important role in human health. Industrial uses of carotenoids include pharmaceuticals, food supplements, animal feed additives, and colorants in cosmetics, to mention a few. Because animals are unable to synthesize carotenoids de novo, they must obtain them by dietary means. Thus, manipulation of carotenoid production and composition in bacteria can provide new or improved sources for carotenoids.
Carotenoids come in many different forms and chemical structures. Most naturally occurring carotenoids are hydrophobic tetraterpenoids containing a C40 methyl-branched hydrocarbon backbone derived from successive condensation of eight C5 isoprene units (IPP). In addition, novel carotenoids with longer or shorter backbones occur in some species of nonphotosynthetic bacteria. Carotenoids may be acyclic, monocyclic, or bicyclic depending on whether the ends of the hydrocarbon backbones have been cyclized to yield aliphatic or cyclic ring structures (G. Armstrong, (1999) In Comprehensive Natural Products Chemistry, Elsevier Press, volume 2, pp 321–352).
Carotenoid biosynthesis starts with the isoprenoid pathway to generate the C5 isoprene unit, isopentenyl pyrophosphate (IPP). IPP is then condensed with its isomer dimethylallyl pyrophosphate (DMAPP) to generate the C10 geranyl pyrophosphate (GPP) which is then elongated to form the C15 farnesyl pyrophosphate (FPP). FPP synthesis is common in both carotenogenic and non-carotenogenic bacteria. Additional enzymes in the carotenoid pathway are able to then generate carotenoid pigments from the FPP precursor, segregating into two categories: (i) carotene backbone synthesis enzymes and (ii) subsequent modification enzymes. The backbone synthesis enzymes include geranyl geranyl pyrophosphate synthase, phytoene synthase, phytoene dehydrogenase and lycopene cyclase, etc. The modification enzymes include ketolases, hydroxylases, dehydratases, glycosylases, etc.
It is known that β-carotene can be converted to isorenieratene, an aromatic carotenoid, by a CrtU carotene desaturase. The crtU gene, encoding the carotene desaturase, has been identified in a few actinomycetes including Streptomyces, Mycobacterium and Brevibacterium (Krugel et al., Biochimica et Biophysica Acta, 1439: 57–64 (1999); Krubasik and Sandmann, Mol Gen Genet 263: 423–432 (2000); and Viveiros et al., FEMS Microbiol Lett, 187: 95–101 (2000)). Another aryl-carotene, chlorobactene, was reported in photosynthetic green bacteria (Liaaen-Jensen et al., Acta Chem. Scand 18: 1703–1718 (1964); Takaichi et al., Arch Microbiol, 168: 270–276 (1997)). Recent genomic sequencing of Chlorobium tepidum identified a putative carotene desaturase gene (Eisen et al., PNAS USA, 99: 9509–9514 (2002), which might be responsible for the synthesis of the native chlorobactene and derivatives. However, function of the putative carotene desaturase gene from Chlorobium has not yet been determined. It is likely that the CrtU from actinomycetes might also act on other substrates in addition to β-carotene to produce a variety of aryl-carotenoids, such as converting γ-carotene to chlorobactene.
Schumann et al. (Mol Gen Genet, 252: 658–666 (1996)) reported difficulty in attempting to express crtU in heterologous hosts. However, Lee et al. (Chem Biol 10(5): 453–462 (2003)) recently reported successful expression of the Brevibacterium linens crtU (DSMZ 20426) in E. coli using a pUC-derived expression vector. Lee et al. were able to detect the production of isorenieratene (in cells engineered to produce β-carotene) and didehydro-β-θ-carotene (in cells engineered to produce torulene). Lee et al. did not report the levels of aromatic carotenoids produced. It is likely the level was low since a low copy number pACYC-base plasmid was used to produce β-carotene precursor in a non-engineered E. coli host. Production of commercially-significant amounts of aryl carotenoids has not been reported in the literature.
Expressing genes from gram positive bacteria (with high G+C content) in E. coli is known to be often difficult. Low yields of protein in heterologous expression systems can been attributed to differences in codon usage. Difficulties in expressing heterologous genes in a host strain are generally due to an extremely rare codon used by host strain and correlates with low levels of its corresponding tRNA.
The inability to adequately express CrtU carotene desaturases in a gram-negative host for production of aryl carotenoids at commercially-useful levels presents a significant hurdle to the synthesis of a variety of aryl-carotenoids by genetic engineering. Furthermore, natural aryl-carotenoids are always present as mixtures of the aryl-carotenoid with their precursors or derivatives (Kohl et al., Phytochemistry, 22: 207–213 (1983); Takaichi et al., supra). Production of a pure aryl-carotenoid requires the ability to efficiently express the carotene desaturase in an industrially-useful heterologous host, such as E. coli.
The problem to be solved is to express a functional carotene desaturase (crtU) gene for the production of aryl-carotenoids in a gram-negative production host at commercially-significant concentrations. Applicants have solved the stated problem by isolating the crtU gene from Brevibacterium linens and expressing an optimized version of this gene in an Escherichia coli strain engineered to produce high levels of carotenoids.

Production or aromatic carotenoids in gram negative bacteria


A rotary blower (26) including a pair of shafts (70,56) on which are mounted a pair of rotors (28,29), input to the first shaft (70) being by way of an input pulley (76;108;201). The first shaft (70) has a forward terminal portion (72) extending forwardly of a first timing gear (60) to a location disposed within the input pulley. A torsion damping means is associated with the input pulley (76;108;201) and includes a resilient means (94;124;213) which resists relative rotation between the input pulley and the terminal portion (72) of the first shaft. The torsion damper also includes means (88,90,92;118,122;207,211) for limiting the relative rotation of the input pulley and the first shaft. The disclosed arrangement provides a more compact, less expensive input portion of the blower which eliminates the need for the conventional "third shaft" and its associated bearings.

The present invention relates to a rotary blower, such as a supercharger, and a torsion damping or isolating mechanism therefor. More specifically, the invention relates to a combination pulley and isolator for reducing audible noise of timing gears in a backflow-type supercharger driven by an internal combustion engine.
Rotary blowers of the backflow-type, particularly Roots-type blowers, have been characterized by noisy operation. The noise generated by Roots-type blowers may be classified as either: (a) solid borne noise caused by clashing of components subjected to fluctuating loads; or (b) fluid borne noise caused by fluid flow characteristics, such as rapid changes in fluid velocity, the "fluid", in the case of a supercharger, comprising air. The present invention is concerned with the former, i.e., solid borne noise, and more specifically, noise caused by timing gear rattle.
The timing gears of Roots-type blowers may produce an objectionable gear rattle when the meshed teeth of the gears are substantially unloaded. Such unloaded conditions occur during non-supercharging, low engine speed modes of operation. The gear rattle may be mitigated by a torsion damping mechanism having a low torque transmitting capacity, low rate spring, as well as forward and reverse stops, the forward stop being operative in case of an abrupt increase in engine speed, or in the input drive torque, and the reverse stop being operative in case of an abrupt change in input speed, such as in the case of engine shut down. Such a torsion damping mechanism is illustrated and described in U.S. Pat. No. 4,944,278, assigned to the assignee of the present invention and incorporated herein by reference.
Although the prior art torsion damping mechanism has been generally satisfactory in operation, it has added substantially to the cost of the blower. For example, its location immediately forward of the timing gear means that, in addition to the two rotor shafts, there must also be a third shaft, transmitting input torque from the supercharger pulley to the input of the torsion damping mechanism. The third shaft requires a bearing, disposed toward each end of the third shaft, the third shaft and the bearings thus adding to the overall axial length, complexity, and cost of the input portion of the blower.


Disclosed is a novel electrical probe that stores probe-specific information. A probe implemented in accordance with the invention includes a processor, memory, and a communications interface. Probe-specific information such as a probe identifier and/or calibration parameters that affect the true value of a measurement are stored in the probe memory. The probe-specific information may be retrieved by the processor from the probe memory via the communications interface.

Obtaining electrical measurements from an electrical device requires at least some physical probing of the device nodes. As known in the art, all electrical probes introduce measurement error due to the intrinsic resistance, capacitance, and inductance of the probe itself. Knowledge of a probe's measurement error value is therefore essential in calculating the true measurement value of a measurement made by the probe. Factors that impact the measurement error of a probe (for example, the probe amplifier gain and probe resistance/capacitance/inductance values) may vary from probe to probe, and therefore even probes that are identical by design are subject to some slight variations relative to one another.
It would therefore be desirable to have a technique for obtaining the measurement error value specific to a given probe. It would also be desirable that such probe-specific measurement error value be static and easily accessible. In a broader sense, it would also be desirable to store probe-specific information on board the probe itself.
It is therefore an object of the invention to provide a probe and novel technique for storing and retrieving probe-specific information thereon.

Probe based information storage for probes used for opens detection in in-circuit testing


Provided is a method for manufacturing a metal card which is capable of allowing metal card antennas to have no interference with a metal sheet by including a processed plastic layer formed on the metal sheet, and an insulating sheet. The metal card is capable of improving sensitivity of antenna coil, thereby solving an existing problem of the difficulties in performing RF communication because of material characteristics of a metal layer.

Generally, credit cards are used instead of cash, and as they are recently developed into smart cards in which IC chips for recording a large quantity of information are embedded, they are dynamically utilized as all kinds of membership cards as well as payment cards. In such smart card markets. Furthermore, specific cards made of various materials have been developed. Particularly, specialized credit cards made of metal materials have been provided for VIP customers, and as the metal cards have metallic luster, they have high-level outer appearances, so that they are provided for special customers.
In case of such conventional metal cards, however, at the time of contactless communication to a reader it is hard to operate antennas because of the characteristics of the metal, so that they are often limited in using an RF function, ATM, and so on. Further, the conventional metal cards are made of a thin film type metal sheet or a thin layer coated with metal powder, thereby making it difficult to print patterns and characters on their surface, and contrarily, if the metal cards are made of relatively lightweight materials, no weight is transferred from the metal to the metal cards. Accordingly, there is a need to develop a novel metal card capable of overcoming such limitations in use and expressing specific weight and beauty of the metal material.
A conventional metal thin film plastic card is disclosed in Korean Utility Model Registration No. 20-0382725, which includes a core sheet 13 made of a synthetic resin, metal thin films 12 attached to the top and bottom side of the core sheet 13 to a size smaller than the core sheet 13, margins 13a formed on the top and bottom side edges of the core sheet 13, and antenna coil 21 disposed along the margins 13a. In case of the conventional metal thin film plastic card, however, the metals are disposed on the center of the card to prevent the antenna coil from coming into contact therewith, thereby causing the whole outer appearance thereof to look bad and making it hard to express the metal texture on the surface of the card.

Metal card and method for manufacturing the same


A solid state imaging device includes an array of active pixels and an infrared cut filter formed over the sensor. Optionally, a slot in the infrared cut filter allows infrared illumination to reach the sensor to be detected by pixels covered by a visually opaque filter and surrounded by pixels of special types that limit charge leakage and enable high dynamic range sensing of infrared illumination. A ratio of average infrared signal to average brightness indicates an amount of infrared illumination reaching the imaging device.

Image sensors are used in many different types of electronic devices to capture an image. For example, consumer devices such as video cameras and digital cameras as well as numerous scientific applications use image sensors to capture an image. An image sensor is comprised of photosensitive elements that sense incident illumination and produces an electrical signal indicative of that illumination. Each photosensitive element is typically referred to as a picture element or pixel.
Image sensors include charge coupled devices (CCD) and complementary metal oxide semiconductor (CMOS) sensors. Imaging sensors may be capable of capturing grayscale and/or color images. Imaging sensors capable of capturing color images often employ a color filter array (CFA) to separate visible illumination of different color. For example, each of the pixels can be covered with a red, green, or blue filter according to a specific pattern. For example, the Bayer pattern has a repeating pattern of an alternating row of green and red and an alternating row of blue and green. As a result of the filtering, each pixel of the color image captured by a CMOS sensor with CFA responds to only the illumination of wavelengths determined by the color filter of the three primary light colors.
CFA color filters are typically transparent to infrared illumination. In video and still digital cameras, an infrared-cutoff filter is typically placed in front of the sensor to ensure that only visible wavelength illumination reaches the sensor. This is done to make possible accurate color reproduction in captured images.
White balance is the compensation of an image for variation in color temperature of scene illuminant. Images are adjusted in such a way that gray objects will look gray when displayed on a standard output device with a predefined color temperature. Other colors displayed on the output device will also appear as they appeared during image capture. Without white balance, images captured using illuminants having a low temperature will exhibit a reddish cast when displayed on a standard RGB monitor with the color temperature of the white point of 6500K. Illuminants of higher color temperature can create a bluish cast. The human eye can compensate for the different color temperatures. Both film and digital cameras, however, need to correct for different light sources in order to render an image in its true colors.
In a film camera, the color correction can be accomplished manually by the camera user attaching a color correction filter over the lens. A digital camera can correct the color temperature automatically by estimating the color temperature of the scene illuminant. Then the entire image is adjusted by the difference between the scene illuminant color temperature and the color temperature of the white point of the target output device (e.g., a standard display). One problem with this approach is that the white balance algorithm has to be informed as to the correct color temperature of the scene illuminant.
Various techniques exist in the art to determine the color temperature and spectral content of the illuminant. The color temperature of the illuminant can be reliably identified if one knows which objects in the scene are white. Determining the current lighting conditions in a digital camera may be difficult since cameras cannot reliably automatically identify which objects in the scene are white and which are not and thus must rely on other estimation techniques. However, illumination sources often vary with respect to how much infrared radiation they emit. Having an estimate of how much infrared radiation is present in the scene compared to visible illumination can provide information about the nature of the illuminant. For example, incandescent lamps emit visible light accompanied with strong infrared content. Office fluorescent lighting typically emits very little infrared when compared to scene luminance. Outdoor daylight contains moderate amounts of infrared compared to scene luminance. For the reasons stated above, and for other reasons stated below which will become apparent to those skilled in the art upon reading and understanding the present specification, there is a need in the art for detecting ambient infrared in a sensor equipped with an IR cut-off filter.

Ambient infrared detection in solid state sensors


A light-emitting element storing package which ensures the efficient reflection of light emitted by a light-emitting element by a reflector frame and thereby improves the brightness of the emitted light, and a method of manufacturing the same are provided. In a light-emitting element storing package includes: an insulating substrate consisting of a ceramic board, a reflector frame composed of a ceramic material, joined to the upper surface of the substrate along its outer edge and having an inner wall surface defining a light-reflecting surface, and a wiring pattern layer formed on the upper surface of the substrate for connection with a light-emitting element, a light-emitting element storing concave portion, which is defined by the substrate and the reflector frame, and in which the light-emitting element is mounted on the wiring pattern layer, the reflector frame is mainly composed of nitride ceramics and its light-reflecting surface is composed of white ceramics.

Light-emitting elements, such as light-emitting diodes, have recently come to be used widely as, for example, a source of light for electroluminescent display panels, or a source of backlight for cellular phones or personal computers, owing to the improved brightness of light thereby emitted. These light-emitting elements are used in packages in which they are stored.
Conventionally, as for a light-emitting element storing package, a light-emitting element storing package disclosed in Patent Document 1 (Japanese Patent Provisional Publication No. 2002-232017) is proposed.
The light-emitting element storing package 100 disclosed in the Patent Document 1, as shown in FIG. 6, has an insulating substrate 111, a reflector frame 112 disposed along the outer periphery of the substrate 111. Furthermore, in the package 100, a light-emitting element storing concave portion 119 is defined between the substrate 111 and the reflector frame 112.
At the position of the concave portion 119 of the insulating substrate 111, i.e. at the just under the position of the concave portion 119, a wiring through-hole (so called "via-hole") 116, which is penetrated vertically through the substrate 111, is provided.
The wiring through-hole 116 is filled with a conductive member 117 and wiring pattern layers 114 and 115, which are respectively formed on the upper and lower surfaces of the substrate 111, are electrically connected to each other through the conductive member 117. As a result, the light-emitting element 118 mounted on the upper wiring pattern layer 114 may be electrically connected with an external electrical circuit.
After the light-emitting element 118 is mounted on the bottom of the light-emitting element storing concave portion 119, the concave portion 119 is filled with a transparent resin, such as an epoxy resin so that the light-emitting element is sealed gas-tightly. As a result, a light-emitting device as a final product is produced.
In the light-emitting element storing package 100, a light-reflecting layer 113 is formed on the inner wall surface of the concave portion 119, i.e. on the inner wall surface of the reflector frame 112. The light emitted by the light-emitting element 118 is reflected by the light-reflecting layer 113 so that brightness of the light-emitting element 118 is substantially increased.
As a result, the light emitted by the light-emitting element 118 shines brightly by the action of this light-reflecting layer 113, so that an electroluminescent display panel may display bright and very clear characters and images.
As for the light-reflecting layer 113, for example, gold, silver or nickel, etc. is utilized. In addition, for example, a metallized metal layer is previously formed on the inner concave wall surface of the insulating substrate 111 and gold, silver or nickel, etc. is formed on the metallized metal layer by plating, so that the light-reflecting layer 113 is formed on the inner wall surface of the reflector frame 112.
However, in such light-emitting element storing package 100 disclosed in the Patent Document 1, the light-reflecting layer 113 is formed on the whole inner wall surface of the reflector frame 112. Therefore, lower portion of the light-reflecting layer 113 and the wiring pattern layer 114 at the bottom of the light-emitting element storing concave portion 119 is short-circuited, so that there is a possibility of impairing the function of the light-emitting element 118.
For this reason, in a light-emitting element storing package 200 of Patent Document 2 (Japanese Patent Provisional Publication No. 2003-273405), as shown in FIG. 7, a light-reflecting layer 213 is formed on the inner wall surface of the light-emitting element storing concave portion 219 not to cover whole inner wall surface of the reflector frame 212. Moreover, in the package 200, the light-reflecting layer 213 is formed as it is spaced apart from the bottom of the light-emitting element storing concave portion 219.
As a result, the electrical short-circuit between the light-reflecting layer 213 and a wiring pattern layer 214 at the bottom of the light-emitting element storing concave portion 219 is prevented effectively.
Furthermore, in the package 200, an insulating layer 220 is disposed between the light-emitting layer 213 and the wiring pattern layer 214 to ensure the prevention of their electrical short-circuiting.
In addition, in the light-emitting element storing package 200 disclosed in Patent Document 2, as shown in FIG. 7, there is no wiring through-hole in an insulating substrate 211, and a wiring pattern layer 201, which is provided between the reflector frame 212 and the substrate 211, is extended along the outer surface of the substrate 211. As a result, the wiring pattern layers 214 and 215, which are respectively formed on the upper and lower surfaces of the substrate 211, are electrically connected to each other.
However, in the light-emitting element storing package 200 disclosed in this Patent Document 2, the light-reflecting layer 213 is formed as it is spaced apart from the bottom of the light-emitting element storing concave portion 219 and the insulating layer 220 is disposed therebetween. Therefore, the light emitted from the light-emitting element 218 is not reflected by the surface of the insulating layer 220 so that brightness is substantially lowered.
Furthermore, according to both of Patent Documents 1 and 2, the light-reflecting layer is of, for example, gold, silver or nickel. However, gold and nickel have a light reflectance of as low as 50% or less for a wavelength of 400 nm or less. In addition, silver generally has a reflectance of as low as 50% or less for a wavelength of 350 nm or less, since it has absorption at a wavelength of 300 to 350 nm.
However, a light-emitting element for a white LED usually emits blue or near-ultraviolet light and it is converted to various wavelengths by various fluorescent materials. Therefore, it is important for improving its brightness that a light emitted from a light-emitting element having a wavelength of 350 to 430 nm is efficiently reflected.
Therefore, in Patent Document 3 (Japanese Patent Provisional Publication No. 8 (1996)-274378), as shown in FIG. 8, a light-reflecting layer is not formed and an insulating substrate 312 itself formed from a white sintered compact of aluminum oxide having relatively high light-reflecting property. As a result, a light emitted from a light-emitting element 318 is reflected by a light-reflecting surface 320.
In addition, in the light-emitting element storing package 300 disclosed in Patent Document 3, as shown in FIG. 8, a wiring through-hole 316 is formed. The wiring through-hole 316 is extending from the lower portion of a light-emitting element storing concave portion 319 of the insulating substrate 312 to the bottom surface of the insulating substrate 312 through an intermediate wiring portion 313 formed in the middle position of the insulating substrate 312.
The wiring through-hole 316 is filled with a conductive member 317 and wiring pattern layers 314 and 315, which are respectively formed on the upper and lower surfaces of the insulating substrate 312, are electrically connected to each other. Consequently, the light-emitting element 318, which is mounted on the upper wiring pattern layer 314, may be electrically connected with an external electrical circuit.
However, the white sintered compact of aluminum oxide constituting the substrate 312 according to Patent Document 3 has a relatively low thermal conductivity in the order of about 20 W/m·K despite its reflectance of 50% or more for light having a wavelength of 350 to 400 nm. Therefore, the heat from the light-emitting element 318 is thermally accumulated in the light-emitting element storing package 300 and the accumulated heat can not radiate therefrom so that there is possibility of damaging the light-emitting element 318.
Moreover, Patent Document 4 (Japanese Patent Provisional Publication No. 2004-152952) discloses a light-emitting element storing package in which a reflector frame is composed of white ceramics.
However, in this Patent Document, the ceramics actually used for the reflector frame are SiO2—Al2O3—MgO—ZrO2—CaO ceramics having a specific composition, which is mainly consisting of alumina. As apparent from this Patent Document, the ceramic has 96.25% by weight of alumina content so that it has a low thermal conductivity.
Patent Document 4 also states that, as a reflectance of 80% or higher for light having a wavelength of 400 to 700 nm with respect to aluminum nitride (AlN), the amount of Er2O3 in a sintered compact of aluminum nitride is preferably from 1 to 10% by weight based on the weight of the sintered compact.
However, in Patent Document 4, there is no specific embodiment corresponding to this statement. In addition, in fact, it has been confirmed that no white sintered compact of aluminum nitride can be obtained by sintering a material having an Er2O3 content of 1 to 10% by weight (see Comparative Example 4 below).
Patent Document 1 (Japanese Patent Provisional Publication No. 2002-232017)
Patent Document 2 (Japanese Patent Provisional Publication No. 2003-273405)
Patent Document 3 (Japanese Patent Provisional Publication No. 8 (1996)-274378)
Patent Document 4 (Japanese Patent Provisional Publication No. 2004-152952)

Package for storing light emitting element and method for producing package for storing light emitting element


A method for bulk cryopreservation of biological material includes the steps of providing a flexible container, such as a freezer bag, containing biological material that is treated with a cryoprotectant and freezing the biological material to below -100.degree. C. and preferably below -196.degree. C. for deep freeze long-term storage. In the preferred embodiment, the bag is placed in a holder that maintains the cross-sectional area of the bag essentially constant and small enough (e.g., about 5 mm width to facilitate uniform heat transfer to and from all regions the bag. This facilitates uniform nucleation of the biological material after supercooling which enables controlled and uniform slow cooling through from about -7.5.degree. C. to a temperature in the range of about -40.degree. C. to -80.degree. C., thereby maintaining the viability of the cells. The single freezer bag method facilitates cryopreservation of large amounts of material, such as entire preparations of isolated islets, as compared to conventional multiple tube cryopreservation protocols and yields similar or improved recovery. In addition, the single freezer bag method reduces the risk of cross-contamination, a problem when adding and withdrawing material form multiple tubes before, during and after the cryopreservation freeze-thaw cycle. The bag construction also reduces the risk of freezing medium (e.g., liquid nitrogen) seeping into the bag and causing the bag to burst when thawing the material. The present invention is directed, in particular, to the cryopreservation of encapsulated islets in a flexible container wherein the container thickness during freezing is maintained around 5 mm. The freezing may also be accomplished by supercooling the encapsulated islets and inducing ice nucleation.

Cryopreservation has been an effective method for long-term storage of biological material such as islets. Long-term storage of cells and tissue for use in clinical transplantation is based on the inherent need to collect adequate donor cells or tissue and to have this available at times that are suitable for transplantation into a patient. For example, since current methods to isolate and purify sufficient numbers of islets of Langerhans from a human pancreas are limited and multiple donors are required for successful reversal of insulin-dependent diabetes mellitus, long-term storage allows the collection of adequate quantities of islets for subsequent transplantation. Also, with long-term storage, the recipient pool can be extended to include patients in other medical centers.
Current islet cryopreservation protocols generally are based on protocols originally developed for the cryopreservation of rodent islets. See Rajotte et al., "Viability Studies on Frozen-Thawed Rat Islets of Langerhans," Cryobiology, 14:116-120 (1977) (which is hereby incorporated herein by reference). These protocols use multiple glass freezing tubes and aliquot small quantities of islets per individual glass freezing tube. When these freeze-thaw protocols are expanded to large animals and humans, greater numbers of freezing tubes are needed to accommodate the increased number of islets being frozen. This may amount to 30-40 tubes for a typical human islet isolation. Also, the cryopreservation of large numbers of freezing tubes is labor-intensive and has an increased potential for microbial contamination. In addition, seepage of liquid nitrogen into the glass tubes during low-temperature storage is a potential hazard since the tubes most likely will explode if thawed without expelling the liquid nitrogen.
Thus, there is a need to provide a more effective method for cryopreservation of biological material in bulk (e.g., entire preparations of isolated islets) efficiently and with minimal risk of contamination or loss.
There is also a need to provide a more effective method for stabilizing, storing, and retaining the viability of biological material for transplantation, since multiple donors are usually required for the collection of materials, such as islets in adequate quantities. Collecting these materials over time requires proper storage and then culturing; therefore, improvements in the processes are needed whereby the viability of the materials is retained.

Methods for bulk cryopreservation encapsulated islets

The Governors of the University of Alberta