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<SOH> SUMMARY OF THE INVENTION <EOH>Hence, it is an object to provide a sensor of the type mentioned initially that avoids this problem. In order to prevent a buckling of the membrane, a tensile coating is applied on the membrane, This coating leaves at least part, preferably all, of the active electronic components integrated on the semiconductor device uncovered. As it has been found, the coating can otherwise lead to a change or degradation of the function of these components because it affects the electronic parameters of the semiconductor. Preferably, all active electronic components are therefore left uncovered by the tensile coating. The tensile coating covers preferably the whole membrane. In order to exert a pulling force suited for tightening the membrane, it should preferably extend beyond the membrane somewhat at least at two opposite sides. The invention is especially suited for being applied in integrated flow sensors. |
Graft copolymers and impact-resistant flame-retardant resin compositions containing the same |
The present invention provides a polyorganosiloxane-containing graft copolymer which is obtainable by polymerizing 0.5 to 10 parts by weight of a vinyl monomer (B) comprising 100 to 50% by weight of a polyfunctional monomer (b-1) containing two or more polymerizable unsaturated bonds in the presence of 40 to 90 parts of polyorganosiloxane particles, followed by further polymerizing 5 to 50 parts by weight of a vinyl monomer (C); A polyorganosiloxane-containing graft copolymer which is obtainable by polymerizing 0 to 10 parts by weight of a vinyl monomer (B) comprising 100 to 50% by weight of a polyfunctional monomer containing two or more polymerizable unsaturated bonds in the presence of 30 to 95 parts of a polyorganosiloxane in a latex form as obtained by seed polymerization using, as a seed polymer, a hydrophilic polymer capable of swelling in the corresponding organosiloxane, followed by further polymerizing 5 to 70 parts by weight of a vinyl monomer (C); a flame retardant which comprises said copolymer; and a resin composition which comprises said retardant and a thermoplastic resin. |
1. A polyorganosiloxane-containing graft copolymer which is obtainable by polymerizing 0.5 to 10 parts by weight of a vinyl monomer (B) comprising 100 to 50% by weight of a polyfunctional monomer (b-1) containing two or more polymerizable unsaturated bonds and 0 to 50% by weight of another copolymerizable monomer (b-2), in the presence of 40 to 90 parts (as solid content) by weight of polyorganosiloxane particles (A1), followed by further polymerization of 5 to 50 parts by weight of a vinyl monomer (C), with the sum of (A1), (B) and (C) being 100 parts by weight. 2. The polyorganosiloxane-containing graft copolymer according to claim 1, wherein the polyorganosiloxane particles (A1) have a volume average particle diameter of 0.008 to 0.6 μm. 3. The polyorganosiloxane-containing graft copolymer according to claim 1, wherein the vinyl monomer (C) gives a polymer thereof having a solubility parameter of 9.15 to 10.15 (cal/cm3)1/2. 4. The polyorganosiloxane-containing graft copolymer according to claim 1, wherein the polyorganosiloxane particles (A1) are in a latex form. 5. The polyorganosiloxane-containing graft copolymer according to claim 1, wherein the vinyl monomer (C) comprises at least one monomer selected from the group consisting of aromatic vinyl monomers, vinyl cyanide monomers, (meth)acrylate ester monomers and carboxyl group-containing vinyl monomers. 6. A flame retardant which comprises the polyorganosiloxane-containing graft copolymer according to claim 1. 7. A flame retardant resin composition which comprises 0.1 to 30 parts by weight, per 100 parts by weight of a thermoplastic resin, of the flame retardant according to claim 6 as incorporated in the thermoplastic resin. 8. The flame retardant resin composition according to claim 7, wherein the thermoplastic resin is a polycarbonate resin. 9. A polyorganosiloxane-containing graft copolymer which is obtainable by polymerizing 0 to 10 parts by weight of a vinyl monomer (B) comprising 100 to 50% by weight of a polyfunctional monomer (b-1) containing two or more polymerizable unsaturated bonds and 0 to 50% by weight of another copolymerizable monomer (b-2), in the presence of 30 to 95 parts by weight (as solid content) of a polyorganosiloxane (A2) in a latex form obtainable by seed polymerization using, as a seed polymer, a hydrophilic polymer capable of swelling in the corresponding organosiloxane, followed by further polymerizing 5 to 70 parts by weight of a vinyl monomer (C), with the sum of (A2), (B) and (C) being 100 parts by weight. 10. The polyorganosiloxane-containing graft copolymer according to claim 9, wherein the seed polymer has such a degree of hydrophilicity that the extraction rate of water-soluble components in dry seed polymer is 10 to 100% by weight, as determined after adding water, in an amount of 20 weight-times that of the seed polymer in a dry state, to the dry seed polymer, followed by stirring at 23° C. for 1 hour and wherein the seed polymer shows such a degree of swelling in the organosiloxane that the rate of swelling by volume as determined from the ratio between the latex particle diameter after stirring and the latex particle diameter before stirring is 3 to 50 times after adding the organosiloxane, in an amount 50 times by weight that of the dry seed polymer, to the seed polymer latex, followed by stirring at 23° C. for 1 hour. 11. The polyorganosiloxane-containing graft copolymer according to claim 9, wherein the seed polymer has such a degree of hydrophilicity that the extraction rate of water-soluble components in dry seed polymer is 50 to 100% by weight, as determined after adding water, in an amount of 20 weight-times that of the seed polymer in a dry state, to the dry seed polymer, followed by stirring at 23° C. for 1 hour and wherein the seed polymer shows such a degree of swelling in the organosiloxane that the rate of swelling by volume as determined from the ratio between the latex particle diameter after stirring and the latex particle diameter before stirring is 3 to 15 times after adding the organosiloxane, in an amount 50 weight-times that of the dry seed polymer, to the seed polymer latex, followed by stirring at 23° C. for 1 hour. 12. The polyorganosiloxane-containing graft copolymer according to claim 9, wherein the vinyl monomer (C) comprises at least one monomer selected from the group consisting of aromatic vinyl monomers, vinyl cyanide monomers, (meth)acrylate ester monomers and carboxyl group-containing vinyl monomers. 13. A flame retardant which comprises the polyorganosiloxane-containing graft copolymer according to claim 9. 14. A resin composition excellent in impact resistance and flame retardancy which comprises a thermoplastic resin and the flame retardant according to claim 13 as incorporated therein in an amount of 0.1 to 30 parts by weight per 100 parts by weight of the thermoplastic resin. 15. The resin composition according to claim 14, wherein the thermoplastic resin is a polycarbonate resin. 16. The polyorganosiloxane-containing graft copolymer according to claim 2, wherein the vinyl monomer (C) gives a polymer thereof having a solubility parameter of 9.15 to 10.15 (cal/cm3)1/2. 17. The polyorganosiloxane-containing graft copolymer according to claim 2, wherein the polyorganosiloxane particles (A1) are in a latex form. 18. The polyorganosiloxane-containing graft copolymer according to claim 3, wherein the polyorganosiloxane particles (A1) are in a latex form. 19. The polyorganosiloxane-containing graft copolymer according to claim 2, wherein the vinyl monomer (C) comprises at least one monomer selected from the group consisting of aromatic vinyl monomers, vinyl cyanide monomers, (meth)acrylate ester monomers and carboxyl group-containing vinyl monomers. 20. The polyorganosiloxane-containing graft copolymer according to claim 3, wherein the vinyl monomer (C) comprises at least one monomer selected from the group consisting of aromatic vinyl monomers, vinyl cyanide monomers, (meth)acrylate ester monomers and carboxyl group-containing vinyl monomers. |
<SOH> BACKGROUND ART <EOH>Owing to their good impact resistance, heat resistance and electric characteristics, among others, thermoplastic resins, in particular polycarbonate resins, are widely used as materials of electric and electronic parts, OA (office automation) apparatus and instruments, and household utensils, or as building materials. Polycarbonate resins, though higher in flame retardancy as compared with polystyrene and other resins, are required to be highly flame retardant in particular in such fields as electric and electronic parts, OA apparatus and instruments and the like and, therefore, attempts have been made to improve their flame retardancy by adding various flame retardants. Thus, for instance, the addition of organohalogen compounds or organophosphorus compounds has so far been in wide practice. However, organohalogen compounds and organophosphorus compounds have a problem from the toxicity viewpoint. In particular, it is a drawback of organohalogen compounds that they generate a corrosive gas upon combustion thereof. Thus, the demand for halogen-free and phosphorus-free flame retardants has been increasing in recent years. The utilization of polyorganosiloxane compounds (also called silicones) as halogen-free and phosphorus-free flame retardants has been proposed. For example, Japanese Kokai Publication Sho-54-36365 describes that kneading of a monoorganopolysiloxane-based silicone resin with a non-silicone polymer gives a flame retardant resin. Japanese Kohyo Publication Hei-3-48947 describes that a mixture of a silicone resin and a salt of a metal of the group IIA provides thermoplastic resins with flame retardancy. Japanese Kokai Publication Hei-8-113712 describes a method of producing flame retardant resin compositions which comprises dispersing a silicone resin prepared by blending 100 parts by weight of a polyorganosiloxane with 10 to 150 parts by weight of a silica filler in thermoplastic resins. Japanese Kokai Publication Hei-10-139964 describes that flame retardant resin compositions are obtained by adding a solvent-soluble silicone resin having a weight average molecular weight of not less than 10,000 but not more than 270,000 to an aromatic ring-containing non-silicone resin. However, the silicone resins described in the above-cited publications are indeed effective in providing flame retardancy but their effects are still unsatisfactory. When the addition level is increased to fill up the shortage, a problem arises that the impact resistance of the resin composition decreases, making it difficult to obtain flame retardant resin composition balanced between flame retardancy and impact resistance. Japanese Kokai Publication 2000-17029 describes that when a composite rubber-based flame retardant produced by graft polymerization of a vinyl monomer onto a composite rubber composed of a polyorganosiloxane rubber and a polyalkyl (meth)acrylate rubber is incorporated in thermoplastic resins, flame retardant resin compositions can be obtained. Japanese Kokai Publication 2000-226420 describes that flame retardant resin compositions can be obtained by incorporating a polyorganosiloxane-based flame retardant produced by grafting a vinyl monomer onto composite particles consisting of an aromatic group-containing polyorganosiloxane and a vinyl polymer in thermoplastic resins. Japanese Kokai Publication 2000-264935 describes that flame retardant resin compositions can be obtained by incorporating, in thermoplastic resins, a polyorganosiloxane-containing graft copolymer prepared by graft copolymerization of a vinyl monomer onto polyorganosiloxane particles not larger than 0.2 μm in size. The flame retardant resin compositions described in the above-cited Japanese Kokai Publication 2000-17029, Japanese Kokai Publication 2000-226420 and Japanese Kokai Publication 2000-264935 all indeed show satisfactory levels of impact resistance but are unsatisfactory in flame retardancy. Thus, they have a problem that the flame retardancy-impact resistance balance is poor. |
<SOH> SUMMARY OF THE INVENTION <EOH>It is an object of the present invention to provide a polyorganosiloxane-containing graft copolymer utilizable as a halogen-free and phosphorus-free flame retardant and excellent in flame retardancy and impact resistance improving effects as well as a flame-retardant resin composition excellent in flame retardancy and impact resistance using the graft copolymer mentioned above. The present inventors made intensive investigations concerning the above subject and, as a result, found that a specific polyorganosiloxane-containing graft copolymer is excellent in flame retardancy and impact resistance improving effects and that a flame-retardant resin composition excellent in flame retardancy and impact resistance can be obtained by incorporating the polyorganosiloxane-containing graft copolymer in a thermoplastic resin. Based on such findings, the present invention has now been completed. Thus, in accordance with a first aspect thereof, the present invention relates to: a polyorganosiloxane-containing graft copolymer which is obtainable by polymerizing 0.5 to 10 parts (parts by weight; hereinafter the same shall apply) of a vinyl monomer (B) comprising 100 to 50% (% by weight; hereinafter the same shall apply) of a polyfunctional monomer (b-1) containing two or more polymerizable unsaturated bonds and 0 to 50% of another copolymerizable monomer (b-2), in the presence of 40 to 90 parts of polyorganosiloxane particles (A1), followed by further polymerization of 5 to 50 parts of a vinyl monomer (C) [the sum of (A1), (B) and (C) being 100 parts] (claim 1 ); the polyorganosiloxane-containing graft copolymer according to claim 1 , wherein the polyorganosiloxane particles (A1) have a volume average particle diameter of 0.008 to 0.6 μm (claim 2 ); the polyorganosiloxane-containing graft copolymer according to claim 1 or 2 , wherein the vinyl monomer (C) gives a polymer thereof having a solubility parameter of 9.15 to 10.15 (cal/cm 3 ) 1/2 (claim 3 ); the polyorganosiloxane-containing graft copolymer according to any of claims 1 to 3 , wherein the polyorganosiloxane particles (A1) are in a latex form (claim 4 ); the polyorganosiloxane-containing graft copolymer according to any of claims 1 to 4 , wherein the vinyl monomer (C) comprises at least one monomer selected from the group consisting of aromatic vinyl monomers, vinyl cyanide monomers, (meth)acrylate ester monomers and carboxyl group-containing vinyl monomers (claim 5 ); a flame retardant which comprises a polyorganosiloxane-containing graft copolymer according to claim 1 (claim 6 ); a flame retardant resin composition which comprises 0.1 to 30 parts, per 100 parts of a thermoplastic resin, of a flame retardant according to claim 6 as incorporated in the thermoplastic resin (claim 7 ); and the flame retardant resin composition according to claim 7 , wherein the thermoplastic resin is a polycarbonate resin (claim 8 ). In accordance with a second aspect thereof, the invention relates to: a polyorganosiloxane-containing graft copolymer which is obtainable by polymerizing 0 to 10 parts by weight of a vinyl monomer (B) comprising 100 to 50% by weight of a polyfunctional monomer (b-1) containing two or more polymerizable unsaturated bonds and 0 to 50% by weight of another copolymerizable monomer (b-2), in the presence of 30 to 95 parts by weight (as solid content) of a polyorganosiloxane (A2) in a latex form obtainable by seed polymerization using, as a seed polymer, a hydrophilic polymer capable of swelling in the corresponding organosiloxane, followed by further polymerizing 5 to 70 parts by weight of a vinyl monomer (C) [the sum of (A2), (B) and (C) being 100 parts] (claim 9 ); the polyorganosiloxane-containing graft copolymer according to claim 9 , wherein the seed polymer has such a degree of hydrophilicity that the extraction rate of water-soluble components in dry seed polymer is 10 to 100% by weight, as determined after adding water, in an amount of 20 weight-times that of the seed polymer in a dry state, to the dry seed polymer, followed by stirring at 23° C. for 1 hour and wherein the seed polymer shows such a degree of swelling in the organosiloxane that the rate of swelling by volume as determined from the ratio between the latex particle diameter after stirring and the latex particle diameter before stirring is 3 to 50 times after adding the organosiloxane, in an amount 50 times by weight that of the dry seed polymer, to the seed polymer latex, followed by stirring at 23° C. for 1 hour (claim 10 ); the polyorganosiloxane-containing graft copolymer according to claim 9 , wherein the seed polymer has such a degree of hydrophilicity that the extraction rate of water-soluble components in dry seed polymer is 50 to 100% by weight, as determined after adding water, in an amount of 20 weight-times that of the seed polymer in a dry state, to the dry seed polymer, followed by stirring at 23° C. for 1 hour, and wherein the seed polymer shows such a degree of swelling in the organosiloxane that the rate of swelling by volume as determined from the ratio between the latex particle diameter after stirring and the latex particle diameter before stirring is 3 to 15 times after adding the organosiloxane, in an amount 50 weight-times that of the dry seed polymer, to the seed polymer latex, followed by stirring at 23° C. for 1 hour (claim 11 ); The polyorganosiloxane-containing graft copolymer according to any of claims 9 to 11 , wherein the vinyl monomer (C) comprises at least one monomer selected from the group consisting of aromatic vinyl monomers, vinyl cyanide monomers, (meth)acrylate ester monomers and carboxyl group-containing vinyl monomers (claim 12 ); a flame retardant which comprises the polyorganosiloxane-containing graft copolymer according to claim 9 (claim 13 ); a resin composition excellent in impact resistance and flame retardancy which comprises a thermoplastic resin and the flame retardant according to claim 13 as incorporated therein in an amount of 0.1 to 30 parts by weight per 100 parts by weight of the thermoplastic resin (claim 14 ); The resin composition according to claim 14 , wherein the thermoplastic resin is a polycarbonate resin (claim 15 ). detailed-description description="Detailed Description" end="lead"? |
Stens with drug-containing amphiphilic polymer coating |
A vascular stent having an amphiphilic polymer coating is loaded with a restenosis inhibiting agent which is sparingly soluble in water, whereby delayed release of the agent takes place after implantation of the stent. |
1. Intravascular stent comprising a a metal body having a coating comprising polymer and at least 20 μg per stent of a restenosis inhibiting agent in which the restenosis inhibiting agent is a sparingly water soluble drug and the polymer in the coating is a cross-linked amphiphilic polymer which, when swollen with water containing pyrene, has hydrophobic domains observable by pyrene fluorescence having an intensity ratio I3:I1of at least 0.8. 2. Stent according to claim 1 in which on at least the outer wall of the stent the coating comprises a layer of the said amphiphilic polymer in which the drug is absorbed. 3. Stent according to claim 1 or claim 2 in which the polymer in the coating when swollen with water containing pyrene has hydrophobic domains observable by I3:I1ratio of about 1. 4. Stent according to any preceding claim in which the amphiphilic polymer comprises, as the groups conferring hydrophilicity, zwitterionic groups. 5. Stent according to any preceding claim in which the amphiphilic polymer comprises, as the groups conferring hydrophobicity, pendant hydrophobic groups selected from C4-23-alkyl, -alkenyl and -alkynyl groups any of which may be substituted by one or more fluorine atoms, aryl, C7-24 aralkyl, oligo (C3-4 alkoxy) alkyl and siloxane groups. 6. Stent according to claim 4 and claim 5 in which the polymer is formed from ethylenically unsaturated monomers including a zwitterionic monomer and a hydrophobic monomer having the said hydrophobic group. 7. Stent according to claim 6 in which the ethylenically unsaturated monomers include one or more reactive monomers having a pendant reactive group capable of forming intermolecular crosslinks. 8. Stent according to claim 6 or claim 7 in which the zwitterionic monomer has the general formula 1: YBX I wherein B is a straight or branched alkylene (alkanediyl), alkyleneoxaalkylene or alkylene oligo-oxaalkylene chain optionally containing one or more fluorine atoms up to and including perfluorinated chains or, if X or Y contains a terminal carbon atom bonded to B, a valence bond; X is a zwitterionic group; and Y is an ethylenically unsaturated polymerisable group selected from CH2═C(R)CH2O—, CH2═C(R)CH2OC(O)—, CH2═C(R)OC(O)—, CH2═C(R)O—, CH2═C(R)CH2OC(O)N(R1)—, R2OOCCR═CRC(O)O—, RCH═CHC(O)O—, RCH═C(COOR2)CH2C(O)O—, wherein: R is hydrogen or a C1-C4 alkyl group; R1 is hydrogen or a C1-C4 alkyl group or R1 is —B—X where B and X are as defined above; and R2 is hydrogen or a C1-4 alkyl group; A is —O— or —NR1—; K is a group —(CH2)pOC(O)—, —(CH2)pC(O)O—, —(CH2)pOC(O)O—, —(CH2)pNR3—, —(CH2)pNR3C(O)—, —(CH2)pC(O)NR3—, —(CH2)pNR3C(O)O—, —(CH2)pOC(O)NR3—, —(CH2)pNR3C(O)NR3—(in which the groups R3 are the same or different), —(CH2)pO—, —(CH2)pSO3—, or, optionally in combination with B, a valence bond p is from 1 to 12; and R3 is hydrogen or a C1-C4 alkyl group. 9. Stent according to claim 8 in which the cationic group in X is an amine. 10. Stent according to claim 9 in which the cationic group is a quaternary ammonium group. 11. Stent according to any of claims 8 to 10 in which the anionic group in X is selected from sulphate, sulphonate, phosphate, phosphonate and carboxylate, and is preferably a phosphate diester. 12. Stent according to claim 11 in which X is selected from groups of the general formula V: in which the moieties X3 and X4, which are the same or different, are —O—, —S—, —NH— or a valence bond, preferably —O—, and W+ is a group comprising an ammonium, phosphonium or sulphonium cationic group and a group linking the anionic and cationic moieties which is preferably a C1-12-alkanediyl group. 13. Stent according to any of claims 7 to 12 in which the hydrophobic monomer has the general formula VII Y1R13 VII wherein Y1 is selected from CH2═C(R14)CH2O—, CH2═C(R14)CH2OC(O)—, CH2═C(R14)OC(O)—, CH2═C(R14)O—, CH2═C(R14)CH2OC(O)N(R15)—, R16OOCCR14═CR14C(O)O—, R14CH═CHC(O)O—, R14CH═C(COOR16)CH2C(O)—O—, wherein: R14 is hydrogen or a C1-C4 alkyl group; R15 is hydrogen or a C1-C4 alkyl group or R15 is R13; R16 is hydrogen or a C1-4 alkyl group; A1 is —O— or —NR15—; and K1 is a group —(CH2)qOC(O)—, —(CH2)qC(O)O—, (CH2)qOC(O)O—, —(CH2)qNR17—, —(CH2)qNR17C(O)—, —(CH2)qC(O)NR17—, —(CH2)qNR17C(O)O—, —(CH2)qOC(O)NR17—, —(CH2)qNR17C(O)NR17—(in which the groups R17 are the same or different), —(CH2)qO—, —(CH2)qSO3—, or a valence bond p is from 1 to 12; and R17 is hydrogen or a C1-C4 alkyl group; and R13 is the hydrophobic group. 14. Stent according to claim 13 in which R13 is selected from a) C4-8 alkyl groups; b) aryl and aralkyl; and c) a siloxane group —(CR182)qq(SiR192)(OSiR192)ppR19 in which each group R18 is the same or different and is hydrogen or alkyl of 1 to 4 carbon atoms, or aralkyl, for example benzyl or phenethyl, each group R19 is alkyl of 1 to 4 carbon atoms, qq is from 1 to 6 and pp is from 0 to 49. 15. Stent according to claim 12 in which the or each reactive monomer has the general formula VIII Y2B2R20 VIII wherein B2 is a straight or branched alkylene, oxaalkylene or oligo-oxaalkylene chain optionally containing one or more fluorine atoms up to and including perfluorinated chains, or B2 is a valence bond; Y2 is an ethylenically unsaturated polymerisable group selected from CH2═C(R21)CH2—O—, CH2═C(R21)CH2OC(O)—, CH2═C(R21)OC(O)—, CH2═C(R21)O—, CH2═C(R21)CH2OC(O)N(R22)—, R23OOCCR21═CR21C(O)O—, R21H═CHC(O)O—, R21H═C(COOR23)CH2C(O)O— where R21 is hydrogen or C1-C4 alkyl; R23 is hydrogen, or a C1-4-alkyl group; A2 is —O— or —NR22—; R22 is hydrogen or a C1-C4 alkyl group or R22 is a group B2R20; K2 is a group —(CH2)kOC(O)—, —(CH)kC(O)O—, —(CH2)kOC(O)O—, —(CH2)kNR22—, —(CH2)kNR22C(O)—, —(CH2)kOC(O)O—, —(CH2)kNR22—, —(CH2)kNR22C(O)—, —(CH2)kC(O)NR22—, —(CH2)kNR22C(O)O—, —(CH2)kOC(O)NR22—, —(CH2)kNR22C(O)NR22—(in which the groups R22 are the same or different), —(CH2)kO—, —CH2)kSO3—, a valence bond and k is from 1 to 12; and R20 is a cross-linkable group. 16. Stent according claim 15 in which R20 is selected from the group consisting of ethylenically and acetylenically unsaturated group containing radicals; aldehyde groups; silane and siloxane groups containing one or more substituents selected from halogen atoms and C1-4-alkoxy groups; hydroxyl; amino; carboxyl; epoxy; —CHOHCH2Hal (in which Hal is selected from chlorine, bromine and iodine atoms); succinimido; tosylate; triflate; imidazole carbonyl amino; optionally substituted triazine groups; acetoxy; mesylate; carbonyl di(cyclo)alkyl carbodiimidoyl; isocyanate, acetoacetoxy; and oximino, preferably R20 comprises a silane group containing at least one, preferably three substituents selected from halogen atoms and C1-4-alkoxy groups, more preferably containing three methoxy groups. 17. Stent according to any preceding claim in which the restenosis inhibiting agent has a logP (where P is the partition coefficient between octanol and water) in the range 1.2-4.5, preferably in the range 1.4-4. 18. Stent according to any preceding claim in which the resenosis inhibiting agent is a steroid, preferably an estrogen, for instance 17β-estradiol, or a corticosteroid, such as 6α-methylprednisolone or dexamethasone. 19. Stent according to any preceding claim in which the restenosis inhibiting agent is present in an amount in the range of 20 to 1000 μg preferably 50 to 500 μg, more preferably more than 100 μg, per stent. 20. Method for producing a drug coated intravascular stent comprising the steps: a) a metallic stent body is coated on its inner and outer walls with a cross-linkable amphiphilic polymer; b) the cross-linkable polymer is subjected to conditions under which cross-linking takes place to produce a stent coated with polymer which, when swollen with water containing pyrene, has hydrophobic domains observable by pyrene fluorescence having an intensity ratio I3:I1of at least 0.8.; c) at least the outer coated wall of the polymer coated stent is contacted with liquid drug composition comprising a sparingly water-soluble restenosis inhibiting agent as the drug and an organic solvent in which the drug is at least partially dissolved and which is capable of swelling the cross- linked polymer of the coating, for a time sufficient to swell the polymer coating on the outer wall, to produce a wet drug-coated stent in which drug is present in an amount of at least 20 μg per stent; d) organic solvent is evaporated from the wet stent to produce a dry drug-coated stent. 21. Method according to claim 20 in which, in step c), the drug is both absorbed into the polymer and adsorbed at the surface of the polymer coating, whereby, upon evaporation of the solvent in step d) crystals of drug are formed which are adherent to the surface of the dry-drug coated stent. 22. Method according to claim 20 or 21 in which, in step c) the contact is by dipping the polymer coated stent in the liquid composition, optionally repeatedly. 23. Method according to any of claims 20 to 22 in which in step c) the contact includes flowing, spraying or dripping the liquid composition onto the stent and immediately allowing evaporation of solvent from the wet stent. 24. Method according to any of claims 20 to 23 in which the stent is, between steps b) and c), mounted onto the stent delivery section of a is delivery catheter, whereby the stent delivery section is also contacted with the said liquid drug composition. 25. Method according to claim 24 in which the delivery catheter is a balloon catheter in which the balloon is formed of polyamide, and in which the organic solvent in the liquid drug composition is selected from the group consisting of dichloromethane, dimethylsulphoxide, C1-4 alcohol and admixtures thereof. 26. Method according to any of claims 20 to 25 having the further feature(s) of any of claims 4 to 19. |
Power converter control for automatic maximum power point tracking |
The invention concerns a method and a circuit for maximum power point tracking of a variable power source from a comparison of an image of the power (P) supplied by the power source, the circuit comprising two elements (14, 31) providing different propagating delays to a physical quantity proportional to the power image, a comparator (16) of the outputs of the delaying elements to control a trigger (17) supplying a signal (Q) with two automatic control states to a static power converter, and means (33) for detecting a transitory operating condition from variations in oscillations of an established operating condition and means (32) for modifying the delay input by the slower delaying element (31). |
1. A circuit for tracking the maximum power point of a variable power source (1) based on a comparison of an image of the power (P) provided by the power source, the circuit comprising: two elements (14, 31) introducing different propagation delays in a quantity proportional to the power image; a comparator (16) of the outputs of the delay elements to control a flip-flop (17) providing a two-state signal (Q) for controlling a static power converter; characterized in that it further comprises means (33) for detecting a transient state from variations of oscillations of a steady state; and means (32) for modifying the delay introduced by the slowest delay element (31). 2. The circuit of claim 1, wherein said means (32) for modifying the delay are formed of a switching element (321) capable of, in transient state, inhibiting the operation of the slower delay element (31). 3. The circuit of claim 1 or 2, wherein said detection means (33) compare the duration of an active state on each output signal (Q, {overscore (Q)}) of the flip-flop (17) with a predetermined threshold (TH1, TH2). 4. The circuit of claim 3, wherein the detection means (33) compare, independently from each other, the forward (Q) and reverse ({overscore (Q)}) outputs of the flip-flop (17) and combine (36) the result of these comparisons to provide a control pulse (DEM) to the means (32) for making the delay variable. 5. The circuit of any of claims 1 to 4, wherein the duration of the transient state is selected according to the desired oscillation amplitude around a nominal power reference value. 6. The circuit of any of claims 1 to 5, wherein the different voltage, current, and time measurement elements are analog. 7. The circuit of any of claims 1 to 6, comprising means for resetting the flip-flop (17) upon occurrence of a transient state. 8. The circuit of any of claims 1 to 7, comprising means for, upon occurrence of a transient state, resetting a ramp generator (13′) conditioning the duty cycle of a pulse-width modulation control signal of the power converter. 9. A method for controlling a circuit for tracking the maximum power point of a variable power source (1) of the type applying two delays of different value to an image of the power (P) provided by the power source, consisting of inhibiting or shortening the shortest delay during a transient state. 10. The method of claim 9, consisting of determining the existence of a transient state from a measurement of the frequency of oscillations around a nominal operating point of the maximum power point detector. |
<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention The present invention relates to the field of power converters and, more specifically, power converters equipped with a maximum power point tracking control circuit. Such converters are generally applied to the conversion of power provided by an irregular source. In the context of the present invention, “irregular” power source means a power source providing a power likely to undergo abrupt variations, as opposed to power sources providing a stable or slowly-varying power, as is the case for a battery or for the A.C. supply network. Such sources are, for example, photovoltaic panels providing a power varying according to the lighting, wind engines providing a power varying according to the wind speed, elements of tidal power exploitation providing a power varying according to the wave intensity, etc. The present invention will be described hereafter in relation with photovoltaic element panels. However, the present invention more generally applies to different power sources for which an automated tracking of the maximum power point is needed to optimize the output in case of a power generation. 2. Discussion of the Related Art A power converter of the type to which the present invention applies is of static converter type, with its component operating in switched mode (on/off). The input and output voltages may indifferently be D.C., A.C. voltages, or others (for example, pulse voltages). The converter can then be a D.C./D.C., D.C./A.C., A.C./D.C. converter, etc. A currently-used control technique for the switching of the converter semiconductor component(s) is the control by pulse width modulation (PWM) at the turning-off and at the turning on of a power transistor. The width of the pulses for controlling the turning-on of the power transistor is regulated according to the load and to the power required by said load. In the applications of the present invention, the pulse width is further regulated according to the power provided by the power source by tracking, for yield reasons, the maximum power point. FIG. 1 very schematically shows in the form of blocks a conventional example of a power converter of the type to which the present invention applies. In this example, the converter is a voltage step-up D.C./D.C. converter. Assume a power source 1 formed of photovoltaic elements PV providing a voltage V which is applied across an inductive element L in series with a PWM controlled power switch 2 . In the example shown, power switch 2 is formed of a MOS transistor having a gate receiving a signal CTRL formed of a train of pulses of variable width according to the control orders. The junction 3 of inductive element L and switch 2 is connected to the anode of a free wheel diode D having a cathode connected to a first (positive) electrode 4 of a storage capacitor C. Capacitor C provides, between its electrodes 4 and 5 , a regulated voltage Vout or current Iout of D.C., A.C. or other type according to the nature of the load connected between electrodes 4 and 5 . Electrode 5 of capacitor C corresponds to a reference voltage, for example the ground, for voltage V of panel 1 , for power switch 2 , and for the output voltage. When switch 2 is on (for a MOS transistor, this corresponds to an operation in ohmic mode), diode D is reverse biased. Capacitor C supplies the load connected across terminals 4 and 5 . Power is accumulated in inductive element L across which is applied voltage V provided by the photovoltaic panel 1 . When transistor 2 is off, the power stored in inductance L is transferred to capacitor C by diode D. The operation of a pulse-width modulated power converter is well known and will not be detailed any further. Various types of power switch assemblies are known, according to whether the converter is a step-down, step-up, or step-up/step-down converter. When the voltage source providing voltage V is irregular, a maximum power point tracking control circuit (MPPT) 10 is generally used. Such a circuit has the function of modifying the width of the pulses for turning on switch 2 according to the variations of the power provided by power source 1 . At its input, circuit 10 thus receives a signal (for example, a voltage) proportional to power P provided by source 1 . In the example of FIG. 1 , power P is obtained by means of a multiplier 7 of a current measurement I in the photovoltaic elements by a measurement of voltage V across panel 1 . Circuit 10 provides a two-state signal Q intended to increase, respectively, decrease, the width of the control pulses of switch 2 . Signal CTRL of control of switch 2 is provided by a comparator 11 (COMP) of the converter controlled by circuit 10 . This comparator receives, on a first input, a periodic signal provided by a generator 12 , for example, a sawtooth of constant high frequency. A second input of comparator 11 receives the output of a ramp generator 13 (RAMP) having its direction inversion (ascending ramp, descending ramp) conditioned by the state of signal Q. The frequency of the sawtooth conditions the frequency, generally constant, of the pulse train of signal CTRL. The instantaneous level provided by generator 13 , formed for example of an RC circuit, sets the comparison reference, and thus the pulse duty cycle. To generate signal Q, circuit 10 comprises two resistive and capacitive circuits 14 , 15 (RCF and RCS) forming delay lines of power signal P with different time constants. Circuit 14 is, for example, a high speed circuit as compared to circuit 15 , which has a longer time constant. The respective outputs of circuits 14 and 15 are connected to the inputs of a comparator 16 (COMP), the output of which controls a flip-flop 17 (T) providing signal Q. Hereafter, Q will indifferently be used to designate the forward (non inverted) output terminal of flip-flop 17 or the signal present on this terminal. Flip-flop 17 is a flip-flop with no clock signal. It is, for example, a JK-type flip-flop assembled as a so-called T-type flip-flop. The structure and operation of a circuit such as shown in FIG. 1 is perfectly well known. An example of such a circuit is described in article “Step-Up Maximum Power Point Tracker for Photovoltaic Arrays” by Ziyad Salameh, published in the proceedings of the American Solar Energy Society Conference of Jun. 20 to 24, 1988, pages 409-414. Its operation will briefly be reminded hereafter. The examination of the slow and fast variations of power P provides an image of the derivative of this power. Due to the time constant difference of RC circuits 14 and 15 , the output of comparator 16 oscillates. The frequency and amplitude of these oscillations depend on the time constants of the RC circuits. In fact, comparator 16 indicates, according to its output state (high or low) the sign of the derivative of the power. As long as the output of comparator 16 remains in a same state, the output of flip-flop 17 does not switch state. Assuming a state 1 at the input and at the output of flip-flop 17 , the resistive and capacitive circuit of ramp generator 13 builds up power. This increases the corresponding input level of comparator 11 and increases the duty cycle of signal CTRL. Assuming that the load receiving voltage Vout is constant, power P will increase to a maximum, then start decreasing along with the increase in voltage V. When the power starts decreasing, the output of comparator 16 switches, which causes a switching of output signal Q of flip-flop 17 . Said signal then switches low, which causes the discharge of the RC circuit of ramp generator 13 and a decrease in the duty cycle. The output voltage then starts increasing again. At constant load, the circuit converges towards a maximum power point and oscillates around this point. This operation is illustrated in FIG. 2 , which shows two examples of the course of power P according to voltage V for two lighting quantities received by panel 1 . A first curve 21 illustrates, for example, the case of a maximum lighting. As just described, at constant load, the system will oscillate around maximum power point PMM 1 . If the lighting of panel 1 changes (for example, by the coming of shadow), characteristic P=f(V) of panel 1 becomes a curve 22 of lower level. This curve also exhibits a maximum power point PMM 2 . However, the control system shown in FIG. 1 cannot make out a lighting change from an abrupt variation of the load connected at the converter output or from a mere variation around the maximum power point of curve P=f(V) on which stands its operating point. The control system is then lost and may even find itself in a steady state no longer corresponding to the maximum power point. In fact, the circuit diverges towards a minimum load or maximum load state according to the flip-flop state preceding the change of curve P=f (V). The same problem is posed in the case of an abrupt variation in the supplied load. A first solution consists of choosing very different time constants of delay elements 14 and 15 . However, this adversely affects the output because of the significant generated oscillations. Another known solution consists of forcing the system to start back from the origin of curves P=f (V). It is then started from a very small duty cycle, which is increased to converge back towards the maximum power point of the current lighting curve. A disadvantage of such a solution is that it considerably slows down the control by the lighting of the photovoltaic panel or by the abrupt variations of any power source connected upstream of the system. Further, the differentiation between a maximum power point change (curve change) and a normal variation also poses a problem in terms of detection duration and reliability. FIG. 3 illustrates an example of characteristic of current I provided by the photovoltaic panel along time at a power curve change of the panel. It is assumed to initially be (times t0 to t1) on a maximum lighting curve ( 21 , FIG. 2 ). Current I then slightly oscillates around a value Imax, assuming a constant load. A lighting change at time t1 causes a reference loss for the control system. In the example shown in FIG. 3 , it is assumed that the system is then restarted at a time t2 subsequent to time t1 after having discovered the system reference loss. It is then converged until a time t3 towards a new maximum power point corresponding to a current Iomb around which the system then starts slightly oscillating. The amplitude of the oscillations around values Imax and Iomb of course depends on the time constants of RC circuits 14 and 15 . The greater the difference between time constants, the larger the amplitude of the oscillations at the output of comparator 16 . The faster it is converged towards the maximum power point (duration between times t2 and t3), the greater the oscillation amplitude. However, the greater the oscillations, the more adversely this affects the system output. A compromise must thus be made between output, speed, and stability. Problems of system convergence after maximum power point changes are posed especially in case of a variable power source. However, even if the input power source is stable a priori as should be the case, for example, for photovoltaic panels used in space (without clouds), such convergence problems may be encountered. Indeed, space infrastructures having more and more complex geometries, shadow areas due to the very structure of satellites may appear. Further, sensors may be partially damaged by dust impact, which leads to the same result. Another known solution to overcome the disadvantages linked to abrupt variations of the power source is to use a digital circuit. The different operating points are successively memorized to recognize a drift. A digital system however remains slow to isolate a drift from a normal operating variation. On this regard, the larger the amplitude of the accepted oscillations in steady state, the slower the system will be in recognizing a state change due to a change in the power source. Another disadvantage of a digital circuit is that it is in practice limited to frequencies of pulse trains for controlling switch 2 of some hundred kHz. On this regard, an analog control circuit such as that illustrated in FIG. 1 has the advantage of being able to operate at higher cut-off frequencies (on the order of one MHz). This eases the converter integration. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention aims at overcoming the disadvantages of known circuits for tracking the maximum power point of a static converter of switched-mode power supply type. The present invention more specifically aims at optimizing the converter output without adversely affecting its response speed. The present invention also aims at enabling the control circuit to converge back towards a new maximum power point in case of a variation in the power source, due to a simple circuit of analog type. The present invention also aims at preserving the control performed by the circuit in case of a variation in the load connected at its output. The present invention further aims at providing an integrable solution compatible with a high-frequency operation of the switched-mode power supply. To achieve these objects, the present invention provides a circuit for tracking the maximum power point of a variable power source based on a comparison of an image of the power provided by the power source, the circuit comprising: two elements introducing different propagation delays in a quantity proportional to the power image; a comparator of the outputs of the delay elements to control a flip-flop providing a two-state signal for controlling a static power converter; means for detecting a transient state from variations of oscillations of a steady state; and means for modifying the delay introduced by the slowest delay element. According to an embodiment of the present invention, said means for modifying the delay are formed of a switching element capable of, in transient state, inhibiting the operation of the slower delay element. According to an embodiment of the present invention, said detection means compare the duration of an active state on each output signal of the flip-flop with a predetermined threshold. According to an embodiment of the present invention, the detection means compare, independently from each other, the forward and reverse outputs of the flip-flop and combine the result of these comparisons to provide a control pulse to the means for making the delay variable. According to an embodiment of the present invention, the duration of the transient state is selected according to the desired oscillation amplitude around a nominal power reference value. According to an embodiment of the present invention, the different voltage, current, and time measurement elements are analog. According to an embodiment of the present invention, the circuit comprises means for resetting the flip-flop upon occurrence of a transient state. According to an embodiment of the present invention, the circuit comprises means for, upon occurrence of a transient state, resetting a ramp generator conditioning the duty cycle of a pulse-width modulation control signal of the power converter. The present invention also provides a method for controlling a circuit for tracking the maximum power point of a variable power source of the type applying two delays of different value to an image of the power provided by the power source, which consists of inhibiting or shortening the shortest delay during a transient state. According to an embodiment of the present invention, the existence of a transient state is determined from a measurement of the frequency of oscillations around a nominal operating point of the maximum power point detector. The foregoing objects, features, and advantages of the present invention will be discussed in detail in the following non-limiting description of specific embodiments in connection with the accompanying drawings. |
High shrink polyethylene films |
A homogeneous blend of a low density polyethylene with a metallocene-catalysed polyethylene having a density of from 0.906 g/cm3 and a Dow Rheology Index of at least 5/MI2, MI2 being the melt index measured according to ASTMD-1238 condition 190° C./2.16 kg and the Dow Rheology Index being determined by a dynamic rheological analysis performed at 190°. |
1-8. (Cancelled) 9. A polyethylene composition comprising a homogenous blend of a low density polyethylene with a metallocene-catalysed polyethylene having a density of at least 0.906 g/cm3 and a Dow Rheology Index of at least 5/MI2, wherein MI2 is the melt index measured according to ASTMD-1238 condition 190° C./2.16 kg and the Dow Rheology Index being determined by a dynamic rheological analysis performed at 190°, said metallocene-catalysed polyethylene being catalysed with a catalyst system comprising a metallocene component and an activating agent selected from the group consisting of an alumoxane or an aluminum alkyl providing a mole ratio of aluminum to the transition metal of said metallocene component within the range of 50:1-300:1. 10. The composition of claim 9 wherein the metallocene-catalysed polyethylene has a Dow Rheology Index of at least 10/MI2. 11. The composition of claim 9 wherein the metallocene-catalysed polyethylene has a Dow Rheology Index of at least 20/MI2. 12. The composition of claim 9 wherein the metallocene-catalysed polyethylene has a density of from 0.925 g/cm3 to less than 0.965 g/cm3. 13. The composition of claim 12 wherein the metallocene-catalysed polyethylene has a Dow Rheology Index of at least 10/MI2 14. The composition of claim 12 wherein the metallocene-catalysed polyethylene has a Dow Rheology Index of at least 20/MI2. 15. The composition of claim 9 wherein the metallocene-catalysed polyethylene has a density of from 0.906 g/cm3 to less than 0.925 g/cm3. 16. The composition of claim 15 wherein the metallocene-catalysed polyethylene has a Dow Rheology Index of at least 10/MI2. 17. The composition of claim 15 wherein the metallocene-catalysed polyethylene has a Dow Rheology Index of at least 20/M2. 18. A blown film comprising at least one layer formed of a polyethylene composition comprising a homogenous blend of a low density polyethylene with a metallocene-catalysed polyethylene having a density of at least 0.906 g/cm3 and a Dow Rheology Index of at least 5/MI2, wherein MI2 is the melt index measured according to ASTMD-1238 condition 190° C./2.16 kg and the Dow Rheology Index being determined by a dynamic rheological analysis performed at 190°, said metallocene-catalysed polyethylene being catalysed with a catalyst system comprising a metallocene component and an activating agent selected from the group consisting of an alumoxane or an aluminum alkyl providing a mole ratio of aluminum to the transition metal of said metallocene component within the range of 50:1-300:1. 19. The film of claim 18 wherein said layer is a monolayer blown film. 20. The film of claim 18 wherein said layer comprises at least one layer of a multilayer blown film. 21. A process for the preparation of a blown film, forming said film in a blown film line from a polyethylene composition comprising a homogenous blend of a low density polyethylene with a metallocene-catalysed polyethylene having a density of at least 0.906 g/cm3 and a Dow Rheology Index of at least 5/MI2, wherein MI2 is the melt index measured according to ASTMD-1238 condition 190° C./2.16 kg and the Dow Rheology Index being determined by a dynamic rheological analysis performed at 190°, said metallocene-catalysed polyethylene being catalysed with a catalyst system comprising a metallocene component and an activating agent selected from the group consisting of an alumoxane or an aluminum alkyl providing a mole ratio of aluminum to the transition metal of said metallocene component within the range of 50:1-300:1, said film being characterized by: a cohesion force in the transverse direction at room temperature of at least 5% greater than the cohesion force in the transverse direction of a corresponding biaxially-oriented film formed of said low density polyethylene in a pure form; and a gloss at an angle of 45° of at least 60 and a haze of less than 10% while keeping a good rigidity. 22. A biaxially-oriented film which has been oriented in the machine direction and the transverse direction, formed from a homogenous blend of a polyethylene composition comprising a homogenous blend of a low density polyethylene with a metallocene-catalysed polyethylene having a density of at least 0.906 g/cm3 and a Dow Rheology Index of at least 5/MI2, wherein MI2 is the melt index measured according to ASTMD-1238 condition 190° C./2.16 kg and the Dow Rheology Index being determined by a dynamic rheological analysis performed at 190°, said metallocene-catalysed polyethylene being catalysed with a catalyst system comprising a metallocene component and an activating agent selected from the group consisting of an alumoxane or an aluminum alkyl providing a mole ratio of aluminum to the transition metal of said metallocene component within the range of 50:1-300:1, said film having a cohesion force in the transverse direction which is greater than the cohesion force in the transverse direction of a corresponding biaxially-oriented film formed of said low density polyethylene in a pure form. 23. The biaxially-oriented film of claim 22, wherein said film has a cohesion force in the machine direction which is greater than the cohesion force in the machine direction of the corresponding film formed of said low density polyethylene in a pure form. 24. The film of claim 23, having a gloss at an angle of 45° of at least 60, and a haze which is less than 10%. |
Extraction bedplate with laser or water jet cut apertures |
The present invention relates to extraction bedplates (10), (110), (210), (310), (410), (510), (610) for use in apparatus (5) for defiberizing paper making stock and methods for making such bedplates. Preferred methods for making such bedplates (10), (110), (210), (310), (410), (510), (610) include the step of cutting a disc shaped blank from a metal plate and the step of forming holes (45), (145), (245), (345), (445), (545), (645), (646) either the metal plate or the disc shaped blank. The holes (45), (145), (245), (345), (445), (545), (645), (646) preferably are formed using a cutting stream, most preferably either a laser or a water jet. Use of a cutting stream to form the holes facilitates the cutting of holes (45), (145), (245), (345), (445), (545), (645), (646) having non-circular, and preferably tesselatory, cross sections as well as holes (45), (145), (245), (345), (445), (545), (645), (646) extending at acute angles with respect to an axis (20) of the bedplate. |
1. An extraction bedplate for use in defiberizing stock for making paper, comprising: a plate defining first and second surfaces; and a plurality of holes lacking substantially circular cross-sections extending from said first surface to said second planar surface. 2. The extraction bedplate as recited in claim 1, wherein said plate defines an axis normal to said first and second surfaces and wherein said holes extend at an acute angle with respect to said axis. 3. The extraction bedplate as recited in claim 1, wherein said plate defines an axis normal to said first and second surface; said holes are arranged along arcs coincident with anticipated stock flow lines immediately above the upstream surface of said bedplate; and said holes are extend through said bedplate at an acute angle along said anticipated stock flow lines so as to define relatively sharp downstream side edges facing said anticipated flow lines. 4. The extraction bedplate as recited in claim 1, wherein said holes have cross sections which tesselate a plane. 5. The extraction bedplate as recited in claim 1, wherein said holes have substantially rhombic cross sections. 6. The extraction bedplate as recited in claim 1, wherein said holes have substantially square cross sections. 7. The extraction bedplate as recited in claim 1, wherein said holes have substantially rectangular cross sections. 8. The extraction bedplate as recited in claim 1, wherein said holes have substantially chevronic cross sections. 9. The extraction bedplate as recited in claim 1, wherein said holes have substantially triangular cross sections. 10. The extraction bedplate as recited in claim 1, wherein said holes have substantially crescentic cross sections. 11. The extraction bedplate as recited in claim 1, wherein said holes have substantially semi-circular cross-sections. 12. An extraction bedplate for use in defiberizing stock for making paper, comprising: a plate defining a first surface, a second surface and an axis normal to said first and second surfaces; and a plurality of holes extending through said plate symmetrically at an acute angle with respect to said axis from said first surface to said second planar surface. 13. The extraction bedplate as recited in claim 12, wherein said holes have cross sections in the shape of polygons which tesselate a plane. 14. The extraction bedplate as recited in claim 12, wherein said holes have substantially circular cross sections. 15. The extraction bedplate as recited in claim 12, wherein said holes have substantially rhombic cross sections. 16. The extraction bedplate as recited in claim 12, wherein said holes have substantially square cross sections. 17. The extraction bedplate as recited in claim 12, wherein said holes have substantially rectangular cross sections. 18. The extraction bedplate as recited in claim 12, wherein said holes have substantially chevronic cross sections. 19. The extraction bedplate as recited in claim 12, wherein said holes have substantially triangular cross sections. 20. The extraction bedplate as recited in claim 12, wherein said holes have substantially crescentic cross sections. 21. The extraction bedplate as recited in claim 12, wherein said holes have substantially semi-circular cross sections. 22. A method for fabricating an extraction bedplate from a metal plate defining a first surface and a second surface, said method comprising the steps of: (a) cutting a disc-shaped blank from said metal plate; and (b) forming a plurality of holes lacking substantially circular cross-sections through one of said metal plate and said disc-shaped blank from said first surface to said second surface. 23. The method as recited in claim 22, wherein said step (b) includes directing a stream of energy against said one of said metal plate and said disc-shaped blank to ablate said plurality of holes. 24. The method as recited in claim 23, wherein said step (b) includes directing a stream of laser energy against said one of said metal plate and said disc-shaped blank to ablate said plurality of holes. 25. The method as recited in claim 22, wherein said step (b) includes directing a stream of pressurized fluid against said one of said metal plate and said disc-shaped blank to cut said plurality of holes. 26. The method as recited in claim 22, wherein said step (b) includes directing a cutting stream against said one of said metal plate and said disc-shaped blank and wherein said method includes the additional step of: (c) programming a programmable electronic controller to induce said cutting stream to move across said one of said metal plate and said disc-shaped blank so as to shape said plurality of holes. 27. A method for fabricating an extraction bedplate from a metal plate defining a first surface and a second surface, said method comprising the steps of: (a) cutting a disc-shaped blank from said metal plate; and (b) forming a plurality of holes extending symmetrically with respect to said axis at an acute angle with respect to said axis through one of said metal plate and said disc-shaped blank from said first surface to said second surface. 28. The method as recited in claim 27, wherein said step (b) includes directing a stream of energy against said one of said metal plate and said disc-shaped blank to ablate said plurality of holes. 29. The method as recited in claim 28, wherein said step (b) includes directing a stream of laser energy against said one of said metal plate and said disc-shaped blank to ablate said plurality of holes. 30. The method as recited in claim 27, wherein said step (b) includes directing a stream of pressurized fluid against said one of said metal plate and said disc-shaped blank to cut said plurality of holes. 31. The method as recited in claim 27, wherein said step (b) includes directing a cutting stream against said one of said metal plate and said disc-shaped blank and wherein said method includes the additional step of: (c) programming a programmable electronic controller to induce said cutting stream to move across said one of said metal plate and said disc-shaped blank so as to shape said plurality of holes. |
<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention The present invention relates to apparatus for use in defiberizing papermaking stock. More particularly, the invention relates to extraction bedplates with specially shaped and contoured holes cut by laser energy or a fluid jet for use in pulping apparatus. 2. Background Art Apparatus for pulping paper making stock is shown in Chupka U.S. Pat. No. 4,725,007, the disclosure of which is incorporated by reference. The apparatus shown in U.S. Pat. No. 4,725,007 includes a tub and a rotor mounted within the tub for inducing shear forces which serve to defiberize the stock An extraction bedplate is positioned at the bottom of this tub, surrounded by a frusto-conical wall which serves as a funnel to direct the stock toward the bedplate. The preferred bedplate is disc-shaped, defining an upstream surface facing into the tub; a downstream surface facing oppositely from the upstream surface; and holes or apertures extending through the bedplate from the upstream surface to the downstream surface. The rotor is mounted near the center of the perforated bedplate and coupled to a motor for rotation about an axis normal to the upstream surface of the bedplate. The holes extending through the extraction bedplate allow accepted fiber, that is, pulp which has been defiberized to a degree which is acceptable for further processing to flow out from the apparatus, while retaining larger, undefiberized particles and other solids in the tub. Conventional bedplates typically range from 24 inches (61 cm) to 96 inches (2.4 m) in diameter and are typically approximately ⅝ inch (1.6 cm) thick. Typically there are 4,000 to 5,000 holes in a 96 inch diameter plate with ⅝ inch holes. Since such holes are formed by conventional drilling processes, they have in the past been formed parallel to the axis of the bedplate with circular cross sections. The holes generally range from {fraction (1/8)} inch (3.2 mm) to 1 inch (25 mm) in diameter. Known extraction bedplates tend to be high maintenance items because of wear. Bedplates are exposed to harsh treatment from sand, metal objects and other debris contained within the stock. The typical clearance between the rotor and the bedplate is approximately 0.060 inch (1.5 mm) to 0.120 inch (3.0 mm). The stock is constantly pushed against, and drug along, the upper surface of the bedplate by the mechanical and hydraulic action of the associated rotor. The accepted fiber along with small contaminates which flow through the bedplate contribute to wear within the holes, particularly near the upper perimeters of the downstream edge portions of the holes. Bedplates typically are manufactured from steel alloys resistant to wear and corrosion. Various stainless steels and 410 hard chrome steel have been used in forming bedplates. The 410 hard chrome steel is preferred because it is more wear resistant than the stainless steels. On the other hand, the 410 hard chrome steel requires heat treatment to harden the material to restore acceptable wear resistance after known machining and hole-drilling steps are performed. Once the heat treatment is performed, further machining is possible only with special tools in a slow and costly procedure. The heat treatment itself tends to warp the steel, so that additional manufacturing steps are required to straighten the bedplate. The defibering characteristics of a given bedplate are dependent to a large degree on the surface indentations defined by the upper edges of the individual holes. More particularly, the paper making stock flows over the upstream surface of the bedplate during operation of the pulping apparatus. Hydraulic shear is generated near downstream side edges (that is, edges facing the oncoming stock now) formed at the intersections of the holes with the upstream surface of the bedplate. This hydraulic shear acts to break up relatively large, undefiberized particles. Increasing the number of such downstream side edges increases the amount of the hydraulic shear, thus improving the efficiency of the pulping apparatus. Therefore, there remains a need in the art for extraction bedplates providing improved efficiency and wear resistance. Additionally, there remains a need for improved methods for making such bedplates. |
<SOH> SUMMARY OF THE INVENTION <EOH>Preferred extraction bedplates in accordance with the present invention have specially shaped and configured holes which provide increased densities of downstream side edges along the upstream surfaces of the bedplates. In accordance with one preferred embodiment of the invention, the holes have non-circular cross sections. Most preferably, the holes have cross sections with shapes which tesselate a plane, that is, which when laid side-to-side will fill a plane without intervening gaps. Individual holes having tesselatory cross sections can be arranged closely to one another, thereby improving the density of the downstream side edges on the upstream surface of the bedplate and increasing the amount of hydraulic shear acting on the unfiberized stock. Especially preferred hole cross sectional shapes include rhombi (that is, “diamond shapes”), squares, rectangles, triangles and chevrons. Other preferred shapes include crescents and semi-circles which, though not tesselatory, can be closely arranged on the bedplate surface so as to improve the density of the downstream side edges. In accordance with another preferred embodiment, the holes extend from one of the upstream and downstream surfaces to the other at an acute angle relative to an axis normal to the upstream and downstream surfaces. Preferably, the holes extend in a pattern combining a helical arrangement with a radial splay so as to present relatively sharp side edges facing into the stock flow immediately above the upstream surface of the bedplate. Most preferably, the holes are arranged along arcs or curves coincident with anticipated stock flow lines immediately above the upstream surface of the bedplate and are oriented such that the holes extend into the bedplate and in the anticipated flow direction of the stock so as to present the sharpest possible downstream side edges to the flow. This arrangement serves to reduces the drag on the flow of accepts fiber through the bedplate and improve the generation of hydraulic shear near the upstream surface. In accordance with yet another preferred embodiment of the invention, the bedplate is fabricated by forming a disc-shaped blank from a metal plate and then forming the holes, preferably by means of a cutting stream. One preferred cutting stream is an energy stream, such as a stream of laser or other electromagnetic energy. Another preferred stream is a pressurized fluid stream such as a water jet. The use of such cutting streams to form the holes simplifies the manufacture of the bedplates and reduces the both time and cost of manufacture. The method also facilitates the cutting of the specially shaped and configured holes to improve the density and sharpness of the downstream side edges facing the stock flow. The method can be practiced on highly wear resistance materials without the heat treatments or special tools required by prior art methods. Since the method is adapted for use with stronger, more wear resistant steels than those typically used in the prior art, it provides for the fabrication of thinner bedplates and of bedplates having useful lives longer than those typical in the prior art. Further advantages, objects and features of the present invention will become apparent in the following detail description when considered together with the drawing figures and appended claims. |
Former and headbox for said former |
A former for a machine for the production of a fibrous web, particularly a paper or cardboard web including a headbox equipped with at least one stock suspension feed, one turbulence block equipped with several channels and/or a tube generator equipped with several channels, and a headbox nozzle whose suspension jet strikes an exposed or open surface of a dewatering belt, specifically a wire. Turbulence generating elements are allocated to at least a section of the channels and/or the headbox nozzle, in order to create turbulent flows in the suspension substreams in the channels, or in the headbox nozzle. The side of the suspension stream facing away from the dewatering belt is covered at least partially by a wall. A danger of the suspension stream bursting open is reduced to a minimum. In addition, swirling motions of considerably higher intensity than occur on conventional Fourdrinier wire formers are now permissible. |
1-53. (Canceled) 54. A former for a machine for the production of a fibrous web, comprising: a headbox having: at least one stock suspension feed; at least one turbulence block connected to said at least one stock suspension feed, at least one said turbulence block having at least one of a plurality of channels and a tube generator having said plurality of channels, said plurality of channels having a plurality of suspension sub-streams running in said channels, said plurality of channels having at least one section; a headbox nozzle connected to at least one said turbulence block, said headbox nozzle producing a suspension stream; and turbulence generating elements allocated to at least one of said at least one section of said channels and said headbox nozzle, said turbulence generating elements creating a plurality of turbulent flows in one of said plurality of suspension sub-streams and said headbox nozzle; a dewatering belt having an open surface, said suspension stream incident on said open surface; and a wall at least partially covering a side of said suspension stream facing away from said dewatering belt. 55. The former of claim 54, wherein said former is a suction former. 56. The former of claim 54, wherein said dewatering belt is a wire. 57. The former of claim 54, wherein said wall is a stationary wall. 58. The former of claim 57, wherein said stationary wall is installed on said headbox. 59.The former of claim 58, wherein said stationary wall is adjustably installed on said headbox. 60. The former of claim 54, wherein said wall is in motion. 61. The former of claim 54, wherein said wall is permeable to water. 62. The former of claim 54, wherein said wall is impermeable to water. 63. The former of claim 54, wherein said wall is formed by a second dewatering belt. 64. The former of claim 63, wherein said second dewatering belt is a revolving wire. 65. The former of claim 54, wherein said wall includes a coverage area, said coverage area includes an at least partially curved progression. 66. The former of claim 54, wherein said wall includes a coverage area, said coverage area includes an at least partially straight progression. 67. The former of claim 54, wherein said wall includes both an upper wall with an upper wall length and a lower wall with a lower wall length, said lower wall length is not greater than 90% of said upper wall length. 68. The former of claim 67, wherein said lower wall length is not greater than 60% of said upper wall length. 69. The former of claim 67, wherein said lower wall length is not greater than 30% of said upper wall length. 70. The former of claim 54, wherein at least one said section of said channels includes at least one turbulence causing insert. 71. A former for a machine for the production of a fibrous web, comprising: a headbox having: at least one stock suspension feed; at least one turbulence block connected to said at least one stock suspension feed, at least one said turbulence block having at least one of a plurality of channels and a tube generator having said plurality of channels, said plurality of channels having a plurality of suspension sub-streams running in said channels, said plurality of channels having at least one section; a headbox nozzle connected to at least one said turbulence block; and turbulence generating elements allocated to at least one said section of said channels, said turbulence generating elements creating a plurality of turbulent flows in said plurality of suspension sub-streams, each said turbulent flow rotating in a similar direction in said plurality of suspension sub-streams. 72. The former of claim 71, wherein said former is one of a suction former and a twin wire former. 73. The former of claim 71, further including helix spirals installed in at least one said section of said channels for a production of said turbulent flows that rotate in said similar direction. 74. The former of claim 71, wherein said headbox includes a tube generator with nozzles for a feeding of a stock suspension into a respective said channel, each said channel has a corresponding center plane progressing in a longitudinal direction through said channel, said feeding occurs asymmetrically relative to each said center plane. 75. The former of claim 74, wherein each said channel has a respective channel wall, in each said channel said feeding occurs approximately tangentially to said respective channel wall. 76. The former of claim 74, further including a plurality of jets in fluid communication with said stock suspension and corresponding said channels, said stock suspension being fed through each said jet to said corresponding channel on only one side of said corresponding center plane. 77. The former of claim 76, wherein said stock suspension is fed through each said jet to said corresponding channel on the same side of said corresponding center plane for each said channel. 78. The former of claim 71, wherein said headbox includes at least one inlet for a supply of at least one of dilution water, air and chemicals. 79. The former of claim 78, wherein said supply of at least one of dilution water, air and chemicals occurs essentially in an axial direction of a respective channel. 80. The former of claim 71, further including both a forming roll having a second radius of curvature and a wall being located in an area opposite said forming roll, said wall being both at least partially curved and having a first radius of curvature, said first radius of curvature equal to or greater than said second radius of curvature. 81. The former of claim 80, wherein said wall is stationary. 82. The former of claim 80, wherein said wall covers a circumferential length of said forming roll, said circumferential length approximately between 100 to 400 mm. 83. The former of claim 81, wherein said wall is one of rigid, deflection resistant and flexible. 84. The former of claim 80, wherein said wall is both movable and is formed by an additional dewatering belt, said wall covers a circumferential length of said forming roll, said circumferential length approximately between 100 to 1500 mm, said circumferential length approximately between 100 to 400 mm corresponds with a circumferential angle of said forming roll approximately between 25° to 120°. 85. The former of claim 84, wherein said additional dewatering belt is a revolving wire. 86. The former of claim 84, wherein said dewatering belt is routed around a breast roll prior to said circumferential length when viewed in a direction of belt travel, said breast roll has a third radius of curvature, said first radius of curvature in an area covering said forming roll is greater than said third radius of curvature. 87. The former of claim 71, further including at least one lamellar plate sectioning said headbox nozzle. 88. The former of claim 87, wherein said headbox nozzle includes at least one nozzle wall, at least one of said at least one lamellar plate and said at least one nozzle wall has a whirl producing contour. 89. The former of claim 88, wherein said whirl producing contour is a washboard countour. 90. The former of claim 88, wherein at least one of said at least one lamellar plate and said at least one nozzle wall include contours which generate turbulence. 91. The former of claim 90, wherein at least one of said at least one lamellar plate and said at least one nozzle wall include at least one interference body. 92. The former of claim 91, wherein said at least one interference body of said at least one nozzle wall is a discontinuous tapering of a cross section of said at least one nozzle wall. 93. The former of claim 87, wherein said headbox nozzle has a headbox nozzle length, said at least one lamellar plate has a lamellar plate length not exceeding 70% of said headbox nozzle length. 94. The former of claim 71, wherein said headbox nozzle has a headbox nozzle length less than approximately 400 mm. 95. The former of claim 71, further including an outlet cross section of said channels being essentially round. 96. A headbox for a machine for the production of a fibrous web, comprising: at least one stock suspension feed; at least one turbulence block connected to said at least one stock suspension feed, at least one said turbulence block having at least one of a plurality of channels and a tube generator having said plurality of channels, said plurality of channels having a plurality of suspension sub-streams running in said channels, said plurality of channels having at least one section; a headbox nozzle connected to at least one said turbulence block; and turbulence generating elements allocated to at least one said section of said channels, said turbulence generating elements creating a plurality of same direction turbulent flows in said plurality of suspension sub-streams. 97. The headbox of claim 96, wherein said headbox is for a former. 98. The headbox of claim 96, further including both a stationary wall connected to said headbox nozzle and a suspension stream emerging from said headbox nozzle, said stationary wall covering said suspension stream. 99. The headbox of claim 98, wherein said stationary wall is adjustable. 100. The headbox of claim 98, wherein said stationary wall is permeable to water. 101. The former of claim 98, wherein said stationary wall is impermeable to water. 102. The former of claim 98, wherein said stationary wall includes both an upper wall with an upper wall length and a lower wall with a lower wall length, said lower wall length is not greater than 90% of said upper wall length. 103. The former of claim 102, wherein said lower wall length is not greater than 60% of said upper wall length. 104. The former of claim 102, wherein said lower wall length is not greater than 30% of said upper wall length. 105. The former of claim 96, wherein said at least one section of said channels includes at least one turbulence generating insert. 106. A headbox for a machine for the production of a fibrous web, comprising: at least one stock suspension feed; at least one turbulence block connected to said at least one stock suspension feed, at least one said turbulence block having at least one of a plurality of channels and a tube generator having said plurality of channels, said plurality of channels having a plurality of suspension sub-streams running in said channels, said plurality of channels having at least one section; a headbox nozzle connected to at least one said turbulence block; and turbulence generating elements allocated to at least one said section of said channels, said turbulence generating elements creating a plurality of turbulent flows in said plurality of suspension sub-streams, each said turbulent flow rotating in a similar direction in said plurality of suspension sub-streams. 107. The headbox of claim 106, wherein said headbox is for a former. 108. The headbox of claim 106, further including helix spirals installed in at least one said section of said channels for a production of said turbulent flows that rotate in said similar direction. 109. The headbox of claim 106, wherein said headbox includes a tube generator with nozzles for a feeding of a stock suspension into a respective said channel, each said channel has a corresponding center plane progressing in a longitudinal direction through said channel, said feeding occurs asymmetrically relative to each said center plane. 110. The headbox of claim 109, wherein each said channel has a respective channel wall, in each said channel said feeding occurs approximately tangentially to said respective channel wall. 111. The headbox of claim 109, further including a plurality of jets in fluid communication with said stock suspension and corresponding said channels, said stock suspension being fed through each said jet to said corresponding channel on only one side of said corresponding center plane. 112. The headbox of claim 111, wherein said stock suspension is fed through each said jet to said corresponding channel on a same side of said corresponding center plane for each said channel. 113. The headbox of claim 106, wherein said headbox includes at least one inlet for a supply of at least one of dilution water, air and chemicals. 114. The headbox of claim 113, wherein said supply of at least one of dilution water, air and chemicals occurs essentially in an axial direction of a respective channel. 115. The headbox of claim 106, further including at least one lamellar plate sectioning said headbox nozzle. 116. The headbox of claim 115, wherein said headbox nozzle includes at least one nozzle wall, at least one of said at least one lamellar plate and said at least one nozzle wall has a whirl producing contour. 117. The headbox of claim 116, wherein said whirl producing contour is a washboard countour. 118. The headbox of claim 116, wherein at least one of said at least one lamellar plate and said at least one nozzle wall include contours which generate turbulence. 119. The headbox of claim 118, wherein at least one of said at least one lamellar plate and said at least one nozzle wall include at least one interference body. 120. The headbox of claim 119, wherein said at least one interference body of said at least one nozzle wall is a discontinuous tapering of a cross section of said at least one nozzle wall. 121. The headbox of claim 115, wherein said headbox nozzle has a headbox nozzle length, said at least one lamellar plate has a lamellar plate length not exceeding 70% of said headbox nozzle length. 122. The headbox of claim 106, wherein said headbox nozzle has a headbox nozzle length less than approximately 400 mm. 123. The headbox of claim 106, further including an outlet cross section of said channels which is essentially round. |
<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention The present invention relates to a machine a machine for the production of a fibrous web, and, more particularly, to a former and former headbox. 2. Description of the Related Art With suction formers, a longitudinal orientation of the fibers occurs at an appropriate increase in the operating speed of the paper machine in question. This may limit the scope of application of such suction formers to low operational speeds. A relatively strong transverse orientation of the fibers, as well as a low longitudinal/transverse ratio can be achieved (see for example U.S. Pat. No. 5,876,364) through transverse movements that are indicated through various swirl-producing bodies in the turbulence block. However, a consequence of these transverse motions is the inherent danger of the suspension stream that is delivered by the headbox of the respective former bursting open when encountering an open surface, for example on the Fourdrinier wire. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention provides an improved former and former headbox whereby the cited problems are eliminated. The present invention provides a former, particularly a suction former of a machine for the production of a fibrous web, particularly a paper or cardboard web comprising a headbox equipped with at least one stock suspension feed, one turbulence block equipped with several channels and/or a tube generator equipped with several channels, and a headbox nozzle whose suspension jet strikes an exposed or open surface of a dewatering belt, specifically a wire. Turbulence generating elements are allocated to at least a section of the channels and/or the headbox nozzle, in order to create turbulent flows in the suspension substreams in the channels, or in the headbox nozzle. The side of the suspension stream facing away from the dewatering belt is covered at least partially by a wall. Based on this configuration, the danger of the suspension stream bursting open is reduced to a minimum. In addition, swirling motions of considerably higher intensity than occur on conventional Fourdrinier wire formers are now permissible. The wall can be stationary or in motion. A stationary wall can, for example, be allocated to the headbox on which it can be installed adjustably. The wall can in addition, be permeable to water or impermeable to water. A movable wall or a wall in motion can be in the embodiment of an additional dewatering belt, that can specifically be in the form of a revolving wire. In the coverage area the wall can possess an at least partially curved progression and/or an at least partially straight progression. Moreover, in a practical embodiment the lower wall has a maximum length of 90%, preferably of 60%, especially of 30% of the length of the upper wall. In a preferred practical embodiment of the former in accordance with the present invention, at least some of the channels are equipped with the turbulence generating inserts. Such turbulence generating inserts can basically be provided in the channels of a respective turbulence block and/or in the channels of a respective tube generator. In hitherto conventional suction formers or in twin wire formers eddies occur in pairs in opposite rotational directions, that can lead to stripes. These are known as the so-called “Taylor-Görtler-Eddies” in Central Europe. The stripes occur especially in curved dewatering surfaces. The present invention provides an improved former, particularly a suction former or twin wire former for a machine for the production of a fibrous web, specifically a paper or cardboard web, in which the previously cited problems are eliminated. In accordance with an additional aspect of the present invention a former, specifically a suction former or twin wire former of a machine for the production of a fibrous web, specifically a paper or cardboard web is provided or this purpose; comprising a headbox that is equipped with at least one stock suspension feed, one turbulence block equipped with several channels and/or a tube generator equipped with several channels and a headbox nozzle. Turbulence generating elements are allocated to at least a section of the channels in order to create turbulent flows that rotate in the same direction in the suspension substreams in the channels. Same directional turbulence movement suppresses the undesirable stripes. In a functional practical embodiment of the present invention helix type spirals are installed in at least a section of the channels in order to create turbulent flows that rotate in the same direction. Such helix type spirals can, for example, be installed in the channels of a turbulence block and/or in the channels of tube generator. The creation of turbulences through the means of helix type spirals can for example occur as described in U.S. Pat. No. 5,876,464. Alternatively, or in addition, turbulent flows that are rotating in the same direction can be created particularly by the fact that, in a headbox comprising a tube generator, the supply of stock suspension through nozzles into a respective tube channel occurs asymmetrically and preferably at least essentially tangentially to the tube wall, relative to a center plane progressing in longitudinal direction through the tube channel. Advantageously, the stock suspension is fed through nozzles only on one side of the center plane respectively. Preferably, suspension supplied to the relevant pipe channels is fed into the various pipe channels through nozzles always on the same side of the respective center planes. In contrast to Fourdrinier wires, the previously discussed, deliberately produced turbulences are kept very small in the sheet formation zone in other types of formers, particularly in suction and twin wire formers, since the surface of the suspension is “covered”, resulting in improved sheet formation, even at an increased stock consistency. In addition the headbox can be equipped with at least one feed for dilution water, air, chemicals and/or similar substances. The supply of dilution water, air, chemicals and/or similar substances may essentially occur in axial direction of a respective channel. In accordance with an advantageous embodiment of the present invention, the wall can be located in an area opposite the forming roll and can be at least partially curved according to a radius of curvature that is preferably larger than or equal to the radius of the forming roll. Basically however, a smaller radius is also feasible, at least in sections. The wall can for example be stationary. Thereby it would preferably cover the circumferential surface of the forming roll, that is in a range of approximately 100 to approximately 400 mm. The stationary wall can particularly be rigid, deflection resistant or not deflection resistant. In accordance with an additional advantageous design of the present invention whereby the wall is again provided in an area opposite the forming roll and is curved, at least partially, according to a curvature radius that is preferably larger than or equal to the radius of the forming roll, the wall can be movable or in motion and can be formed by an additional dewatering belt, particularly a revolving wire. In this instance, the wall preferably covers a circumferential area of this forming roll that is in the range of approximately 100 mm to approximately 1500 mm and/or corresponds with a circumferential angle of the forming roll of approximately 25° to approximately 120°. The additional dewatering belt that forms the wall can be routed around a breast roll, prior to the area covering the forming roll, when viewed in the direction of belt travel. The curvature radius of the wall in the area covering the forming roll is preferably larger than the radius of the breast roll, or respectively the corresponding curvature radius of the wall in the area of this breast roll. The headbox nozzle can be sectioned by at least one lamellar plate. A configuration without lamellar plates is also feasible. In a functional advantageous design at least one lamellar plate and/or at least one nozzle wall exhibit contours, especially swirl-producing washboard contours. Alternatively, or in addition, at least one lamellar plate and/or at least one nozzle wall can have contours that serve to generate turbulent motion. At least one lamellar plate and/or at least one nozzle wall can for example be equipped with at least one interference body. Preferably the at least one interference body of the at least one nozzle wall is in the form of preferably a discontinuous tapering of the cross section. This formation provides a fluidic ideal turbulence chamber. In addition, at least one lamellar plate has a length not exceeding 70% of the length of the headbox nozzle. In order to attain a sufficient effect, the headbox nozzle should be as short as possible. The headbox nozzle should preferably be shorter than approximately 400 mm. It is also advantageous if the outlet cross section of the channels or pipes is at least essentially round, since a square outlet cross section would dampen the effect. In accordance with the present invention a headox is furthermore disclosed especially for a former of the relevant type previously described. Such a headbox includes at least one stock suspension feed, one turbulence block equipped with several channels and/or a tube generator equipped with several channels and a headbox nozzle. Turbulence generating elements are allocated to at least a section of the channels in order to create turbulent flows that rotate in the same direction in the suspension sub-streams in the channels. In accordance with an additional aspect of the present invention a headbox, particularly for a former of the type previously described is provided, including at least one stock suspension feed, one turbulence block equipped with several channels and/or a tube generator equipped with several channels and a headbox nozzle. Turbulence generating elements are allocated to at least a section of the channels in order to create turbulent flows, rotating in the same direction, in the suspension sub-streams in the channels. |
Gmg-3 gmg-4 and gmg-6 polynucleotides and polypeptides and uses thereof |
The present invention relates to the field of metabolic research. Metabolic disorders, such as obesity, are a public health problem that is serious and widespread. GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptides have been identified that are beneficial in the treatment of metabolic disorders. These compounds should be effective for reducing body mass and for treating metabolic-related diseases and disorders. These metabolic-related diseases and disorders include hyperlipidemias, atherosclerosis, diabetes, and hypertension. |
1-11. (canceled) 12. A method of treating or preventing a metabolic-related disease or disorder comprising the step of administering to an individual a composition comprising a polypeptide or biologically active fragment thereof, wherein said polypeptide or fragment thereof comprises all or part of a C-terminal globular C1q homology domain and wherein said polypeptide is selected from the group consisting of: (a) SEQ ID NO: 2; and (b) SEQ ID NO: 4. 13. The method of claim 12, wherein said metabolic-related disease or disorder is selected from the group consisting of: (a) obesity; (b) impaired glucose tolerance; (c) insulin resistance; (d) Syndrome X; and (e) Type II diabetes. 14. The method of claim 12, wherein said polypeptide fragment is selected from the group consisting of: (a) amino acids 20-333 of SEQ ID NO: 2; (b) amino acids 188-333 of SEQ ID NO: 2; (c) amino acids 191-333 of SEQ ID NO: 2; (d) amino acids 193-333 of SEQ ID NO: 2; (e) amino acids 252-317 of SEQ ID NO: 2; (f) amino acids 20-333 of SEQ ID NO: 4; (g) amino acids 188-333 of SEQ ID NO: 4; (h) amino acids 191-333 of SEQ ID NO: 4; (i) amino acids 193-333 of SEQ ID NO: 4; and (O) amino acids 252-317 of SEQ ID NO: 4. 15. The method of claim 13, wherein said polypeptide fragment is selected from the group consisting of: (a) amino acids 20-333 of SEQ ID NO: 2; (b) amino acids 188-333 of SEQ ID NO: 2; (c) amino acids 191-333 of SEQ ID NO: 2; (d) amino acids 193-333 of SEQ ID NO: 2; (e) amino acids 252-317 of SEQ ID NO: 2; (f) amino acids 20-333 of SEQ ID NO: 4; (g) amino acids 188-333 of SEQ ID NO: 4; (h) amino acids 191-333 of SEQ ID NO: 4; (i) amino acids 193-333 of SEQ ID NO: 4; and (j) amino acids 252-317 of SEQ ID NO: 4. 16. An isolated polypeptide fragment selected from the group consisting of: (a) amino acids 20-333 of SEQ ID NO: 2; (b) amino acids 188-333 of SEQ ID NO: 2; (c) amino acids 191-333 of SEQ ID NO: 2; (d) amino acids 193-333 of SEQ ID NO: 2; (e) amino acids 252-317 of SEQ ID NO: 2; (f) amino acids 20-333 of SEQ ID NO: 4; (g) amino acids 188-333 of SEQ ID NO: 4; (h) amino acids 191-333 of SEQ ID NO: 4; (i) amino acids 193-333 of SEQ ID NO: 4; (j) amino acids 252-317 of SEQ ID NO:4; (k) amino acids 20-330 of SEQ ID NO: 8; (l) amino acids 185-330 of SEQ ID NO: 8; (m) amino acids 188-330 of SEQ ID NO: 8; (n) amino acids 190-330 of SEQ ID NO: 8; (o) amino acids 249-314 of SEQ ID NO: 8; (p) amino acids 20-323 of SEQ ID NO: 10; (q) amino acids 178-323 of SEQ ID NO: 10; (r) amino acids 181-323 of SEQ ID NO: 10; (s) amino acids 183-323 of SEQ ID NO: 10; and (t) amino acids 242-307 of SEQ ID NO: 10. 17. A composition comprising a carrier and one or more of the polypeptide fragments of claim 16. 18. An isolated polynucleotide, or complement thereof, encoding any one of the polypeptide fragments of claim 16. 19. The polynucleotide of claim 18 selected from the group consisting of: (a) DNA; (b) RNA; (c) DNA/RNA hybrid; (d) single-stranded; and (e) double-stranded. 20. A composition comprising a carrier and an isolated polynucleotide of claim 19. 21. A vector comprising an isolated polynucleotide of claim 19. 22. A composition comprising a carrier and a vector of claim 21. 23. A transformed host cell comprising a vector of claim 21. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The following discussion is intended to facilitate the understanding of the invention, but is not intended nor admitted to be prior art to the invention. Obesity is a public health problem that is serious, widespread, and increasing. In the United States, 20 percent of the population is obese; in Europe, a slightly lower percentage is obese (Friedman (2000) Nature 404:632-634). Obesity is associated with increased risk of hypertension, cardiovascular disease, diabetes, and cancer as well as respiratory complications and osteoarthritis (Kopelman (2000) Nature 404:635-643). Even modest weight loss ameliorates these associated conditions. While still acknowledging that lifestyle factors including environment, diet, age and exercise play a role in obesity, twin studies, analyses of familial aggregation, and adoption studies all indicate that obesity is largely the result of genetic factors (Barsh et al (2000) Nature 404:644-651). In agreement with these studies, is the fact that an increasing number of metabolic-related genes are being identified. Some of the more extensively studied genes include those encoding leptin (ob) and its receptor (db), pro-opiomelanocortin (Pomc), melanocortin-4-receptor (Mc4r), agouti protein (A y ), carboxypeptidase E (fat), 5-hydroxytryptamine receptor 2C (Htr2c), nescient basic helix-loop-helix 2 (Nhlh2), prohormone convertase 1 (PCSK1), and tubby protein (tubby) (rev'd in Barsh et al (2000) Nature 404:644-651). |
<SOH> SUMMARY OF THE INVENTION <EOH>The instant invention is based on Genset Metabolic Genes-3, 4, and 6 (GMG-3), (GMG-4), and (GMG-6). GMG-3 and GMG-4 are of human origin. Cluster 1 full-length polypeptide can be considered to be a C-terminal fragment of GMG-4 full-length polypeptide. GMG-6 is the mouse orthologue of GMG-3 and GMG-4. GMG-6A and GMG-6B correspond to splice variants of GMG-6. GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B full-length polypeptides are similar at the amino acid level to APM1, a human protein that has been implicated in obesity and diabetes and which structurally resembles TNFα. GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B full-length polypeptides are comprised of a C-terminal globular C1q homology domain preceded by a collagen-like region. By analogy to TNFα, globular head polypeptide fragments of GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B comprising TVFSRNVQVSLV or the extended loop QVTGGERFNGLFAD contact receptor and to have agonist activity. Results from Northern blot analysis and RT-PCR indicates expression of GMG-3 and/or GMG-4 in liver, heart, and skeletal muscle, but not in adipose tissue or brain. The invention includes polypeptides encoded by GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B, which include both the full-length polypeptide and fragments thereof, preferably said polypeptide fragments comprising all or part of the C-terminal globular C1q homology domain. The GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polypeptide fragments containing all or part of the C-terminal globular C1q homology domain have in vitro and in vivo biological activity as described herein, including utility for weight reduction, prevention of weight gain and control of blood glucose levels in humans and other mammals. More specifically, the biological activities of the GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polypeptides, including fragments, include reduction of elevated free fatty acid levels caused by administration of epinephrine, i.v. injection of “intralipid”, or administration of a high fat test meal, as well as increased fatty acid oxidation in muscle cells, reduction in glucose levels, modulation of energy expenditure, resistance to insulin and weight reduction in mammals consuming a high fat/high sucrose diet. Thus, the invention is drawn to GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polypeptides, polynucleotides encoding said GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polypeptides, methods of using GMG-6 genomic sequence, vectors comprising said GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polynucleotides, and cells recombinant for said GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polynucleotides, as well as to pharmaceutical and physiologically acceptable compositions comprising said GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polypeptides and methods of administering said GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B pharmaceutical and physiologically acceptable compositions in order to reduce body weight or to treat metabolic-related diseases and disorders. Assays for identifying agonists and antagonists of metabolic-related activity are also part of the invention. In a first aspect, the invention features purified, isolated, or recombinant GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polypeptides that have lipid partitioning, lipid metabolism, and insulin-like activities. Preferred GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polypeptide fragments are said polypeptide fragments having activity, wherein said activity is also selected from the group consisting of lipid partitioning, lipid metabolism, and insulin-like activity. In preferred embodiments, said polypeptide fragment comprises, consists essentially of, or consists of, at least 6 consecutive amino acids and not more than 333 consecutive amino acids of SEQ ID NO: 2 or 4, preferably wherein said polypeptide fragment is comprised of one or more of amino acids 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 245, 247, 248, 249, 250, 251, 252, or 253, and more preferably wherein said polypeptide fragment is comprised of the sequence TVFSRNVQVSLV (amino acids 256-267 of SEQ ID NO: 2 or 4) or QVTGGERFNGLFAD (amino acids 304-317 of SEQ ID NO: 2 or 4); or at least 6 and not more than 225 consecutive amino acids of SEQ ID NO: 6, preferably wherein said polypeptide fragment is comprised of one or more of amino acids 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, or 145, and more preferably wherein said polypeptide fragment is comprised of the sequence TVFSRNVQVSLV (amino acids 148-159 of SEQ ID NO: 6) or QVTGGERFNGLFAD (amino acids 196-209 of SEQ ID NO: 6); at least 6 consecutive amino acids and not more than 330 consecutive amino acids of SEQ ID NO: 8, preferably wherein said polypeptide fragment is comprised of one or more of amino acids 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, or 250, and more preferably wherein said polypeptide fragment is comprised of the sequence TVFSRNVQVSLV (amino acids 253-264 of SEQ ID NO: 8) or QVTGGERFNGLFAD (amino acids 301-314 of SEQ ID NO: 8); or at least 6 and not more than 323 consecutive amino acids of SEQ ID NO: 10, preferably wherein said polypeptide fragment is comprised of one or more of amino acids 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, or 243, and more preferably wherein said polypeptide fragment is comprised of the sequence TVFSRNVQVSLV (amino acids 246-257 of SEQ ID NO: 10) or QVTGGERFNGLFAD (amino acids 294-307 of SEQ ID NO: 10). In other preferred embodiments, GMG-3 or GMG-4 polypeptide fragments having activity are selected from amino acids 20-333, 43-333, 44-333, 45-333, 46-333, 47-333, 48-333, 49-333, 50-333, 51-333, 52-333, 53-333, 54-333, 55-333, 56-333, 57-333, 58-333, 59-333, 60-333, 61-333, 62-333, 63-333, 64-333, 65-333, 66-333, 67-333, 68-333, 69-333, 70-333, 71-333, 72-333, 73-333, 74-333, 75-333, 76-333, 77-333, 78-333, 79-333, 80-333, 81-333, 82-333, 83-333, 84-333, 85-333, 86-333, 87-333, 88-333, 89-333, 90-333, 91-333, 92-333, 93-333, 94-333, 95-333, 96-333, 97-333, 98-333, 99-333, 100-333, 101-333, 102-333, 103-333, 104-333, 105-333, 106-333, 107-333, 108-333, 109-333, 110-333, 111-333, 112-333, 113-333, 114-333, 115-333, 116-333, 117-333, 118-333, 119-333, 120-333, 121-333, 122-333, 123-333, 124-333, 125-333, 126-333, 127-333, 128-333, 129-333, 130-333, 131-333, 132-333, 133-333, 134-333, 135-333, 136-333, 137-333, 138-333, 139-333, 140-333, 141-333, 142-333, 143-333, 144-333, 145-333, 146-333, 147-333, 148-333, 149-333, 150-333, 151-333, 152-333, 153-333, 154-333, 155-333, 156-333, 157-333, 158-333, 159-333, 160-333, 161-333, 162-333, 163-333, 164-333, 165-333, 166-333, 167-333, 168-333, 169-333, 170-333, 171-333, 172-333, 173-333, 174-333, 175-333, 176-333, 177-333, 178-333, 179-333, 180-333, 181-333, 182-333, 183-333, 184-333, 185-333, 186-333, 187-333, 188-333, 189-333, 190-333, 191-333, 192-333, 193-333, 194-333, 195-333, 196-333, 197-333, 198-333, 199-333, 200-333, 201-333 or 202-333 of SEQ ID NO: 2 or 4. In other preferred embodiments, Cluster 1 polypeptide fragments having activity are selected from amino acids 1-225, 2-225, 3-225, 4-225, 5-225, 6-225, 7-225, 8-225, 9-225, 10-225, 11-225, 12-225, 13-225, 14-225, 15-225, 16-225, 17-225, 18-225, 19-225, 20-225, 21-225, 22-225, 23-225, 24-225, 25-225, 26-225, 27-225, 28-225, 29-225, 30-225, 31-225, 32-225, 33-225, 34-225, 35-225, 36-225, 37-225, 38-225, 39-225, 40-225, 41-225, 42-225, 43-225, 44-225, 45-225, 46-225, 47-225, 48-225, 49-225, 50-225, 51-225, 52-225, 53-225, 54-225, 55-225, 56-225, 57-225, 58-225, 59-225, 60-225, 61-225, 62-225, 63-225, 64-225, 65-225, 66-225, 67-225, 68-225, 69-225, 70-225, 71-225, 72-225, 73-225, 74-225, 75-225, 76-225, 77-225, 78-225, 79-225, 80-225, 81-225, 82-225, 83-225, 84-225, 85-225, 86-225, 87-225, 88-225, 89-225, 90-225, 91-225, 92-225, 93-225 or 94-225 of SEQ ID NO: 6. In other preferred embodiments, GMG-6A polypeptide fragments having activity are selected from 20-330, 43-330, 44-330, 45-330, 46-330, 47-330, 48-330, 49-330, 50-330, 51-330, 52-330, 53-330, 54-330, 55-330, 56-330, 57-330, 58-330, 59-330, 60-330, 61-330, 62-330, 63-330, 64-330, 65-330, 66-330, 67-330, 68-330, 69-330, 70-330, 71-330, 72-330, 73-330, 74-330, 75-330, 76-330, 77-330, 78-330, 79-330, 80-330, 81-330, 82-330, 83-330, 84-330, 85-330, 86-330, 87-330, 88-330, 89-330, 90-330, 91-330, 92-330, 93-330, 94-330, 95-330, 96-330, 97-330, 98-330, 99-330, 100-330, 101-330, 102-330, 103-330, 104-330, 105-330, 106-330, 107-330, 108-330, 109-330, 110-330, 111-330, 112-330, 113-330, 114-330, 115-330, 116-330, 117-330, 118-330, 119-330, 120-330, 121-330, 122-330, 123-330, 124-330, 125-330, 126-330, 127-330, 128-330, 129-330, 130-330, 131-330, 132-330, 133-330, 134-330, 135-330, 136-330, 137-330, 138-330, 139-330, 140-330, 141-330, 142-330, 143-330, 144-330, 145-330, 146-330, 147-330, 148-330, 149-330, 150-330, 151-330, 152-330, 153-330, 154-330, 155-330, 156-330, 157-330, 158-330, 159-330, 160-330, 161-330, 162-330, 163-330, 164-330, 165-330, 166-330, 167-330, 168-330, 169-330, 170-330, 171-330, 172-330, 173-330, 174-330, 175-330, 176-330, 177-330, 178-330, 179-330, 180-330, 181-330, 182-330, 183-330, 184-330, 185-330, 186-330, 187-330, 188-330, 189-330, 190-330, 191-330, 192-330, 193-330, 194-330, 195-330, 196-330, 197-330, 198-330 or 199-330 of SEQ ID NO; 8. In other preferred embodiments, GMG-6B polypeptide fragments having activity are selected from 20-323, 43-323, 44-323, 45-323, 46-323, 47-323, 48-323, 49-323, 50-323, 51-323, 52-323, 53-323, 54-323, 55-323, 56-323, 57-323, 58-323, 59-323, 60-323, 61-323, 62-323, 63-323, 64-323, 65-323, 66-323, 67-323, 68-323, 69-323, 70-323, 71-323, 72-323, 73-323, 74-323, 75-323, 76-323, 77-323, 78-323, 79-323, 80-323, 81-323, 82-323, 83-323, 84-323, 85-323, 86-323, 87-323, 88-323, 89-323, 90-323, 91-323, 92-323, 93-323, 94-323, 95-323, 96-323, 97-323, 98-323, 99-323, 100-323, 101-323, 102-323, 103-323, 104-323, 105-323, 106-323, 107-323, 108-323, 109-323, 110-323, 111-323, 112-323, 113-323, 114-323, 115-323, 116-323, 117-323, 118-323, 119-323, 120-323, 121-323, 122-323, 123-323, 124-323, 125-323, 126-323, 127-323, 128-323, 129-323, 130-323, 131-323, 132-323, 133-323, 134-323, 135-323, 136-323, 137-323, 138-323, 139-323, 140-323, 141-323, 142-323, 143-323, 144-323, 145-323, 146-323, 147-323, 148-323, 149-323, 150-323, 151-323, 152-323, 153-323, 154-323, 155-323, 156-323, 157-323, 158-323, 159-323, 160-323, 161-323, 162-323, 163-323, 164-323, 165-323, 166-323, 167-323, 168-323, 169-323, 170-323, 171-323, 172-323, 173-323, 174-323, 175-323, 176-323, 177-323, 178-323, 179-323, 180-323, 181-323, 182-323, 183-323, 184-323, 185-323, 186-323, 187-323, 188-323, 189-323, 190-323, 191-323 or 192-323 of SEQ ID NO: 10. In more preferred embodiments, GMG-3 or GMG-4 polypeptide fragments having activity are selected from amino acids 20-333, 43-333, 45-333, 46-333, 50-333, 53-333, 61-333, 67-333, 74-333, 75-333, 77-333, 81-333, 82-333, 86-333, 89-333, 95-333, 100-333, 104-333, 109-333, 113-333, 116-333, 125-333, 128-333, 140-333, 160-333, 164-333, 179-333, 182-333, 185-333, 188-333, 191-333, 193-333, 201-333, 202-333, 227-333, 252-333, 252-267, 252-317, 256-267, 256-317, or 304-317 of SEQ ID NO: 2 or 4. In other more preferred embodiments, Cluster 1 polypeptide fragments having activity are selected from amino acids 1-225, 5-225, 8-225, 17-225, 20-225, 32-225, 52-225, 56-225, 71-225, 74-225, 77-225, 80-225, 83-225, 85-225, 93-225, 94-225, 119-225, 144-225, 144-159, 144-209, 148-159, 148-209, or 196-209 of SEQ ID NO: 6. In other more preferred embodiments, GMG-6A polypeptide fragments having activity are selected from amino acids 20-330, 43-330, 45-330, 46-330, 50-333, 53-330, 64-330, 68-330, 71-330, 72-330, 75-330, 78-330, 79-330, 83-330, 86-330, 92-330, 97-330, 101-330, 122-330, 125-330, 146-330, 157-330, 161-330, 176-330, 179-330, 182-330, 185-330, 188-330, 190-330, 198-330, 199-330, 224-330, 249-330, 249-264,249-314, 253-264, 253-314 or 301-314 of SEQ ID NO: 8. In other more preferred embodiments, GMG-6B polypeptide fragments having activity are selected from amino acids 20-323, 43-323, 46-323, 57-323, 61-323, 64-323, 65-323, 68-323, 71-323, 72-323, 76-323, 79-323, 85-323, 90-323, 94-323, 115-323, 118-323, 139-323, 150-323, 154-323, 169-323, 172-323, 175-323, 178-323, 181-323, 183-323, 191-323, 192-323, 217-323, 242-323, 242-257, 242-307, 246-257, 246-307, or 294-307 of SEQ ID NO: 10. In yet more preferred embodiments, GMG-3 or GMG-4 polypeptide fragments having activity are selected from amino acids 20-333, 109-333, 125-333, 128-333, 140-333, 160-333, 164-333, 179-333, 182-333, 185-333, 188-333, 191-333, 193-333, 201-333, 202-333, 227-333, 252-333, 252-267, 252-317, 256-267, 256-317, or 304-317 of SEQ ID NO: 2 or 4. In other yet more preferred embodiments, Cluster 1 polypeptide fragments having activity are selected from amino acids 1-225, 17-225, 20-225, 32-225, 52-225, 56-225, 71-225, 74-225, 77-225, 80-225, 83-225, 85-225, 93-225, 94-225, 119-225, 144-225, 144-159, 144-209, 148-159, 148-209, or 196-209 of SEQ ID NO: 6. In other yet more preferred embodiments, GMG-6A polypeptide fragments having activity are selected from amino acids 20-330, 75-330, 122-330, 125-330, 146-330, 157-330, 161-330, 176-330, 179-330, 182-330, 185-330, 188-330, 190-330, 198-330, 199-330, 224-330, 249-330, 249-264, 249-314, 253-264, 253-314 or 301-314 of SEQ ID NO: 8. In other yet more preferred embodiments, GMG-6B polypeptide fragments having activity are selected from amino acids 20-323, 68-323, 115-323, 118-323, 139-323, 150-323, 154-323, 169-323, 172-323, 175-323, 178-323, 181-323, 183-323, 191-323, 192-323, 217-323, 242-323, 242-257, 242-307, 246-257, 246-307, or 294-307 of SEQ ID NO: 10. In further preferred embodiments, said polypeptide fragment comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the corresponding consecutive amino acids of the polypeptide sequences identified in SEQ ID NO: 2, 4, 6, 8, or 10. The invention further provides a purified or isolated polypeptide comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of: (a) a full-length at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the corresponding amino acids polypeptide of SEQ ID NOs: 2, 4, 6, 8, or 10; (b) a full-length GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptide of SEQ ID NOs: 2, 4, 6, 8, or 10 absent the N-terminal Met; (c) a mature GMG-3, GMG-4, GMG-6A, or GMG-6B polypeptide of SEQ ID NOs: 2, 4, 8, or 10 lacking signal peptide; (d) a GMG-3 or GMG-4 polypeptide of SEQ ID NO: 2 or 4 wherein said GMG-3 or GMG-4 polypeptide is of any one integer in length between 6 amino acids and 333 amino acids (full-length) inclusive of SEQ ID NO: 2 or 4, a Cluster 1 polypeptide of SEQ ID NO: 6 wherein said Cluster 1 polypeptide is of any one integer in length between 6 amino acids and 225 amino acids (full-length) inclusive of SEQ ID NO: 6, a GMG-6A polypeptide of SEQ ID NO: 8 wherein said GMG-6A polypeptide is of any one integer in length between 6 amino acids and 330 amino acids (full-length) inclusive of SEQ ID NO: 8, or a GMG-6B polypeptide of SEQ ID NO: 10 wherein said GMG-6B polypeptide is of any one integer in length between 6 amino acids and 323 amino acids (full-length) inclusive of SEQ ID NO: 10; (e) the epitope-bearing fragments of a GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptide of SEQ ID NO: 2, 4, 6, 8, or 10; (f) a fragment of a GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptide of SEQ ID NOs: 2, 4, 6, 8, or 10 comprising the globular head sequence TVFSRNVQVSLV and having agonist activity, wherein said activity is selected from the group consisting of lipid partitioning, lipid metabolism, and insulin-like activity; (g) a fragment of a GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptide of SEQ ID NOs: 2, 4, 6, 8, or 10 comprising the globular head sequence QVTGGERFNGLFAD and having agonist activity, wherein said activity is selected from the group consisting of lipid partitioning, lipid metabolism, and insulin-like activity; (h) the allelic variant polypeptides of any of the polypeptides of (a)-(g). The invention further provides for fragments of the polypeptides of (a)-(h) above, such as those having biological activity or comprising biologically functional domain(s). In other highly preferred embodiments, GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptides comprise, consist essentially of, or consist of, a purified, isolated, or a recombinant GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B fragment comprised of all or part of the C-terminal globular C1q homology domain. Preferably, said GMG-3 or GMG-4 polypeptide fragment comprises, consists essentially of, or consists of, at least 6 consecutive amino acids of amino acids 20-333 of SEQ ID NO: 2 or 4. Preferably, said Cluster 1 polypeptide fragment comprises, consists essentially of, or consists of, at least 6 consecutive amino acids of amino acids 1-225 of SEQ ID NO: 6. Preferably, said GMG-6A polypeptide fragment comprises, consists essentially of, or consists of, at least 6 consecutive amino acids of amino acids 20-330 of SEQ ID NO: 8. Preferably, said GMG-6B polypeptide fragment comprises, consists essentially of, or consists of, at least 6 consecutive amino acids of amino acids 20-323 of SEQ ID NO: 10. In other preferred embodiments, said GMG-3 or GMG-4 polypeptide fragments having activity are selected from amino acids 20-333, 43-333, 44-333, 45-333, 46-333, 47-333, 48-333, 49-333, 50-333, 51-333, 52-333, 53-333, 54-333, 55-333, 56-333, 57-333, 58-333, 59-333, 60-333, 61-333, 62-333, 63-333, 64-333, 65-333, 66-333, 67-333, 68-333, 69-333, 70-333, 71-333, 72-333, 73-333, 74-333, 75-333, 76-333, 77-333, 78-333, 79-333, 80-333, 81-333, 82-333, 83-333, 84-333, 85-333, 86-333, 87-333, 88-333, 89-333, 90-333, 91-333, 92-333, 93-333, 94-333, 95-333, 96-333, 97-333, 98-333, 99-333, 100-333, 101-333, 102-333, 103-333, 104-333, 105-333, 106-333, 107-333, 108-333, 109-333, 110-333, 111-333, 112-333, 113-333, 114-333, 115-333, 116-333, 117-333, 118-333, 119-333, 120-333, 121-333, 122-333, 123-333, 124-333, 125-333, 126-333, 127-333, 128-333, 129-333, 130-333, 131-333, 132-333, 133-333, 134-333, 135-333, 136-333, 137-333, 138-333, 139-333, 140-333, 141-333, 142-333, 143-333, 144-333, 145-333, 146-333, 147-333, 148-333, 149-333, 150-333, 151-333, 152-333, 153-333, 154-333, 155-333, 156-333, 157-333, 158-333, 159-333, 160-333, 161-333, 162-333, 163-333, 164-333, 165-333, 166-333, 167-333, 168-333, 169-333, 170-333, 171-333, 172-333, 173-333, 174-333, 175-333, 176-333, 177-333, 178-333, 179-333, 180-333, 181-333, 182-333, 183-333, 184-333, 185-333, 186-333, 187-333, 188-333, 189-333, 190-333, 191-333, 192-333, 193-333, 194-333, 195-333, 196-333, 197-333, 198-333, 199-333, 200-333, 201-333 or 202-333 of SEQ ID NO: 2 or 4. In other preferred embodiments, said Cluster 1 polypeptide fragments having activity are selected from amino acids 1-225, 2-225, 3-225, 4-225, 5-225, 6-225, 7-225, 8-225, 9-225, 10-225, 11-225, 12-225, 13-225, 14-225, 15-225, 16-225, 17-225, 18-225, 19-225, 20-225, 21-225, 22-225, 23-225, 24-225, 25-225, 26-225, 27-225, 28-225, 29-225, 30-225, 31-225, 32-225, 33-225, 34-225, 35-225, 36-225, 37-225, 38-225, 39-225, 40-225, 41-225, 42-225, 43-225, 44-225, 45-225, 46-225, 47-225, 48-225, 49-225, 50-225, 51-225, 52-225, 53-225, 54-225, 55-225, 56-225, 57-225, 58-225, 59-225, 60-225, 61-225, 62-225, 63-225, 64-225, 65-225, 66-225, 67-225, 68-225, 69-225, 70-225, 71-225, 72-225, 73-225, 74-225, 75-225, 76-225, 77-225, 78-225, 79-225, 80-225, 81-225, 82-225, 83-225, 84-225, 85-225, 86-225, 87-225, 88-225, 89-225, 90-225, 91-225, 92-225, 93-225 or 94-225 of SEQ ID NO: 6. In other preferred embodiments, said GMG-6A polypeptide fragments having activity are selected from amino acids 20-330, 43-330, 44-330, 45-330, 46-330, 47-330, 48-330, 49-330, 50-330, 51-330, 52-330, 53-330, 54-330, 55-330, 56-330, 57-330, 58-330, 59-330, 60-330, 61-330, 62-330, 63-330, 64-330, 65-330, 66-330, 67-330, 68-330, 69-330, 70-330, 71-330, 72-330, 73-330, 74-330, 75-330, 76-330, 77-330, 78-330, 79-330, 80-330, 81-330, 82-330, 83-330, 84-330, 85-330, 86-330, 87-330, 88-330, 89-330, 90-330, 91-330, 92-330, 93-330, 94-330, 95-330, 96-330, 97-330, 98-330, 99-330, 100-330, 101-330, 102-330, 103-330, 104-330, 105-330, 106-330, 107-330, 108-330, 109-330, 110-330, 111-330, 112-330, 113-330, 114-330, 115-330, 116-330, 117-330, 118-330, 119-330, 120-330, 121-330, 122-330, 123-330, 124-330, 125-330, 126-330, 127-330, 128-330, 129-330, 130-330, 131-330, 132-330, 133-330, 134-330, 135-330, 136-330, 137-330, 138-330, 139-330, 140-330, 141-330, 142-330, 143-330, 144-330, 145-330, 146-330, 147-330, 148-330, 149-330, 150-330, 151-330, 152-330, 153-330, 154-330, 155-330, 156-330, 157-330, 158-330, 159-330, 160-330, 161-330, 162-330, 163-330, 164-330, 165-330, 166-330, 167-330, 168-330, 169-330, 170-330, 171-330, 172-330, 173-330, 174-330, 175-330, 176-330, 177-330, 178-330, 179-330, 180-330, 181-330, 182-330, 183-330, 184-330, 185-330, 186-330, 187-330, 188-330, 189-330, 190-330, 191-330, 192-330, 193-330, 194-330, 195-330, 196-330, 197-330, 198-330 or 199-330 of SEQ ID NO: 8. In other preferred embodiments, said GMG-6B polypeptide fragments having activity are selected from amino acids 20-323, 43-323, 44-323, 45-323, 46-323, 47-323, 48-323, 49-323, 50-323, 51-323, 52-323, 53-323, 54-323, 55-323, 56-323, 57-323, 58-323, 59-323, 60-323, 61-323, 62-323, 63-323, 64-323, 65-323, 66-323, 67-323, 68-323, 69-323, 70-323, 71-323, 72-323, 73-323, 74-323, 75-323, 76-323, 77-323, 78-323, 79-323, 80-323, 81-323, 82-323, 83-323, 84-323, 85-323, 86-323, 87-323, 88-323, 89-323, 90-323, 91-323, 92-323, 93-323, 94-323, 95-323, 96-323, 97-323, 98-323, 99-323, 100-323, 101-323, 102-323, 103-323, 104-323, 105-323, 106-323, 107-323, 108-323, 109-323, 110-323, 111-323, 112-323, 113-323, 114-323, 115-323, 116-323, 117-323, 118-323, 119-323, 120-323, 121-323, 122-323, 123-323, 124-323, 125-323, 126-323, 127-323, 128-323, 129-323, 130-323, 131-323, 132-323, 133-323, 134-323, 135-323, 136-323, 137-323, 138-323, 139-323, 140-323, 141-323, 142-323, 143-323, 144-323, 145-323, 146-323, 147-323, 148-323, 149-323, 150-323, 151-323, 152-323, 153-323, 154-323, 155-323, 156-323, 157-323, 158-323, 159-323, 160-323, 161-323, 162-323, 163-323, 164-323, 165-323, 166-323, 167-323, 168-323, 169-323, 170-323, 171-323, 172-323, 173-323, 174-323, 175-323, 176-323, 177-323, 178-323, 179-323, 180-323, 181-323, 182-323, 183-323, 184-323, 185-323, 186-323, 187-323, 188-323, 189-323, 190-323, 191-323 or 192-323 of SEQ ID NO: 10. In more preferred embodiments, said GMG-3 or GMG-4 polypeptide fragments comprised of all or part of the C-terminal globular C1q homology domain and having activity are selected from amino acids 20-333, 43-333, 45-333, 46-333, 50-333, 53-333, 61-333, 67-333, 74-333, 75-333, 77-333, 81-333, 82-333, 86-333, 89-333, 95-333, 100-333, 104-333, 109-333, 113-333, 116-333, 125-333, 128-333, 140-333, 160-333, 164-333, 179-333, 182-333, 185-333, 188-333, 191-333, 193-333, 201-333, 202-333, 227-333, 252-333, 252-267, 252-317, 256-267, 256-317, or 304-317 of SEQ ID NO: 2 or 4. In other more preferred embodiments, said Cluster 1 polypeptide fragments having activity are selected from amino acids 1-225, 5-225, 8-225, 17-225, 20-225, 32-225, 52-225, 56-225, 71-225, 74-225, 77-225, 80-225, 83-225, 85-225, 93-225, 94-225, 119-225, 144-225, 144-159, 144-209, 148-159, 148-209, or 196-209 of SEQ ID NO: 6. In other more preferred embodiments, said GMG-6A polypeptide fragments having activity are selected from amino acids 20-330, 43-330, 45-330, 46-330, 50-333, 53-330, 64-330, 68-330, 71-330, 72-330, 75-330, 78-330, 79-330, 83-330, 86-330, 92-330, 97-330, 101-330, 122-330, 125-330, 146-330, 157-330, 161-330, 176-330, 179-330, 182-330, 185-330, 188-330, 190-330, 198-330, 199-330, 224-330, 249-330, 249-264, 249-314, 253-264, 253-314 or 301-314 of SEQ ID NO: 8. In other more preferred embodiments, said GMG-6B polypeptide fragments having activity are selected from amino acids 20-323, 43-323, 46-323, 57-323, 61-323, 64-323, 65-323, 68-323, 71-323, 72-323, 76-323, 79-323, 85-323, 90-323, 94-323, 115-323, 118-323, 139-323, 150-323, 154-323, 169-323, 172-323, 175-323, 178-323, 181-323, 183-323, 191-323, 192-323, 217-323, 242-323, 242-257, 242-307, 246-257, 246-307, or 294-307 of SEQ ID NO: 10. In yet more preferred embodiments, said GMG-3 or GMG-4 polypeptide fragments comprised of all or part of the C-terminal globular C1q homology domain and having activity are selected from amino acids 20-333, 109-333, 125-333, 128-333, 140-333, 160-333, 164-333, 179-333, 182-333, 185-333, 188-333, 191-333, 193-333, 201-333, 202-333, 227-333, 252-333, 252-267, 252-317, 256-267, 256-317, or 304-317 of SEQ ID NO: 2 or 4. In other yet more preferred embodiments, said Cluster 1 polypeptide fragments having activity are selected from amino acids 1-225, 17-225, 20-225, 32-225, 52-225, 56-225, 71-225, 74-225, 77-225, 80-225, 83-225, 85-225, 93-225, 94-225, 119-225, 144-225, 144-159, 144-209, 148-159, 148-209, or 196-209 of SEQ ID NO: 6. In other yet more preferred embodiments, said GMG-6A polypeptide fragments having activity are selected from amino acids 20-330, 75-330, 122-330, 125-330, 146-330, 157-330, 161-330, 176-330, 179-330, 182-330, 185-330, 188-330, 190-330, 198-330, 199-330, 224-330, 249-330, 249-264, 249-314, 253-264, 253-314 or 301-314 of SEQ ID NO: 8. In other yet more preferred embodiments, said GMG-6B polypeptide fragments having activity are selected from amino acids 20-323, 68-323, 115-323, 118-323, 139-323, 150-323, 154-323, 169-323, 172-323, 175-323, 178-323, 181-323, 183-323, 191-323, 192-323, 217-323, 242-323, 242-257, 242-307, 246-257, 246-307, or 294-307 of SEQ ID NO: 10. Alternatively, said GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptide fragment comprises, consists essentially of, or consists of, an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the corresponding amino acids 197-333 of SEQ ID NO: 2 or 4, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the corresponding amino acids 88-225 of SEQ ID NO: 6, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the corresponding amino acids 197-330 of SEQ ID NO: 8, or at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the corresponding amino acids 190-323 of SEQ ID NO: 10. In a further preferred embodiment, GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polypeptides are able to lower circulating (either in blood, serum or plasma) levels (concentration) of: (i) free fatty acids, (ii) glucose, and/or (iii) triglycerides. Further preferred polypeptides of the invention demonstrating free fatty acid level lowering activity, glucose level lowering activity, and/or triglyceride level lowering activity, have an activity that is the same or greater than full-length GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptides at the same molar concentration, have the same or greater than transient activity and/or have a sustained activity. Further preferred GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polypeptides are those that significantly stimulate muscle lipid or free fatty acid oxidation. Further preferred GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polypeptides are those that significantly stimulate muscle lipid or free fatty acid oxidation. Further preferred GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polypeptides are those that cause C2C 12 cells differentiated in the presence of said polypeptides to undergo at least 10%, 20%, 30%, 35%, or 40% more oleate oxidation as compared to untreated cells. Further preferred GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polypeptides are those that increase leptin uptake in a liver cell line (preferably BPRCL mouse liver cells (ATCC CRL-2217)). Further preferred GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polypeptides are those that significantly reduce the postprandial increase in plasma free fatty acids due to a high fat meal. Further preferred GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polypeptides are those that significantly reduce or eliminate ketone body production as the result of a high fat meal. Further preferred GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polypeptides are those that increase glucose uptake in skeletal muscle cells. Further preferred GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polypeptides are those that increase glucose uptake in adipose cells. Further preferred GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polypeptides are those that increase glucose uptake in neuronal cells. Further preferred GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polypeptides are those that increase glucose uptake in red blood cells. Further preferred GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polypeptides are those that increase glucose uptake in the brain. Further preferred GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polypeptides are those that significantly reduce the postprandial increase in plasma glucose following a meal, particularly a high carbohydrate meal. Further preferred GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polypeptides are those that significantly prevent the postprandial increase in plasma glucose following a meal, particularly a high fat or a high carbohydrate meal. Further preferred GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polypeptides are those that increase insulin sensitivity. Further preferred GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polypeptides are those that inhibit the progression from impaired glucose tolerance to insulin resistance. Further preferred GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polypeptides are those that form multimers (e.g., heteromultimers or homomultimers) in vitro and/or in vivo. Preferred multimers are homodimers or homotrimers. Other preferred multimers are homomultimers comprising at least 4, 6, 8, 9, 10 or 12 GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptide subunits. Other preferred mulimers are hetero multimers comprising a GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptide of the invention. Further preferred embodiments include heterologous polypeptides comprising one of the GMG 3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptides of the invention. In a second aspect, the invention features purified, isolated, or recombinant polynucleotides encoding said GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptides described in the first aspect, or the complement thereof. A further preferred embodiment of the invention is a recombinant, purified or isolated polynucleotide comprising, or consisting of a mammalian genomic sequence, gene, or fragments thereof. In one aspect the sequence is derived from a human, mouse or other mammal. In a preferred aspect, the genomic sequence includes isolated, purified, or recombinant polynucleotides comprising a contiguous span of at least 12, 15, 18, 20, 22, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 150, 200, 500, 1000, 2000, 5000, 10000 or 50000 nucleotides of any one of the polynucleotide sequences described in SEQ ID NOs: 1, 3, 5, 7, or 9, or the complements thereof, wherein said contiguous span comprises a nucleotide sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the corresponding nucleotide sequence of the C-terminal globular C1q homology domains of SEQ ID NOs: 1, 3, 5, 7, or 9. In further embodiments the polynucleotides are DNA, RNA, DNA/RNA hybrids, single-stranded, and double-stranded. In a third aspect, the invention features a recombinant vector comprising, consisting essentially of, or consisting of, said polynucleotide described in the second aspect. In a fourth aspect, the invention features a recombinant cell comprising, consisting essentially of, or consisting of, said recombinant vector described in the third aspect. A further embodiment includes a host cell recombinant for a polynucleotide of the invention. In a fifth aspect, the invention features a pharmaceutical or physiologically acceptable composition comprising, consisting essentially of, or consisting of, said GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptides described in the first aspect and, alternatively, a pharmaceutical or physiologically acceptable diluent. In a sixth aspect, the invention features a method of reducing body mass comprising providing or administering to individuals in need of reducing body mass said pharmaceutical or physiologically acceptable composition described in the fifth aspect. In preferred embodiments, the identification of said individuals in need of reducing body mass to be treated with said pharmaceutical or physiologically acceptable composition comprises genotyping GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B single nucleotide polymorphisms (SNPs) or measuring metabolic polypeptide or mRNA levels in clinical samples from said individuals. Preferably, said clinical samples are selected from the group consisting of plasma, urine, and saliva. Preferably, a GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptide fragment of the present invention is administered to an individual with at least a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in blood, serum or plasma levels of full-length any one or all of the GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptides or the naturally proteolytically cleaved GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B fragments as compared to healthy, non-obese patients. In a seventh aspect, the invention features a method of preventing or treating an metabolic-related disease or disorder comprising providing or administering to an individual in need of such treatment said pharmaceutical or physiologically acceptable composition described in the fifth aspect. In preferred embodiments, the identification of said individuals in need of such treatment to be treated with said pharmaceutical or physiologically acceptable composition comprises genotyping GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B single nucleotide polymorphisms (SNPs) or measuring GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptide or mRNA levels in clinical samples from said individuals. Preferably, said clinical samples are selected from the group consisting of blood, serum, plasma, urine, and saliva. Preferably, said metabolic-related disease or disorder is selected from the group consisting of obesity, impaired glucose tolerance, insulin resistance, atherosclerosis, atheromatous disease, heart disease, hypertension, stroke, Syndrome X, non-insulin-dependent diabetes and Type II diabetes. Type II diabetes-related complications to be treated by the methods of the invention include microangiopathic lesions, ocular lesions, and renal lesions. Heart disease includes, but is not limited to, cardiac insufficiency, coronary insufficiency, and high blood pressure. Other metabolic-related disorders to be treated by compounds of the invention include hyperlipidemia and hyperuricemia. Yet other metabolic-related diseases or disorders of the invention include cachexia, wasting, AIDS-related weight loss, cancer-related weight loss, anorexia, and bulimia. In preferred embodiments, said individual is a mammal, preferably a human. In related aspects, embodiments of the present invention includes methods of causing or inducing a desired biological response in an individual comprising the steps of: providing or administering to an individual a composition comprising a GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptide, wherein said biological response is selected from the group consisting of: (a) modulating circulating (either blood, serum, or plasma) levels (concentration) of free fatty acids, wherein said modulating is preferably lowering; (b) modulating circulating (either blood, serum or plasma) levels (concentration) of glucose, wherein said modulating is preferably lowering; (c) modulating circulating (either blood, serum or plasma) levels (concentration) of triglycerides, wherein said modulating is preferably lowering; (d) stimulating muscle lipid or free fatty acid oxidation; (c) modulating leptin uptake in the liver or liver cells, wherein said modulating is preferably increasing; (e) modulating the postprandial increase in plasma free fatty acids due to a high fat meal, wherein said modulating is preferably reducing; (f) modulating ketone body production as the result of a high fat meal, wherein said modulating is preferably reducing or eliminating; (g) increasing cell or tissue sensitivity to insulin, particularly muscle, adipose, liver or brain; and (h) inhibiting the progression from impaired glucose tolerance to insulin resistance; and further wherein said biological response is significantly greater than, or at least 10%, 20%, 30%, 35%, 40%, 50% 75% 100% or 500% greater than, the biological response caused or induced by insulin alone at the same molar concentration. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition can be used as a method to control blood glucose in some persons with Non-Insulin Dependent Diabetes Mellitus (NIDDM, Type II diabetes) in combination with insulin therapy. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition can be used as a method to control blood glucose in some persons with Insulin Dependent Diabetes Mellitus (IDDM, Type I diabetes) in combination with insulin therapy. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition can be used as a method to control body weight in some persons with Non-Insulin Dependent Diabetes Mellitus (NIDDM, Type II diabetes) in combination with insulin therapy. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition can be used as a method to control body weight in some persons with Insulin Dependent Diabetes Mellitus (IDDM, Type I diabetes) in combination with insulin therapy. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition can be used as a method to control blood glucose in some persons with Non-Insulin Dependent Diabetes Mellitus (NIDDM, Type II diabetes) alone, without combination of insulin therapy. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition can be used as a method to control blood glucose in some persons with Insulin Dependent Diabetes Mellitus (IDDM, Type I diabetes) alone, without combination of insulin therapy. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition can be used as a method to control body weight in some persons with Non-Insulin Dependent Diabetes Mellitus (NIDDM, Type II diabetes) alone, without combination of insulin therapy. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition can be used as a method to control body weight in some persons with Insulin Dependent Diabetes Mellitus (IDDM, Type I diabetes) alone, without combination of insulin therapy. In a further preferred embodiment, the present invention may be used in complementary therapy of NIDDM patients to improve their weight or glucose control in combination with an insulin secretagogue (preferably oral form) or an insulin sensitising (preferably oral form) agent. Preferably, the oral insulin secretagogue is 1, 1-dimethyl-2-(2-morpholino phenyl)guanidine fumarate (BTS67582) or a sulphonylurea selected from tolbutamide, tolazamide, chlorpropamide, glibenclamide, glimepiride, glipizide and glidazide. Preferably, the insulin sensitising agent is selected from metformin, ciglitazone, troglitazone and pioglitazone. The present invention further provides a method of improving the body weight or glucose control of NIDDM patients alone, without an insulin secretagogue or an insulin sensitising agent. In a further preferred embodiment, the present invention may be used in complementary therapy of IDDM patients to improve their weight or glucose control in combination with an insulin secretagogue (preferably oral form) or an insulin sensitising (preferably oral form) agent. Preferably, the insulin secretagogue is 1,1-dimethyl-2-(2-morpholino phenyl)guanidine fumarate (BTS67582) or a sulphonylurea selected from tolbutamide, tolazamide, chlorpropamide, glibenclamide, glimepiride, glipizide and glidazide. Preferably, the insulin sensitising agent is selected from metformin, ciglitazone, troglitazone and pioglitazone. The present invention further provides a method of improving the body weight or glucose control of IDDM patients alone, without an insulin secretagogue or an insulin sensitising agent. In a further preferred embodiment, the present invention may be administered either concomitantly or concurrently, with the insulin secretagogue or insulin sensitising agent for example in the form of separate dosage units to be used simultaneously, separately or sequentially (either before or after the secretagogue or either before or after the sensitising agent). Accordingly, the present invention further provides for a composition of pharmaceutical or physiologically acceptable composition and an insulin secretagogue or insulin sensitising agent as a combined preparation for simultaneous, separate or sequential use for the improvement of body weight or glucose control in NIDDM or IDDM patients. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition further provides a method for the use as an insulin sensitiser. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition can be used as a method to improve insulin sensitivity in some persons with Non-Insulin Dependent Diabetes Mellitus (NIDDM, Type II diabetes) in combination with insulin therapy. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition can be used as a method to improve insulin sensitivity in some persons with Insulin Dependent Diabetes Mellitus (IDDM, Type I diabetes) in combination with insulin therapy. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition can be used as a method to improve insulin sensitivity in some persons with Non-Insulin Dependent Diabetes Mellitus (NIDDM, Type II diabetes) without insulin therapy. In an eighth aspect, the invention features a method of making the GMG-3, GMG-4, Cluster 1, GMG-6A, and GMG-6B polypeptides described in the first aspect, wherein said method is selected from the group consisting of: proteolytic cleavage, recombinant methodology and artificial synthesis. In a ninth aspect, the present invention provides a method of making a recombinant GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptide fragment or a full length GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptide, the method comprising providing a transgenic, non-human mammal whose milk contains said recombinant GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptide fragment or full-length protein, and purifying said recombinant GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptide fragment or said full-length GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptide from the milk of said non-human mammal. In one embodiment, said non-human mammal is a cow, goat, sheep, rabbit, or mouse. In another embodiment, the method comprises purifying a recombinant full-length GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptide from said milk, and further comprises cleaving said protein in vitro to obtain a desired GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptide fragment. In a tenth aspect, the invention features a purified or isolated antibody capable of specifically binding to a polypeptide of the present invention. In one aspect of this embodiment, the antibody is capable of binding to a polypeptide comprising at least 6 consecutive amino acids, at least 8 consecutive amino acids, or at least 10 consecutive amino acids of the sequence of one of the polypeptide sequences described in SEQ ID NOs: 2, 4, 6, 8, or 10. In an eleventh aspect, the invention features a use of the polypeptide described in the first aspect for treatment of metabolic-related diseases and disorders and/or reducing or increasing body mass. Preferably, said metabolic-related diseases and disorders are selected from the group consisting of obesity, insulin resistance, atherosclerosis, atheromatous disease, heart disease, hypertension, stroke, Syndrome X, non-insulin-dependent diabetes and Type II diabetes. Type II diabetes-related complications to be treated by the methods of the invention include microangiopathic lesions, ocular lesions, and renal lesions. Heart disease includes, but is not limited to, cardiac insufficiency, coronary insufficiency, and high blood pressure. Other metabolic-related disorders to be treated by compounds of the invention include hyperlipidemia and hyperuricemia. Yet other metabolic-related diseases or disorders of the invention include cachexia, wasting, AIDS-related weight loss, anorexia, and bulimia. In preferred embodiments, said individual is a mammal, preferably a human. In a twelth aspect, the invention provides a polypeptide of the first aspect of the invention, or a composition of the fifth aspect of the invention, for use in a method of treatment of the human or animal body. In a thirteenth aspect, the invention features methods of reducing body weight for cosmetic purposes comprising providing to an individual said pharmaceutical or physiologically acceptable composition described in the fifth aspect, or a polypeptide described in the first aspect. Preferably, for said reducing body weight said individual has a BMI of at least 20 and no more than 25. Alternatively, for said increasing body weight said individual preferably has a BMI of at least 15 and no more than 20. In a fourteenth aspect, the invention features the pharmaceutical or physiologically acceptable composition described in the fifth aspect for reducing body mass and/or for treatment or prevention of metabolic-related diseases or disorders. Preferably, said metabolic-related disease or disorder is selected from the group consisting of obesity, impaired glucose tolerance, insulin resistance, atherosclerosis, atheromatous disease, heart disease, hypertension, stroke, Syndrome X, non-insulin-dependent diabetes and Type II diabetes. Type II diabetes-related complications to be treated by the methods of the invention include microangiopathic lesions, ocular lesions, and renal lesions. Heart disease includes, but is not limited to, cardiac insufficiency, coronary insufficiency, and high blood pressure. Other metabolic-related disorders to be treated by compounds of the invention include hyperlipidemia and hyperuricemia. Yet other metabolic-related diseases or disorders of the invention include cachexia, wasting, ADS-related weight loss, cancer-related weight loss, anorexia, and bulimia. In preferred embodiments, said individual is a mammal, preferably a human. In preferred embodiments, the identification of said individuals to be treated with said pharmaceutical or physiologically acceptable composition comprises genotyping GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B single nucleotide polymorphisms (SNPs) or measuring GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptides or mRNA levels in clinical samples from said individuals. Preferably, said clinical samples are selected from the group consisting of blood, serum, plasma, urine, and saliva. In a fifteenth aspect, the invention features the pharmaceutical or physiologically acceptable composition described in the fifth aspect for reducing body weight for cosmetic reasons. In a sixteenth aspect, the invention features methods of treating insulin resistance comprising providing to an individual said pharmaceutical or physiologically acceptable composition described in the fifth aspect, or a polypeptide described in the first aspect. In a seventeenth aspect, the invention features the pharmaceutical or physiologically acceptable composition described in the fifth aspect in a method of treating individuals with normal glucose tolerance (NGT) who are obese or who have fasting hyperinsulinemia, or who have both. In further preferred embodiments, the invention features the pharmaceutical or physiologically acceptable composition described in the fifth aspect in a method of treating individuals with gestational diabetes. Gestational diabetes refers to the development of diabetes in an individual during pregnancy, usually during the second or third trimester of pregnancy. In further preferred embodiments, the invention features the pharmaceutical or physiologically acceptable composition described in the fifth aspect in a method of treating individuals with impaired fasting glucose (IFG). Impaired fasting glucose (IFG) is that condition in which fasting plasma glucose levels in an individual are elevated but not diagnostic of overt diabetes, i.e. plasma glucose levels of less than 126 mg/dl and less than or equal to 110 mg/dl. In further preferred embodiments, the invention features the pharmaceutical or physiologically acceptable composition described in the fifth aspect in a method of treating and preventing impaired glucose tolerance (IGT) in an individual. By providing therapeutics and methods for reducing or preventing IGT, i.e., for normalizing insulin resistance, the progression to NIDDM can be delayed or prevented. Furthermore, by providing therapeutics and methods for reducing or preventing insulin resistance, the invention provides methods for reducing and/or preventing the appearance of Insulin-Resistance Syndrome. In further preferred embodiments, the invention features the pharmaceutical or physiologically acceptable composition described in the fifth aspect in a method of treating a subject having polycystic ovary syndrome (PCOS). PCOS is among the most common disorders of premenopausal women, affecting 5-10% of this population. Insulin-sensitizing agents, e.g., troglitazone, have been shown to be effective in PCOS and that, in particular, the defects in insulin action, insulin secretion, ovarian steroidogenosis and fibrinolysis are improved (Ehrman et al. (1997) J Clin Invest 100:1230), such as in insulin-resistant humans. Accordingly, the invention provides methods for reducing insulin resistance, normalizing blood glucose thus treating and/or preventing PCOS. In further preferred embodiments, the invention features the pharmaceutical or physiologically acceptable composition described in the fifth aspect in a method of treating a subject having insulin resistance. In further preferred embodiments, a subject having insulin resistance is treated according to the methods of the invention to reduce or cure the insulin-resistance. As insulin resistance is also often associated with infections and cancer, prevention or reducing insulin resistance according to the methods of the invention may prevent or reduce infections and cancer. In further preferred embodiment, the methods of the invention are used to prevent the development of insulin resistance in a subject, e.g., those known to have an increased risk of developing insulin-resistance. Thus, any of the above-described tests or other tests known in the art can be used to determine that a subject is insulin-resistant, which patient can then be treated according to the methods of the invention to reduce or cure the insulin-resistance. Alternatively, the methods of the invention can also be used to prevent the development of insulin resistance in a subject, e.g., those known to have an increased risk of developing insulin-resistance. In an eighteenth aspect, the invention features a method of preventing or treating an metabolic-related disease or disorder comprising providing or administering to an individual in need of such treatment said pharmaceutical or physiologically acceptable composition described in the fifth aspect. In preferred embodiments, the identification of said individuals in need of such treatment to be treated with said pharmaceutical or physiologically acceptable composition comprises genotyping GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B single nucleotide polymorphisms (SNPs) or measuring GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptide or mRNA levels in clinical samples from said individuals. Preferably, said clinical samples are selected from the group consisting of blood, serum, plasma, urine, and saliva. Preferably, said metabolic-related disease or disorder is selected from the group consisting of obesity, impaired glucose tolerance, insulin resistance, atherosclerosis, atheromatous disease, heart disease, hypertension, stroke, Syndrome X, non-insulin-dependent diabetes and Type II diabetes. Type II diabetes-related complications to be treated by the methods of the invention include microangiopathic lesions, ocular lesions, and renal lesions. Heart disease includes, but is not limited to, cardiac insufficiency, coronary insufficiency, and high blood pressure. Other metabolic-related disorders to be treated by compounds of the invention include hyperlipidemia and hyperuricemia. Yet other metabolic-related diseases or disorders of the invention include cachexia, wasting, FIV-related weight loss, cancer-related weight loss, anorexia, and bulimia. In preferred embodiments, said individual is a mammal, preferably non-human, preferably a cat or a dog. In a nineteenth aspect, the invention features a method of using a GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptide or polypeptide fragment to screen compounds for one or more antagonists of GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptide or polypeptide fragment activity, wherein said activity is selected from but not restricted to lipid partitioning, lipid metabolism, and insulin-like activity. In preferred embodiment, said compound is selected from but is not restricted to small molecular weight organic or inorganic compound, protein, peptide, carbohydrate, or lipid. In a twentieth aspect, the invention features a method of using a GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptide to identify one or more cell types expressing a cell surface receptor for said GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptide, preferably wherein said polypeptide comprises all or part of the C-terminal globular C1q homology domain and has lipid partitioning, lipid metabolism, or insulin-like activities. In a twenty-first aspect, the invention features a method of using a GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptide to clone cDNA encoding a cell surface receptor for said GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptide, preferably wherein said polypeptide comprises all or part of the C-terminal globular C1q homology domain and has lipid partitioning, lipid metabolism, or insulin-like activities. In a twenty-second aspect, the invention features a method of using a GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polynucleotide to generate transgenic non-human mammals expressing GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptides, preferably wherein said non-human mammal is mouse, cow, sheep, goat, pig, or rabbit. In a twenty-third aspect, the invention features a method of using a genomic polynucleotide or fragment thereof of SEQ ID NO: 11, 12, or 13 to generate a transgenic mouse in which expression of the gene encoding GMG-6A and GMG-6B is knocked-out either globally or in a tissue-specific manner. In a preferred aspect of the methods above and disclosed herein, the amount of GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptide or polynucleotide administered to an individual is sufficient to bring circulating (blood, serum, or plasma) levels (concentration) of GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptides to their normal levels (levels in non-obese individuals). “Normal levels” may be specified as the total concentration of all circulating GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptides (full-length GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B proteins and fragments thereof) or the concentration of all circulating proteolytically cleaved GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptides only. In a further preferred aspect of the methods above and disclosed herein, weight loss is due in part or in whole to a decrease in mass of either a) subcutaneous adipose tissue and/or b) visceral (omental) adipose tissue. Full-length GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptides and polynucleotides encoding the same may be specifically substituted for a GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptide fragment or polynucleotide encoding the same in any embodiment of the present invention. It is further understood that by GMG-3 polypeptide is meant the amino acid sequence of SEQ ID NO: 2 as well as any related polypeptide incorporating one or more of the amino acid polymorphisms indicated in the sequence listing, namely the related polypeptide with Val at position 219, the related polypeptide with Met at position 301, and the related polypeptide with Val at position 219 and Met at position 301. It is further understood that by GMG-4 polypeptide is meant the amino acid sequence of SEQ ID NO: 4 as well as any related polypeptide incorporating one or more of the amino acid polymorphisms indicated in the sequence listing, namely the related polypeptide with Ala at position 238. It is further understood that by Cluster 1 polypeptide is meant the amino acid sequence of SEQ ID NO: 6 as well as any related polypeptide incorporating one or more of the amino acid polymorphisms indicated in the sequence listing, namely the related polypeptide with Ala at position 130. |
Metabolic gene polynucleotides and polypeptides and uses thereof |
The present invention relates to the field of metabolic research. Metabolic disorders, such as obesity, are a public health problem that is serious and widespread. GMG-3, GMG-4, Cluster 1, GMG-6A, or GMG-6B polypeptides have been identified that are beneficial in the treatment of metabolic disorders. These compounds should be effective for reducing body mass and for treating metabolic-related diseases and disorders. These metabolic-related diseases and disorders include hyperlipidemias, atherosclerosis, diabetes, and hypertension. |
1-11. (canceled) 12. A method of treating or preventing a metabolic-related disease or disorder comprising the step of administering to an individual a composition comprising a polypeptide or biologically active fragment thereof, wherein said polypeptide is selected from the group consisting of: (a) SEQ ID NO: 2; (b) SEQ ID NO: 4; (c) SEQ ID NO: 6; (d) SEQ ID NO: 8; (e) SEQ ID NO: 10; and (f) SEQ ID NO: 12. 13. The method of claim 12, wherein said metabolic-related disease or disorder is selected from the group consisting of: (a) obesity; (b) impaired glucose tolerance; (c) insulin resistance; (d) Syndrome X; and (e) Type II diabetes. 14. The method of claim 12, wherein said polypeptide fragment is selected from the group consisting of: (a) amino acids 2-710 of SEQ ID NO: 2; (b) amino acids 1-262 of SEQ ID NO: 2; (c) amino acids 1-263 of SEQ ID NO: 2; (d) amino acids 1-275 of SEQ ID NO: 2; (e) amino acids 553-710 of SEQ ID NO: 2; (f) amino acids 554-710 of SEQ ID NO: 2; (g) amino acids 568-710 of SEQ ID NO: 2; (h) amino acids 575-710 of SEQ ID NO: 2; (i) amino acids 2-471 of SEQ ID NO: 4; (j) amino acids 1-262 of SEQ ID NO: 4; (k) amino acids 1-263 of SEQ ID NO: 4; (l) amino acids 1-275 of SEQ ID NO: 4; (m) amino acids 1-442 of SEQ ID NO: 4; (n) amino acids 1-443 of SEQ ID NO: 4; (o) amino acids 28-201 of SEQ ID NO: 6; (p) amino acids 54-201 of SEQ ID NO: 6; (q) amino acids 66-201 of SEQ ID NO: 6; (r) amino acids 25-446 of SEQ ID NO: 8; (s) amino acids 228-356 of SEQ ID NO: 8; (t) amino acids 228-360 of SEQ ID NO: 8; (u) amino acids 228-431 of SEQ ID NO: 8; (v) amino acids 228-446 of SEQ ID NO: 8; (w) amino acids 231-356 of SEQ ID NO: 8; (x) amino acids 231-360 of SEQ ID NO: 8; (y) amino acids 231-431 of SEQ ID NO: 8; (z) amino acids 231-446 of SEQ ID NO: 8; (aa) amino acids 241-356 of SEQ ID NO: 8; (bb) amino acids 241-360 of SEQ ID NO: 8; (cc) amino acids 241-431 of SEQ ID NO: 8; (dd) amino acids 241-446 of SEQ ID NO: 8; (ee) amino acids 24-296 of SEQ ID NO: 10; (ff) amino acids 132-296 of SEQ ID NO: 10; (gg) amino acids 135-296 of SEQ ID NO: 10; (hh) amino acids 148-296 of SEQ ID NO: 10; (ii) amino acids 33-205 of SEQ ID NO: 12; (jj) amino acids 53-205 of SEQ ID NO: 12; (kk) amino acids 54-205 of SEQ ID NO: 12; and (ll) amino acids 59-205 of SEQ ID NO: 12. 15. The method of claim 13, wherein said polypeptide fragment is selected from the group consisting of: (a) amino acids 2-710 of SEQ ID NO: 2; (b) amino acids 1-262 of SEQ ID NO: 2; (c) amino acids 1-263 of SEQ ID NO: 2; (d) amino acids 1-275 of SEQ ID NO: 2; (e) amino acids 553-710 of SEQ ID NO: 2; (f) amino acids 554-710 of SEQ ID NO: 2; (g) amino acids 568-710 of SEQ ID NO: 2; (h) amino acids 575-710 of SEQ ID NO: 2; (i) amino acids 2-471 of SEQ ID NO: 4; (j) amino acids 1-262 of SEQ ID NO: 4; (k) amino acids 1-263 of SEQ ID NO: 4; (l) amino acids 1-275 of SEQ ID NO: 4; (m) amino acids 1-442 of SEQ ID NO: 4; (n) amino acids 1-443 of SEQ ID NO: 4; (o) amino acids 28-201 of SEQ ID NO: 6; (p) amino acids 54-201 of SEQ ID NO: 6; (q) amino acids 66-201 of SEQ ID NO: 6; (r) amino acids 25-446 of SEQ ID NO: 8; (s) amino acids 228-356 of SEQ ID NO: 8; (t) amino acids 228-360 of SEQ ID NO: 8; (u) amino acids 228-431 of SEQ ID NO: 8; (v) amino acids 228-446 of SEQ ID NO: 8; (w) amino acids 231-356 of SEQ ID NO: 8; (x) amino acids 231-360 of SEQ ID NO: 8; (y) amino acids 231-431 of SEQ ID NO: 8; (z) amino acids 231-446 of SEQ ID NO: 8; (aa) amino acids 241-356 of SEQ ID NO: 8; (bb) amino acids 241-360 of SEQ ID NO: 8; (cc) amino acids 241-431 of SEQ ID NO: 8; (dd) amino acids 241-446 of SEQ ID NO: 8; (ee) amino acids 24-296 of SEQ ID NO: 10; (ff) amino acids 132-296 of SEQ ID NO: 10; (gg) amino acids 135-296 of SEQ ID NO: 10; (hh) amino acids 148-296 of SEQ ID NO: 10; (ii) amino acids 33-205 of SEQ ID NO: 12; (jj) amino acids 53-205 of SEQ ID NO: 12; (kk) amino acids 54-205 of SEQ ID NO: 12; and (ll) amino acids 59-205 of SEQ ID NO: 12. 16. An isolated polypeptide fragment selected from the group consisting of: (a) amino acids 2-710 of SEQ ID NO: 2; (b) amino acids 1-262 of SEQ ID NO: 2; (c) amino acids 1-263 of SEQ ID NO: 2; (d) amino acids 1-275 of SEQ ID NO: 2; (e) amino acids 553-710 of SEQ ID NO: 2; (f) amino acids 554-710 of SEQ ID NO: 2; (g) amino acids 568-710 of SEQ ID NO: 2; (h) amino acids 575-710 of SEQ ID NO: 2; (i) amino acids 2-471 of SEQ ID NO: 4; (j) amino acids 1-262 of SEQ ID NO: 4; (k) amino acids 1-263 of SEQ ID NO: 4; (l) amino acids 1-275 of SEQ ID NO: 4; (m) amino acids 1-442 of SEQ ID NO: 4; (n) amino acids 1-443 of SEQ ID NO: 4; (o) amino acids 28-201 of SEQ ID NO: 6; (p) amino acids 54-201 of SEQ ID NO: 6; (q) amino acids 66-201 of SEQ ID NO: 6; (r) amino acids 25-446 of SEQ ID NO: 8; (s) amino acids 228-356 of SEQ ID NO: 8; (t) amino acids 228-360 of SEQ ID NO: 8; (u) amino acids 228-431 of SEQ ID NO: 8; (v) amino acids 228-446 of SEQ ID NO: 8; (w) amino acids 231-356 of SEQ ID NO: 8; (x) amino acids 231-360 of SEQ ID NO: 8; (y) amino acids 231-431 of SEQ ID NO: 8; (z) amino acids 231-446 of SEQ ID NO: 8; (aa) amino acids 241-356 of SEQ ID NO: 8; (bb) amino acids 241-360 of SEQ ID NO: 8; (cc) amino acids 241-431 of SEQ ID NO: 8; (dd) amino acids 241-446 of SEQ ID NO: 8; (ee) amino acids 24-296 of SEQ ID NO: 10; (ff) amino acids 132-296 of SEQ ID NO: 10; (gg) amino acids 135-296 of SEQ ID NO: 10; (hh) amino acids 148-296 of SEQ ID NO: 10; (ii) amino acids 33-205 of SEQ ID NO: 12; (jj) amino acids 53-205 of SEQ ID NO: 12; (kk) amino acids 54-205 of SEQ ID NO: 12; and (ll) amino acids 59-205 of SEQ ID NO: 12. 17. A composition comprising a carrier and one or more of the polypeptide fragments of claim 16. 18. An isolated polynucleotide, or complement thereof, encoding any one of the polypeptide fragments of claim 16. 19. The polynucleotide of claim 18 selected from the group consisting of: (a) DNA; (b) RNA; (c) DNA/RNA hybrid; (d) single-stranded; and (e) double-stranded. 20. A composition comprising a carrier and an isolated polynucleotide of claim 19. 21. A vector comprising an isolated polynucleotide of claim 19. 22. A composition comprising a carrier and a vector of claim 21. 23. A transformed host cell comprising a vector of claim 21. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The following discussion is intended to facilitate the understanding of the invention, but is not intended nor admitted to be prior art to the invention. Obesity is a public health problem that is serious, widespread, and increasing. In the United States, 20 percent of the population is obese; in Europe, a slightly lower percentage is obese (Friedman (2000) Nature 404:632-634). Obesity is associated with increased risk of hypertension, cardiovascular disease, diabetes, and cancer as well as respiratory complications and osteoarthritis (Kopelman (2000) Nature 404:635-643). Even modest weight loss ameliorates these associated conditions. While still acknowledging that lifestyle factors including environment, diet, age and exercise play a role in obesity, twin studies, analyses of familial aggregation, and adoption studies all indicate that obesity is largely the result of genetic factors (Harsh et al (2000) Nature 404:644-651). In agreement with these studies, is the fact that an increasing number of metabolic-related genes are being identified. Some of the more extensively studied genes include those encoding leptin (ob) and its receptor (db), pro-opiomelanocortin (Poinc), melanocortin-4-receptor (Mc4r), agouti protein (A y ), carboxypeptidase E (at), 5-hydroxytryptamine receptor 2C (Htr2c), nescient basic helix-loop-helix 2 (Nhlh2), prohormone convertase 1 (PCSK1), and tubby protein (tubby) (rev'd in Barsh et al (2000) Nature 404:644-651). |
<SOH> SUMMARY OF THE INVENTION <EOH>The instant invention is based on Genset Metabolic Genes-7, 8, 9, 10, and 11 (GMG-7), (GMG-8; previously referred to as Cluster 9), (GMG-9; previously referred to as Cluster 10), (GMG-10; previously referred to as Cluster 17(a)) and (GMG-11; previously referred to as Cluster 19) of human origin. GMG-7A (previously referred to as Cluster 6 (1900)) and GMG-7B (previously referred to as Cluster 6 (d)) correspond to splice variants of GMG-7. GMG-7A, GMG-8, GMG-10, and GMG-11 are comprised of a C-terminal globular C1q homology domain. GMG-7B lacks the C-terminal globular C1q homology domain present in GMG-7A. GMG-9 is comprised near its N-terminus of a truncated globular C1q homology domain. Analysis of the C-terminal globular C1q homology domain of APM1 has shown it to structurally resemble TNFα. By analogy to APM1, biological activity can also reside in polypeptide fragments exclusive of all or part of the globular C1q homology domain. Results from Northern blot analysis indicate expression of GMG-7 in heart and brain, expression of GMG-8 in brain, and expression of GMG-11 in brain and pancreas. The invention includes polypeptides encoded by GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11, which include both the full-length polypeptide and fragments thereof, preferably but not intended to be limited to said polypeptide fragments comprising all or part of the C-terminal globular C1q homology domain. The GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polypeptide fragments of the invention have in vitro and in vivo biological activity as described herein, including utility for weight reduction, prevention of weight gain and control of blood glucose levels in humans and other mammals. More specifically, the biological activities of the GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polypeptides, including fragments, include reduction of elevated free fatty acid levels caused by administration of epinephrine, i.v. injection of “intralipid”, or administration of a high fat test meal, as well as increased fatty acid oxidation in muscle cells, reduction in glucose levels, modulation of energy expenditure, resistance to insulin and weight reduction in mammals consuming a high fat/high sucrose diet. Polypeptide fragments of the invention have activities overlapping but distinct from that of the full-length polypeptide. Thus, the invention is drawn to GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polypeptides, polynucleotides encoding said GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polypeptides, vectors comprising said GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polynucleotides, and cells recombinant for said GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polynucleotides, as well as to pharmaceutical and physiologically acceptable compositions comprising said GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polypeptides and methods of administering said GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 pharmaceutical and physiologically acceptable compositions in order to reduce body weight or to treat metabolic-related diseases and disorders. Assays for identifying agonists and antagonists of metabolic-related activity are also part of the invention. In a first aspect, the invention features purified, isolated, or recombinant GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polypeptides or GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polypeptide fragments that have lipid partitioning, lipid metabolism, and insulin-like activities. Preferred GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polypeptide fragments have activity, wherein said activity is also selected from the group consisting of lipid partitioning, lipid metabolism, and insulin-like activity. In preferred embodiments, said polypeptide fragment comprises, consists essentially of, or consists of, at least 6 consecutive amino acids and not more than 710 consecutive amino acids of SEQ ID NO: 2; at least 6 and not more than 471 consecutive amino acids of SEQ ID NO: 4; at least 6 consecutive amino acids and not more than 201 consecutive amino acids of SEQ ID NO: 6; at least 6 and not more than 446 consecutive amino acids of SEQ ID NO: 8; at least 6 consecutive amino acids and not more than 296 consecutive amino acids of SEQ ID NO: 10; or at least 6 and not more than 205 consecutive amino acids of SEQ ID NO: 12. In preferred embodiments, GMG-7A polypeptide fragments having activity are selected from amino acids 2-710, 1-262, 263-710, 1-263, 264-710 1-552, 553-710, 554-710, 561-710, 568-710, 575-710, 580-710, 581-710, 1-275 or 276-710 of SEQ ID NO: 2. In other preferred embodiments, GMG-7B polypeptide fragments having activity are selected from amino acids 2-471, 1-442, 443-471, 1-443, 444-471, 1-262, 263-471, 1-263, 264-471, 1-275 or 276-471 of SEQ ID NO: 4. In other preferred embodiments, GMG-8 polypeptide fragments having activity are selected from amino acids 28-201, 40-201, 54-201, 66-201, 70-201, or 71-201 of SEQ ID NO: 6. In other preferred embodiments, GMG-9 polypeptide fragments having activity are selected from amino acids 25-446, 228-356, 228-360, 228-431, 228-446, 231-356, 231-360, 231-431, 231-446, 233-356, 233-360, 233-431, 233-446, 236-356, 236-360, 236-431, 236-446, 240-356, 240-360, 240-431, 240-446, 241-356, 241-360, 241-431, 241-446, 242-356, 242-360, 242-431, or 242-446 of SEQ ID NO: 8. In other preferred embodiments, GMG-10 polypeptide fragments having activity are selected from amino acids 8-296, 9-296, 24-296, 32-296, 39-296, 52-296, 65-296, 71-296, 74-296, 77-296, 78-296, 81-296, 84-296, 90-296, 92-296, 102-296, 110-296, 111-296, 120-296, 132-296, 135-296, 148-296, 154-296 or 155-296 of SEQ ID NO: 10. In other preferred embodiments, GMG-11 polypeptide fragments having activity are selected from amino acids 33-205, 53-205, 54-205, 59-205, 71-205 or 72-205 of SEQ ID NO: 12. In more preferred embodiments, GMG-7A polypeptide fragments having activity are selected from amino acids 2-710, 1-262, 1-263, 553-710, 554-710, 568-710, 575-710 or 1-275 of SEQ ID NO: 2. In other more preferred embodiments, GMG-7B polypeptide fragments having activity are selected from amino acids 2-471, 14-42, 1-443, 1-262, 1-263, or 1-275 of SEQ ID NO: 4. In other more preferred embodiments, GMG-8 polypeptide fragments having activity are selected from amino acids 28-201, 54-201 or 66-201 of SEQ ID NO: 6. In other more preferred embodiments, GMG-9 polypeptide fragments having activity are selected from amino acids 254-46, 228-356, 228-360, 228-431, 228-446, 231-356, 231-360, 231-431, 231-446, 241-356, 241-360, 241-431 or 241-446 of SEQ ID NO: 8. In other more preferred embodiments, GMG-10 polypeptide fragments having activity are selected from amino acids 8-296, 9-296, 24-296, 52-296, 71-296, 74-296, 81-296, 84-296, 110-296, 111-296, 120-296, 132-296, 135-296, 148-296, 154-296 or 155-296 of SEQ ID NO: 10. In other more preferred embodiments, GMG-11 polypeptide fragments having activity are selected from amino acids 33-205, 53-205, 54-205 or 59-205 of SEQ ID NO: 12. In further preferred embodiments, said polypeptide fragment comprises an amino acid sequence at least 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the corresponding consecutive amino acids of the polypeptide sequences identified in SEQ ED NO: 2, 4, 6, 8, 10, or 12. The invention further provides a purified or isolated polypeptide comprising, consisting of, or consisting essentially of an amino acid sequence selected from the group consisting of: (a) a full-length at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the corresponding amino acids polypeptide of SEQ ID NOs: 2, 4, 6, 8, 10, or 12; (b) a full-length GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptide of SEQ ID NOs: 2, 4, 6, 8, 10, or 12 absent the N-terminal Met; (c) a mature GMG-8, GMG-9, GMG-10 or GMG-11 polypeptide of SEQ ID NOs: 6, 8, 10, or 12 lacking signal peptide; (d) a GMG-7A polypeptide of SEQ ID NO: 2 wherein said GMG-7A polypeptide is of any one integer in length between 6 amino acids and 710 amino acids (full-length) inclusive of SEQ ED NO: 2, a GMG-7B polypeptide of SEQ ID NO: 4 wherein said GMG-7B polypeptide is of any one integer in length between 6 amino acids and 471 amino acids (full-length) inclusive of SEQ ID NO: 4, a GMG-8 polypeptide of SEQ ID NO: 6 wherein said GMG-8 polypeptide is of any one integer in length between 6 amino acids and 201 amino acids (full-length) inclusive of SEQ ID NO: 6, a GMG-9 polypeptide of SEQ ID NO: 8 wherein said GMG-8 polypeptide is of any one integer in length between 6 amino acids and 446 amino acids (full-length) inclusive of SEQ ID NO: 8; or a GMG-10 polypeptide of SEQ ID NO: 10 wherein said GMG-10 polypeptide is of any one integer in length between 6 amino acids and 296 amino acids (full-length) inclusive of SEQ ID NO: 10; or a GMG-11 polypeptide of SEQ ID NO: 12 wherein said GMG-11 polypeptide is of any one integer in length between 6 amino acids and 205 amino acids (full-length) inclusive of SEQ ID NO: 12; (e) the epitope-bearing fragments of a GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptide of SEQ ED NO: 2, 4, 6, 8, 10, or 12; (f) the allelic variant polypeptides of any of the polypeptides of (a)-(e). The invention further provides for fragments of the polypeptides of (a)-(f) above, such as those having biological activity or comprising biologically functional domain(s). In other highly preferred embodiments, GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptides comprise, consist essentially of, or consist of, a purified, isolated, or a recombinant GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptide fragment comprised of all or part of the C-terminal globular C1q homology domain. Preferably, said GMG-7A polypeptide fragment comprises, consists essentially of, or consists of, at least 6 consecutive amino acids of amino acids 2-710 of SEQ ID NO: 2. Preferably, said GMG-8 polypeptide fragment comprises, consists essentially of, or consists of, at least 6 consecutive amino acids of amino acids 28-201 of SEQ ID NO: 6. Preferably, said GMG-10 polypeptide fragment comprises, consists essentially of, or consists of, at least 6 consecutive amino acids of amino acids 24296 of SEQ ID NO: 10. Preferably, said GMG-11 polypeptide fragment comprises, consists essentially of, or consists of, at least 6 consecutive amino acids of amino acids 33-205 of SEQ ID NO: 12. In preferred embodiments, said GMG-7A polypeptide fragments comprised of all or part of the C-terminal globular C1q homology domain and having activity are selected from amino acids 2-710, 263-710, 264-710, 553-710, 554-710, 561-710, 568-710, 575-710, 580-710, 581-710, or 276-710 of SEQ ID NO: 2. In other preferred embodiments, said GMG-8 polypeptide fragments having activity are selected from amino acids 28-201, 40-201, 54-201, 66-201, 70-210 or 71-201 of SEQ ID NO: 6. In other preferred embodiments, said GMG-10 polypeptide fragments having activity are selected from amino acids 8-296, 9-296, 24-296, 32-296, 39-296, 52-296, 65-296, 71-296, 74-296, 77-296, 78-296, 81-296, 84-296, 90-296, 92-296, 102-296, 110-296, 111-296, 120-296, 132-296, 135-296, 148-296, 154-296 or 155-296 of SEQ ID NO: 10. In other preferred embodiments, said GMG-11 polypeptide fragments having activity are selected from amino acids 33-205, 53-205, 54-205, 59-205, 71-205 or 72-205 of SEQ ID NO: 12. In more preferred embodiments, said GMG-7A polypeptide fragments comprised of all or part of the C-terminal globular C1q homology domain and having activity are selected from amino acids 2-710, 553-710, 554-710, 568-710, or 575-710 of SEQ ID NO: 2. In other more preferred embodiments, said GMG-8 polypeptide fragments having activity are selected from amino acids 28-201, 54-201 or 66-201 of SEQ ID NO: 6. In other more preferred embodiments, said GMG-10 polypeptide fragments having activity are selected from amino acids 8-296, 9-296, 24-296, 52-296, 71-296, 74-296, 81-296, 84-296, 110-296, 111-296, 120-296, 132-296, 135-296, 148-296, 154-296 or 155-296 of SEQ ID NO: 10. In other more preferred embodiments, said GMG-11 polypeptide fragments having activity are selected from amino acids 33-205, 53-205, 54-205 or 59-205 of SEQ ID NO: 12. Alternatively, said GMG-7A, GMG-8, GMG-10, or GMG-11 polypeptide fragment comprises, consists essentially of, or consists of, an amino acid sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the corresponding amino acids 568-710 of SEQ ID NO: 2, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the corresponding amino acids 54-201 of SEQ ID NO: 6, at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the corresponding amino acids 135-296 of SEQ ED NO: 10, or at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the corresponding amino acids 53-205 of SEQ ID NO: 12. In a further preferred embodiment, GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polypeptides are able to lower circulating (either in blood, serum or plasma) levels (concentration) of: (i) free fatty acids, (ii) glucose, and/or (iii) triglycerides. Further preferred polypeptides of the invention demonstrating free fatty acid level lowering activity, glucose level lowering activity, and/or triglyceride level lowering activity, have an activity that is the same or greater than full-length GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptides at the same molar concentration, have the same or greater than transient activity and/or have a sustained activity. Further preferred GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polypeptides are those that significantly stimulate muscle lipid or free fatty acid oxidation. Further preferred GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polypeptides are those that significantly stimulate muscle lipid or free fatty acid oxidation. Further preferred GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polypeptides are those that cause C2C12 cells differentiated in the presence of said polypeptides to undergo at least 10%, 20%, 30%, 35%, or 40% more oleate oxidation as compared to untreated cells. Further preferred GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polypeptides are those that increase leptin uptake in a liver cell line (preferably BPRCL mouse liver cells (ATCC CRL-2217)). Further preferred GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polypeptides are those that significantly reduce the postprandial increase in plasma free fatty acids due to a high fat meal. Further preferred GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polypeptides are those that significantly reduce or eliminate ketone body production as the result of a high fat meal. Further preferred GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polypeptides are those that increase glucose uptake in skeletal muscle cells. Further preferred GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polypeptides are those that increase glucose uptake in adipose cells. Further preferred GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polypeptides are those that increase glucose uptake in neuronal cells. Further preferred GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polypeptides are those that increase glucose uptake in red blood cells. Further preferred GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polypeptides are those that increase glucose uptake in the brain. Further preferred GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polypeptides are those that significantly reduce the postprandial increase in plasma glucose following a meal, particularly a high carbohydrate meal. Further preferred GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polypeptides are those that significantly prevent the postprandial increase in plasma glucose following a meal, particularly a high fat or a high carbohydrate meal. Further preferred GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polypeptides are those that increase insulin sensitivity. Further preferred GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polypeptides are those that inhibit the progression from impaired glucose tolerance to insulin resistance. Further preferred GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polypeptides are those that form multimers (e.g., heteromultimers or homomultimers) in vitro and/or in vivo. Preferred multimers are homodimers or homotrimers. Other preferred multimers are homomultimers comprising at least 4, 6, 8, 9, 10 or 12 GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptide subunits. Other preferred mulimers are hetero multimers comprising a GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptide of the invention. Further preferred embodiments include heterologous polypeptides comprising one of the GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptides of the invention. In a second aspect, the invention features purified, isolated, or recombinant polynucleotides encoding said GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptides described in the first aspect, or the complement thereof. A further preferred embodiment of the invention is a recombinant, purified or isolated polynucleotide comprising, or consisting of a mammalian genomic sequence, gene, or fragments thereof. In one aspect the sequence is derived from a human, mouse or other mammal. In a preferred aspect, the genomic sequence includes isolated, purified, or recombinant polynucleotides comprising a contiguous span of at least 12, 15, 18, 20, 22, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 150, 200, 500, 1000, 2000, 5000, 10000 or 50000 nucleotides of any one of the polynucleotide sequences described in SEQ ID NOs: 1, 3, 5, 7, 9, or 11 or the complements thereof, wherein said contiguous span comprises a nucleotide sequence at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the corresponding nucleotide sequence of the C-terminal globular C1q homology domains of SEQ ID NOs: 1, 3, 5, 7, 9, or 11. In further embodiments the polynucleotides are DNA, RNA, DNA/RNA hybrids, single-stranded, and double-stranded. In a third aspect, the invention features a recombinant vector comprising, consisting essentially of, or consisting of, said polynucleotide described in the second aspect. In a fourth aspect, the invention features a recombinant cell comprising, consisting essentially of, or consisting of, said recombinant vector described in the third aspect. A further embodiment includes a host cell recombinant for a polynucleotide of the invention. In a fifth aspect, the invention features a pharmaceutical or physiologically acceptable composition comprising, consisting essentially of, or consisting of, said GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptides described in the first aspect and, alternatively, a pharmaceutical or physiologically acceptable diluent. In a sixth aspect, the invention features a method of reducing body mass comprising providing or administering to individuals in need of reducing body mass said pharmaceutical or physiologically acceptable composition described in the fifth aspect. In preferred embodiments, the identification of said individuals in need of reducing body mass to be treated with said pharmaceutical or physiologically acceptable composition comprises genotyping GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 single nucleotide polymorphisms (SNPs) or measuring metabolic polypeptide or mRNA levels in clinical samples from said individuals. Preferably, said clinical samples are selected from the group consisting of plasma, urine, and saliva. Preferably, a GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptide fragment of the present invention is administered to an individual with at least a 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% reduction in blood, serum or plasma levels of full-length any one or all of the GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-11, or GMG-11 polypeptides or the naturally proteolytically cleaved GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 fragments as compared to healthy, non-obese patients. In a seventh aspect, the invention features a method of preventing or treating an metabolic-related disease or disorder comprising providing or administering to an individual in need of such treatment said pharmaceutical or physiologically acceptable composition described in the fifth aspect. In preferred embodiments, the identification of said individuals in need of such treatment to be treated with said pharmaceutical or physiologically acceptable composition comprises genotyping GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 single nucleotide polymorphisms (SNPs) or measuring GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptide or mRNA levels in clinical samples from said individuals. Preferably, said clinical samples are selected from the group consisting of blood, serum, plasma, urine, and saliva. Preferably, said metabolic-related disease or disorder is selected from the group consisting of obesity, impaired glucose tolerance, insulin resistance, atherosclerosis, atheromatous disease, heart disease, hypertension, stroke, Syndrome X, non-insulin-dependent diabetes and Type II diabetes. Type II diabetes-related complications to be treated by the methods of the invention include microangiopathic lesions, ocular lesions, and renal lesions. Heart disease includes, but is not limited to, cardiac insufficiency, coronary insufficiency, and high blood pressure. Other metabolic-related disorders to be treated by compounds of the invention include hyperlipidemia and hyperuricemia. Yet other metabolic-related diseases or disorders of the invention include cachexia, wasting, AIDS-related weight loss, cancer-related weight loss, anorexia, and bulimia. In preferred embodiments, said individual is a mammal, preferably a human. In related aspects, embodiments of the present invention includes methods of causing or inducing a desired biological response in an individual comprising the steps of: providing or administering to an individual a composition comprising a GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptide, wherein said biological response is selected from the group consisting of: (a) modulating circulating (either blood, serum, or plasma) levels (concentration) of free fatty acids, wherein said modulating is preferably lowering; (b) modulating circulating (either blood, serum or plasma) levels (concentration) of glucose, wherein said modulating is preferably lowering; (c) modulating circulating (either blood, serum or plasma) levels (concentration) of triglycerides, wherein said modulating is preferably lowering; (d) stimulating muscle lipid or free fatty acid oxidation; (c) modulating leptin uptake in the liver or liver cells, wherein said modulating is preferably increasing; (e) modulating the postprandial increase in plasma free fatty acids due to a high fat meal, wherein said modulating is preferably reducing; (f) modulating ketone body production as the result of a high fat meal, wherein said modulating is preferably reducing or eliminating; (g) increasing cell or tissue sensitivity to insulin, particularly muscle, adipose, liver or brain; and (h) inhibiting the progression from impaired glucose tolerance to insulin resistance; and further wherein said biological response is significantly greater than, or at least 10%, 20%, 30%, 35%, 40%, 50% 75% 100% or 500% greater than, the biological response caused or induced by insulin alone at the same molar concentration. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition can be used as a method to control blood glucose in some persons with Non-Insulin Dependent Diabetes Mellitus (NIDDM, Type II diabetes) in combination with insulin therapy. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition can be used as a method to control blood glucose in some persons with Insulin Dependent Diabetes Mellitus (IDDM, Type I diabetes) in combination with insulin therapy. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition can be used as a method to control body weight in some persons with Non-Insulin Dependent Diabetes Mellitus (NIDDM, Type II diabetes) in combination with insulin therapy. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition can be used as a method to control body weight in some persons with Insulin Dependent Diabetes Mellitus (IDDM, Type I diabetes) in combination with insulin therapy. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition can be used as a method to control blood glucose in some persons with Non-Insulin Dependent Diabetes Mellitus (NIDDM, Type II diabetes) alone, without combination of insulin therapy. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition can be used as a method to control blood glucose in some persons with Insulin Dependent Diabetes Mellitus (IDDM, Type I diabetes) alone, without combination of insulin therapy. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition can be used as a method to control body weight in some persons with Non-Insulin Dependent Diabetes Mellitus (NIDDM, Type II diabetes) alone, without combination of insulin therapy. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition can be used as a method to control body weight in some persons with Insulin Dependent Diabetes Mellitus (IDDM, Type I diabetes) alone, without combination of insulin therapy. In a further preferred embodiment, the present invention may be used in complementary therapy of NIDDM patients to improve their weight or glucose control in combination with an insulin secretagogue (preferably oral form) or an insulin sensitising (preferably oral form) agent. Preferably, the oral insulin secretagogue is 1,1-dimethyl-2-(2-morpholino phenyl)guanidine fumarate (BTS67582) or a sulphonylurea selected from tolbutamide, tolazamide, chlorpropamide, glibenclamide, glimepiride, glipizide and glidazide. Preferably, the insulin sensitising agent is selected from metformin, ciglitazone, troglitazone and pioglitazone. The present invention further provides a method of improving the body weight or glucose control of NIDDM patients alone, without an insulin secretagogue or an insulin sensitising agent. In a further preferred embodiment, the present invention may be used in complementary therapy of IDDM patients to improve their weight or glucose control in combination with an insulin secretagogue (preferably oral form) or an insulin sensitising (preferably oral form) agent. Preferably, the insulin secretagogue is 1,1-dimethyl-2-(2-morpholino phenyl)guanidine fumarate (BTS67582) or a sulphonylurea selected from tolbutamide, tolazamide, chlorpropamide, glibenclamide, glimepiride, glipizide and glidazide. Preferably, the insulin sensitising agent is selected from metformin, ciglitazone, troglitazone and pioglitazone. The present invention further provides a method of improving the body weight or glucose control of IDDM patients alone, without an insulin secretagogue or an insulin sensitising agent. In a further preferred embodiment, the present invention may be administered either concomitantly or concurrently, with the insulin secretagogue or insulin sensitising agent for example in the form of separate dosage units to be used simultaneously, separately or sequentially (either before or after the secretagogue or either before or after the sensitising agent). Accordingly, the present invention further provides for a composition of pharmaceutical or physiologically acceptable composition and an insulin secretagogue or insulin sensitising agent as a combined preparation for simultaneous, separate or sequential use for the improvement of body weight or glucose control in NIDDM or IDDM patients. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition further provides a method for the use as an insulin sensitiser. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition can be used as a method to improve insulin sensitivity in some persons with Non-Insulin Dependent Diabetes Mellitus (NIDDM, Type II diabetes) in combination with insulin therapy. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition can be used as a method to improve insulin sensitivity in some persons with Insulin Dependent Diabetes Mellitus (IDDM, Type I diabetes) in combination with insulin therapy. In further preferred embodiments, the present invention of said pharmaceutical or physiologically acceptable composition can be used as a method to improve insulin sensitivity in some persons with Non-Insulin Dependent Diabetes Mellitus (NIDDM, Type II diabetes) without insulin therapy. In an eighth aspect, the invention features a method of making the GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, and GMG-11 polypeptides described in the first aspect, wherein said method is selected from the group consisting of: proteolytic cleavage, recombinant methodology and artificial synthesis. In a ninth aspect, the present invention provides a method of making a recombinant GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptide fragment or a full length GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptide, the method comprising providing a transgenic, non-human mammal whose milk contains said recombinant GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptide fragment or full length protein, and purifying said recombinant GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptide fragment or said full-length GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptide from the milk of said non-human mammal. In one embodiment, said non-human mammal is a cow, goat, sheep, rabbit, or mouse. In another embodiment, the method comprises purifying a recombinant full-length GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptide from said milk, and further comprises cleaving said protein in vitro to obtain a desired GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptide fragment. In a tenth aspect, the invention features a purified or isolated antibody capable of specifically binding to a polypeptide of the present invention. In one aspect of this embodiment, the antibody is capable of binding to a polypeptide comprising at least 6 consecutive amino acids, at least 8 consecutive amino acids, or at least 10 consecutive amino acids of the sequence of one of the polypeptide sequences described in SEQ ID NO: 2, 4, 6, 8, 10, or 12. In an eleventh aspect, the invention features a use of the polypeptide described in the first aspect for treatment of metabolic-related diseases and disorders and/or reducing or increasing body mass. Preferably, said metabolic-related diseases and disorders are selected from the group consisting of obesity, insulin resistance, atherosclerosis, atheromatous disease, heart disease, hypertension, stroke, Syndrome X, non-insulin-dependent diabetes and Type II diabetes. Type II diabetes-related complications to be treated by the methods of the invention include microangiopathic lesions, ocular lesions, and renal lesions. Heart disease includes, but is not limited to, cardiac insufficiency, coronary insufficiency, and high blood pressure. Other metabolic-related disorders to be treated by compounds of the invention include hyperlipidemia and hyperuricemia. Yet other metabolic-related diseases or disorders of the invention include cachexia, wasting, AIDS-related weight loss, anorexia, and bulimia. In preferred embodiments, said individual is a mammal, preferably a human. In a twelth aspect, the invention provides a polypeptide of the first aspect of the invention, or a composition of the fifth aspect of the invention, for use in a method of treatment of the human or animal body. In a thirteenth aspect, the invention features methods of reducing body weight for cosmetic purposes comprising providing to an individual said pharmaceutical or physiologically acceptable composition described in the fifth aspect, or a polypeptide described in the first aspect. Preferably, for said reducing body weight said individual has a BMI of at least 20 and no more than 25. Alternatively, for said increasing body weight said individual preferably has a BMI of at least 15 and no more than 20. In a fourteenth aspect, the invention features the pharmaceutical or physiologically acceptable composition described in the fifth aspect for reducing body mass and/or for treatment or prevention of metabolic-related diseases or disorders. Preferably, said metabolic-related disease or disorder is selected from the group consisting of obesity, impaired glucose tolerance, insulin resistance, atherosclerosis, atheromatous disease, heart disease, hypertension, stroke, Syndrome X, non-insulin-dependent diabetes and Type II diabetes. Type II diabetes-related complications to be treated by the methods of the invention include microangiopathic lesions, ocular lesions, and renal lesions. Heart disease includes, but is not limited to, cardiac insufficiency, coronary insufficiency, and high blood pressure. Other metabolic-related disorders to be treated by compounds of the invention include hyperlipidemia and hyperuricemia. Yet other metabolic-related diseases or disorders of the invention include cachexia, wasting, AIDS-related weight loss, cancer-related weight loss, anorexia, and bulimia. In preferred embodiments, said individual is a mammal, preferably a human. In preferred embodiments, the identification of said individuals to be treated with said pharmaceutical or physiologically acceptable composition comprises genotyping GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 single nucleotide polymorphisms (SNPs) or measuring GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptides or mRNA levels in clinical samples from said individuals. Preferably, said clinical samples are selected from the group consisting of blood, serum, plasma, urine, and saliva. In a fifteenth aspect, the invention features the pharmaceutical or physiologically acceptable composition described in the fifth aspect for reducing body weight for cosmetic reasons. In a sixteenth aspect, the invention features methods of treating insulin resistance comprising providing to an individual said pharmaceutical or physiologically acceptable composition described in the fifth aspect, or a polypeptide described in the first aspect. In a seventeenth aspect, the invention features the pharmaceutical or physiologically acceptable composition described in the fifth aspect in a method of treating individuals with normal glucose tolerance (NGT) who are obese or who have fasting hyperinsulinemia, or who have both. In further preferred embodiments, the invention features the pharmaceutical or physiologically acceptable composition described in the fifth aspect in a method of treating individuals with gestational diabetes. Gestational diabetes refers to the development of diabetes in an individual during pregnancy, usually during the second or third trimester of pregnancy. In further preferred embodiments, the invention features the pharmaceutical or physiologically acceptable composition described in the fifth aspect in a method of treating individuals with impaired fasting glucose (IFG). Impaired fasting glucose (IFG) is that condition in which fasting plasma glucose levels in an individual are elevated but not diagnostic of overt diabetes, i.e. plasma glucose levels of less than 126 mg/dl and less than or equal to 110 mg/dl. In further preferred embodiments, the invention features the pharmaceutical or physiologically acceptable composition described in the fifth aspect in a method of treating and preventing impaired glucose tolerance (IGT) in an individual. By providing therapeutics and methods for reducing or preventing IGT, i.e., for normalizing insulin resistance, the progression to NIDDM can be delayed or prevented. Furthermore, by providing therapeutics and methods for reducing or preventing insulin resistance, the invention provides methods for reducing and/or preventing the appearance of Insulin-Resistance Syndrome. In further preferred embodiments, the invention features the pharmaceutical or physiologically acceptable composition described in the fifth aspect in a method of treating a subject having polycystic ovary syndrome (PCOS). PCOS is among the most common disorders of premenopausal women, affecting 5-10% of this population. Insulin-sensitizing agents, e.g., troglitazone, have been shown to be effective in PCOS and that, in particular, the defects in insulin action, insulin secretion, ovarian steroidogenosis and fibrinolysis are improved (Ehrman et al. (1997) J Clin Invest 100:1230), such as in insulin-resistant humans. Accordingly, the invention provides methods for reducing insulin resistance, normalizing blood glucose thus treating and/or preventing PCOS. In further preferred embodiments, the invention features the pharmaceutical or physiologically acceptable composition described in the fifth aspect in a method of treating a subject having insulin resistance. In further preferred embodiments, a subject having insulin resistance is treated according to the methods of the invention to reduce or cure the insulin-resistance. As insulin resistance is also often associated with infections and cancer, prevention or reducing insulin resistance according to the methods of the invention may prevent or reduce infections and cancer. In further preferred embodiment, the methods of the invention are used to prevent the development of insulin resistance in a subject, e.g., those known to have an increased risk of developing insulin-resistance. Thus, any of the above-described tests or other tests known in the art can be used to determine that a subject is insulin-resistant, which patient can then be treated according to the methods of the invention to reduce or cure the insulin-resistance. Alternatively, the methods of the invention can also be used to prevent the development of insulin resistance in a subject, e.g., those known to have an increased risk of developing insulin-resistance. In an eighteenth aspect, the invention features a method of preventing or treating an metabolic-related disease or disorder comprising providing or administering to an individual in need of such treatment said pharmaceutical or physiologically acceptable composition described in the fifth aspect. In preferred embodiments, the identification of said individuals in need of such treatment to be treated with said pharmaceutical or physiologically acceptable composition comprises genotyping GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 single nucleotide polymorphisms (SNPs) or measuring GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptide or mRNA levels in clinical samples from said individuals. Preferably, said clinical samples are selected from the group consisting of blood, serum, plasma, urine, and saliva. Preferably, said metabolic-related disease or disorder is selected from the group consisting of obesity, impaired glucose tolerance, insulin resistance, atherosclerosis, atheromatous disease, heart disease, hypertension, stroke, Syndrome X, non-insulin-dependent diabetes and Type II diabetes. Type II diabetes-related complications to be treated by the methods of the invention include microangiopathic lesions, ocular lesions, and renal lesions. Heart disease includes, but is not limited to, cardiac insufficiency, coronary insufficiency, and high blood pressure. Other metabolic-related disorders to be treated by compounds of the invention include hyperlipidemia and hyperuricemia. Yet other metabolic-related diseases or disorders of the invention include cachexia, wasting, FIV-related weight loss, cancer-related weight loss, anorexia, and bulimia. In preferred embodiments, said individual is a mammal, preferably non-human, preferably a cat or a dog. In a nineteenth aspect, the invention features a method of using a GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptide or polypeptide fragment to screen compounds for one or more antagonists of GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptide or polypeptide fragment activity, wherein said activity is selected from but not restricted to lipid partitioning, lipid metabolism, and insulin-like activity. In preferred embodiment, said compound is selected from but is not restricted to small molecular weight organic or inorganic compound, protein, peptide, carbohydrate, or lipid. In a preferred aspect of the methods above and disclosed herein, the amount of GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptide or polynucleotide administered to an individual is sufficient to bring circulating (blood, serum, or plasma) levels (concentration) of GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptides to their normal levels (levels in non-obese individuals). “Normal levels” may be specified as the total concentration of all circulating GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptides (full-length GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 proteins and fragments thereof) or the concentration of all circulating proteolytically cleaved GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptides only. In a further preferred aspect of the methods above and disclosed herein, weight loss is due in part or in whole to a decrease in mass of either a) subcutaneous adipose tissue and/or b) visceral (omental) adipose tissue. Full-length GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptides and polynucleotides encoding the same may be specifically substituted for a GMG-7A, GMG-7B, GMG-8, GMG-9, GMG-10, or GMG-11 polypeptide fragment or polynucleotide encoding the same in any embodiment of the present invention. |
Watermarked paper |
Watermarked paper, preferably shadow-watermarked paper is produced in conventional manner and then size-press dyed using a pigment dyestuff composition. This results in unusual and attractive decorative effects as a result of preferential dye take-up in parts of the watermarked areas, resulting in enhanced contrast between watermarked and non-watermarked areas of the paper. The invention finds particular application in wallpaper base, but can also be used in decorative or security papers. The pigment dyestuff can be fluorescent for security paper use. |
1. A method of producing a dyed watermarked paper, wherein paper carrying a watermark is produced on a papermachine in conventional manner, characterized in that dyeing is carried out at the size press of the papermachine using a pigment dyestuff composition. 2. A method as claimed in claim 1, wherein the watermark carried by the paper is a shadow watermark. 3. A method as claimed in claim 2, wherein the shadow watermark is applied by means of a dandy roll which is driven slightly faster than the papermachine wire. 4. A method as claimed in any preceding claim, wherein the pigment dyestuff provides colour under daylight illumination. 5. A method as claimed in any of claims 1 to 3, wherein the pigment dyestuff is fluorescent and provides colour under ultra-violet illumination. 6. A method as claimed in any preceding claim, wherein the paper is a wallpaper base made from a blend of a major proportion of hardwood pulp to provide bulk characteristics and a minor, but still quite high, proportion of softwood pulp to provide strength and dimensional stability. 7. A method as claimed in claim 6, wherein said blend comprises about 70% by weight of eucalyptus pulp and 30% by weight of Kraft or pine softwood pulp. 8. A method as claimed in claim 6 or claim 7, wherein the paper is calendered to a Bendtsen roughness value of about 350-400 ml min−1. 9. A method as claimed in any of claims 1 to 5, wherein the paper is a security paper or a decorative paper. |
Device for metering a urea soulution |
A device for metering urea solutions permitting a reliable reduction of nitrogen oxides in the exhaust gas of an internal combustion engine is provided. This is achieved by the fact that the device for metering the urea solution includes a sensor unit for monitoring one or more physical state variables of an enzyme-free Urea solution. |
1. A device for metering a urea solution, in particular for spraying the urea solution into the exhaust gas stream of an internal combustion engine, wherein a sensor unit is provided for monitoring one or more physical state variables of an enzyme-free urea solution using a physical measuring sensor (3, 6, 9). 2. The device as recited in claim 1, wherein the measuring sensor (3, 6) is designed for detecting an electric state variable. 3. The device as recited in one of the preceding claims, wherein the measuring sensor (3, 6, 7) is designed for detecting the pH, the dielectric constant, and/or the conductance of the enzyme-free urea solution. 4. The device as recited in one of the preceding claims, wherein the measuring sensor (3, 6, 7) includes at least two electrodes. 5. The device as recited in one of the preceding claims, wherein at least one electrode (3, 6, 7) has a structure for increasing the surface area. 6. The device as recited in one of the preceding claims, wherein two electrodes (3, 6) have an intermeshing comb-like structure. 7. The device as recited in one of the preceding claims, wherein at least one third electrode (7) is provided for detecting at least one second electric state variable. 8. The device as recited in one of the preceding claims, wherein the measuring sensor (9) is designed for detecting a physicomechanical state variable. 9. The device as recited in one of the preceding claims, wherein the measuring sensor (9) is designed for measuring the viscosity and/or density of the enzyme-free urea solution. 10. The device as recited in one of the preceding claims, wherein a vibration generator (9) is provided. 11. The device as recited in one of the preceding claims, wherein the vibration generator includes a quartz oscillator (9) and/or a piezoelectric crystal. 12. The device as recited in one of the preceding claims, wherein a sensor unit (1) having a measuring sensor (3, 6, 7) for an electric state variable of the urea solution and having a measuring sensor (9) for a physicomechanical state variable is provided, an analyzer unit being provided for determining the urea concentration from the two measured values. 13. The device as recited in one of the preceding claims, wherein a temperature sensor is provided. 14. The device as recited in one of the preceding claims, wherein a filling level sensor is provided for a storage container. 15. The device as recited in one of the preceding claims, wherein the filling level sensor is a measuring sensor according to one of the preceding claims. 16. The device as recited in one of the preceding claims, wherein a plurality of filling level sensors is provided. 17. An internal combustion engine having catalytic exhaust gas treatment, wherein a device for metering a urea solution according to one of the preceding claims is provided. |
<SOH> BACKGROUND INFORMATION <EOH>To reduce nitrogen oxides in the exhaust gas of motor vehicles, urea solution has in the past been sprayed into the exhaust gas during catalytic reduction. Urea is broken down into carbon dioxide and ammonia by chemical reaction on a hydrolysis catalyst. Ammonia then reacts selectively with nitrogen oxides to form nitrogen and water, thus removing nitrogen oxides from the exhaust gas. For reliable reduction of nitrogen oxides with a urea solution, various parameters are important, in particular the urea concentration in the aqueous solution. Sensor applications known in the past for measuring the urea concentration in the fields of medicine and biology have used urease, which enzymatically and selectively breaks down urea to form ammonia. Sensors then detect the influence of the ammonia on the pH of the solution. Information regarding the urea concentration is obtainable in this way. One disadvantage of this method of measuring the concentration of a urea solution is the instability of urease, in particular in an environment where temperatures may vary greatly. However, such temperature variations occur during use in motor vehicles, so that previous sensors according to the related art are not suitable for such an application. Therefore, the object of the present invention is to propose a device for metering urea solutions which may be used reliably for reduction of nitrogen oxides, even under difficult conditions, e.g., within broad temperature intervals. |
<SOH> SUMMARY OF THE INVENTION <EOH>Accordingly, a device according to the present invention for metering urea is characterized in that a sensor unit is provided for monitoring a physical state variable of an enzyme-free urea solution. The sensor unit here preferably includes a measuring sensor. In this way, a measurement is possible directly on the basis of the physical properties of urea in solution without intermediate enzymatic breakdown. Accordingly, this measurement is not subject to the instabilities to which an enzyme such as urease is subject. In an exemplary embodiment of the present invention, a measuring sensor is provided for detecting one or more electric state variables. Such a state variable may include, for example, the pH, the dielectric constant and/or the conductance of the solution. By measuring these or other electric state variables, it is possible to obtain information regarding the properties of the urea solution, e.g., its concentration. Measurement of these state variables is comparatively unproblematical and in particular it is possible to perform these measurements in situations of extreme temperature variations. Two electrodes may be provided to detect the electric state variables, these electrodes protruding into the urea solution. By applying an electric d.c. or a.c. voltage to the electrodes, it is possible to determine directly the aforementioned electric state variables, such as the pH, the dielectric constant, and/or the conductance. To improve the sensitivity of the measuring sensor the electrodes may be provided with a structure which increases their surface area. Such a surface area enlarging structure may be achieved, e.g., by a comb-shaped design of the electrodes, which additionally has the advantage that two electrodes designed in this way may be arranged to intermesh, so that a small distance between the two electrodes is adjustable simultaneously with a comparatively large surface area. Due to the large surface area, in particular in combination with the small distance, the test voltage and/or test current may be reduced and therefore the control and analyzing unit for a measuring sensor according to the present invention may be designed with small dimensions. A separate electrode may be provided for simultaneous determination of multiple state variables, if necessary. For example, by using such a third electrode, it is possible to determine the pH, while another state variable, e.g., the dielectric constant, is determined using the two aforementioned electrodes. In an exemplary embodiment of the present invention, a measuring sensor is provided for detecting one or more physicomechanical state variables of the urea solution. Such a physicomechanical state variable may be the viscosity or density, for example. Such physicomechanical state variables may be determined in a traditional manner, e.g., by weighing the solution and/or a part of the solution or by measuring the buoyancy of a displacement body, etc. However, in an exemplary embodiment the physicomechanical state variable is detected by a dynamic sensor. Thus, a physicomechanical state variable may be measured with the help of a vibration generator, for example. The behavior of the urea solution when agitated with the help of mechanical vibration depends to a significant extent on the physico-mechanical state variables to be detected, e.g., the density or viscosity. In an exemplary embodiment, this property may be detected directly on the vibration generator itself by measurement technology, e.g., by measuring the electric current, the frequency, etc. A quartz oscillator may be used as the vibration generator. However, any other known or future means for inducing mechanical vibration is also conceivable. For example, a piezoelectric crystal could also be used as well as a high-speed out-of-balance motor or an electromagnetic coil in conjunction with a diaphragm based on the loudspeaker principle. In an exemplary embodiment, a sensor unit is provided with a measuring sensor for an electric state variable and with a measuring sensor for a physicomechanical state variable. The measured values of the two measuring sensors are used in an analyzer unit to determine the urea concentration in solution. By analyzing two independent state variables, this yields the possibility of a more accurate and more selective determination of the urea concentration. In addition, a device according to the present invention may be combined with a temperature sensor. Since the state variables to be determined may under some circumstances be dependent upon temperature, correction of errors due to temperature variations is possible through simultaneous measurement and consideration of temperature in analysis of the state variable detected, e.g., for determination of the urea concentration in solution. In combination with a metering device for urea solution a filling level sensor may be provided for measuring the degree of filling of a storage container for the urea solution. In an exemplary embodiment, such a filling level sensor is combined directly with a measuring sensor according to the present invention for detecting one or more physical state variables. The measuring sensor according to an exemplary embodiment of the present invention shows definite differences in the measurement in solution in comparison with the measurement in the gas phase, so a filling level may also be readily measured in this way. To do so, various embodiments of the measuring sensor according to the present invention are again conceivable. For example, a measuring sensor according to the present invention may be mounted at a certain filling level and used as a threshold value sensor as the filling level passes the threshold value. For a more precise filling level measurement at different filling levels, a plurality of sensors may also be mounted at different levels. Such a sensor system may be mounted, e.g., in a sensor housing which extends over the corresponding height or on a rod-shaped sensor mount, for example. A continuous filling level measurement may be achieved by designing the measuring sensor according to an exemplary embodiment of the present invention to extend over a corresponding height. The sensor signal here is a function of the ratio of sensor areas situated in the gas phase or in the liquid solution. These sensor areas in turn vary with the filling level, so that information about the filling level is obtainable from the sensor signal in this way. |
Method of enhancing the efficiency of data flow in communication systems |
A method of improving the flow of data in a communication system having at least two links, comprising inserting into one of said links at least one enhancer, the operation of which is to a) communicate with a the unit upstream of the data flow such that the upstream unit perceives that it is communicating with the unit (s) downstream of the enhancer; b) obtaining a measure of the efficacy of operation of the down stream unit(s), and c) dependent upon the measure, varying the control of data flow sent to downstream units. |
1. A method of improving the flow of data in a communication system having at least two links connecting units at least one link has multiple simultaneous connections, comprising splitting and inserting into one of said links at least one enhancer, the operation of which is to a) communicate with a unit upstream of the data flow such that the upstream unit perceives that it is communicating with unit(s) downstream of the enhancer; b) obtaining a measure of the efficacy of operation of the down stream unit(s), by assessing the aggregate amount of unacknowledged data set (10) on the link having multiple simultaneous connections; and c) dependent upon the measure, varying the control of data flow sent to downstream units, by not sending data down a particular connection if the amount of unacknowledged data sent down that particular connection exceeds a first predetermined amount and the amount of said aggregate data exceeds a second predetermined amount. 2. A method as claimed in claim 1, wherein said communication with the upstream unit by the enhancer uses standard TCP and communication with downstream units uses a modified and adaptive protocol. 3. A method as claimed in claim 1, wherein the enhancer(s) are located in positions where upstream links are generally faster than those downstream from the enhancer. 4. A method as claimed in claim 1, wherein the upstream unit is the Internet. 5. A method as claimed in claim 1, wherein the downstream links are wireless links. 6. A communication system having at least two links connecting units at least one link having multiple simultaneous connections, and including at least one enhancer located by splitting and inserting it into one of said links, said enhancer including means to communicate with a unit upstream of the data flow such that the upstream unit perceives that it is communicating with the unit(s) downstream of the enhancer; means to obtain a measure of the efficacy of operation of the down stream unit(s) by assessing the aggregate amount of unacknowledged data set on the link having multiple simultaneous connections, and means to adjustably control data sent to downstream units, dependent upon the said measure, by not sending data down a particular connection if the amount of unacknowledged data sent down that particular connection exceeds a first predetermined amount and the amount of said aggregate data exceeds a second predetermined amount. 7. A communication system as claimed in claim 6 wherein the enhancer(s) is/are located in positions where upstream links are generally faster than those downstream from the enhancer. 8. A communication system as claimed in claim 6, wherein the upstream unit is the Internet. 9. A communication system as claimed in claim 6, wherein downstream links are wireless links. |
Promoting cell regeneration and/or cell differentiation with non-metabolizable sugar and a polymeric absorbent |
A composition comprising at least one absorbent and at least one non-metabolizable sugar, and a method for using the composition, for promoting cell regeneration and/or cell differentiation. |
1-19. (canceled) 20. A composition for promoting cellular reconstruction and/or cellular differentiation, comprising at least one absorbent and at least one nonmetabolizable sugar. 21. The composition as claimed in claim 20, wherein the composition is in an injectable form. 22. The composition as claimed in claim 20, wherein the nonmetabolizable sugar is xylose, arabinose, rhamnose or fucose. 23. The composition as claimed in claim 20, wherein the nonmetabolizable sugar is xylose or arabinose. 24. The composition as claimed in claim 20, wherein the nonmetabolizable sugar is xylose. 25. The composition as claimed in claim 20, wherein the absorbent is a polymer. 26. The composition as claimed in claim 20, wherein the absorbent is a polyacrylate, a polymethacrylate, a dextran, a carboxyvinyl polymer or an alginate. 27. The composition as claimed in claim 20, wherein the absorbent is sodium alginate, guar gum, polyacrylic acid, a carboxyvinyl polymer or carboxymethyl cellulose. 28. The composition as claimed in claim 20, wherein the absorbent is a carboxyvinyl polymer. 29. The composition as claimed in claim 20, wherein the composition is in the form of a powder. 30. The composition as claimed in claim 20, wherein the composition further comprises at least one antibiotic, antiseptic or corticosteroid. 31. The composition as claimed in claim 20, wherein the composition comprises between 50 and 95% by weight of the at least one nonmetabolizable sugar and between 5 and 50% by weight of the at least one absorbent. 32. The composition as claimed in claim 20, wherein the composition comprises between 80 and 95% by weight of the at least one nonmetabolizable sugar and between 5 and 20% by weight of the at least one absorbent. 33. A method for promoting cellular reconstruction and/or cellular differentiation, comprising administering the composition as claimed in claim 20 to an affected area in need of cellular reconstruction and/or cellular differentiation. 34. The method as claimed in claim 33, wherein the affected area is a wrinkle, deficit of dermal tissue or tissue underlying skin. 35. The method as claimed in claim 33, wherein the affected area is nerve tissue, bone, or cartilage in need of reconstruction. 36. The method as claimed in claim 33, wherein the affected area is a burn in need of healing. 37. The method as claimed in claim 33, wherein the affected area is a bedsore in need of alleviating or area susceptible to a bedsore. 38. The method as claimed in claim 33, wherein the affected area is a solid tumor. 39. The method as claimed in claim 33, wherein the affected area is a bottom of a cell culture dish to promote the attachment, differentiation, migration or growth of a cell. 40. The method as claimed in claim 33, wherein the absorbent and nonmetabolizable sugar are administered simultaneously, separately or staggered over time. |
Implant |
An artefact which is suitable for use as an implant is provided. The artefact includes a body having at least an outer surface layer of a calcium phosphate-based material. The outer surface layer has a surface area of at least 1,5m2/g. A plurality of micropores are provided in at least the outer surface layer of the body. The micropores have a maximum dimension of up to about 150 μm. |
1. An artefact which is suitable for use as an implant, the artefact including a body having at least an outer surface layer of a calcium phosphate-based material, with the outer surface layer having a surface area of at least 1,5 m2/g; and a plurality of micropores in at least the outer surface layer of the body, with the micropores having a maximum dimension of up to about 150 μm. 2. An artefact according to claim 1, wherein the calcium phosphate-based material is hydroxyapatite. 3. An artefact according to claim 1, wherein the entire body is of the calcium phosphate-based ceramic material having the plurality of micropores 4. An artefact according to claim 1, wherein the body comprises a core of dense material, and the outer surface layer which covers the core. 5. An artefact according to claim 4, wherein the core is substantially devoid of any micropores. 6. An artefact according to claim 4, wherein the core is of a different material to that of the outer surface layer material. 7. An artefact according to claim 4, wherein the core is of the same material as the outer surface layer save that it has a lower concentration of the micropores 8. An artefact according to claim 1, wherein the surface area of the outer surface layer of the body is at least 2,0 m2/g. 9. An artefact according to claim 1, wherein macropores are provided in the body. 10. An artefact according to claim 9, wherein the macropores are substantially spherical, and at least some of them are interconnected, with the macropores that are interconnected being of spherical, intercoalesced form so that adjacent macropores are coalesced together. 11. An artefact according to claim 10, wherein the macropores are from 100 to 2000 microns in size. 12. An artefact according to claim 9, wherein the majority of the macropores are of substantially the same size, and/or wherein the macropores occupy from 20% to 80% of the total volume of that portion of the body in which they occur, and/or wherein the macropores are randomly interspersed throughout that portion of the body in which they occur. 13. An artefact according to claim 9, wherein substantially all of the macropores are in communication with the outer surface of the artefact by means of capillary passages. 14. An artefact according to claim 9, wherein the maximum dimension of the micropores is from sub-micron to 150 μm. 15. An artefact according to claim 14, wherein the majority of the micropores are substantially spherical. 16. An artefact according to claim 14, wherein the majority of the micropores are of irregular shape. 17. An artefact according to claim 9, wherein the micropores are randomly interspersed throughout the body; and/or wherein the micropores are separate from one another; and/or wherein the majority of the micropores are of substantially the same size; and/or wherein the micropores occupy 60% or less of the total volume of that portion of the body in which they occur, excluding the volume occupied by any macropores. 18. An artefact according to claim 1, wherein substantially all of the micropores are in communication with the outer surface of the artefact by means of capillary passages so that the calcium phosphate-based ceramic material contains substantially no sealed or isolated micropores. 19. An artefact according to claim 1, wherein hemispherical surface concavities are provided in the outer surface layer of the body, with the surface concavities having diameters of from 100 to 2000 microns and depths of 50 to 1000 microns. 20. A method of making an artefact which is suitable for use as an implant, the method including mixing, at elevated temperature, calcium phosphate-based material in powder form with a thermoplastic binder, to produce a powder/binder mixture; granulating the powder/binder mixture; forming a green compact from the mixture; and sintering the green compact, with the maximum temperature during the sintering being ≦1050° C., thereby to obtain an artefact comprising a sintered body having a surface area of at least 1,5 m2/g and a plurality of micropores interspersed throughout the body, with the micropores having a maximum dimension of up to about 150 μm. 21. A method of making an artefact which is suitable for use as an implant, the method including mixing, at elevated temperature, a mixture of a calcium phosphate-based material in powder form and a powdered solid substance which is oxidizable into gaseous form, with a thermoplastic binder, to produce a powder/binder mixture; granulating the powder/binder mixture; forming a green compact from the mixture; sintering the green compact at a temperature, T1, and in a wet reducing or inert atmosphere, to obtain an artefact precursor; cooling the precursor to a temperature, T2, at which no further sintering takes place, while maintaining the wet reducing or inert atmosphere; while maintaining the precursor at about T2, exposing it to an oxidizing environment, so as to oxidize at least some of the solid substance and render it into gaseous form, so that it is thereby substantially removed from the body, thereby to obtain an artefact comprising a sintered body having a surface area of at least 1,5 m2/g, with the spaces which were occupied by the solid substance thus being micropores interspersed throughout thc body and having a maximum dimension of up to about 150 μm. 22. A method according to claim 21, wherein the powdered calcium phosphate-based material is hydroxyapatite, with the hydroxyapatite particles having a narrow size distribution and a mean particle size of about 1 μm. 23. A method according to claim 22, wherein the powdered solid substance is carbon, with the carbon particles having a narrow size distribution and a mean particle size of about 5 μm. 24. A method according to claim 23, wherein the formation of the green compact is effected by pressing, moulding or extruding the mixture; and/or wherein the temperature, T1, is above 1100° C.; and/or wherein the atmosphere in which the sintering is effected is a combination of a 5% hydrogen in nitrogen mixture, and steam; and/or wherein the temperature, T2, is about 900° C.; and/or wherein the oxidizing environment is air; and/or wherein the mass proportion of carbon to hydroxyapatite in the powder/binder mixture is about 1:3. 25. A method according to claim 23, wherein the carbon particles are smaller than the hydroxyapatite particles so that the carbon particles in the artefact precursor occupy interstitial sites between hydroxyapatite particles. 26. A method according to claim 23, wherein the carbon particles are of substantially the same size as the hydroxyapatite particles so that the resultant micropores are of similar shape and size to the starting carbon particles. 27. A method of making an artefact which is suitable for use as an implant, the method including mixing, at elevated temperature, a mixture of a calcium phosphate-based material in powder form and a powdered solid substance which is oxidizable into gaseous form, with a thermoplastic binder, to produce a first powder/binder mixture; granulating the first powder/binder mixture; mixing, at elevated temperature, calcium phosphate-based material in powder form with a thermoplastic binder, to produce a second powder/binder mixture containing no oxidizable powdered solid substance; granulating the second powder/binder mixture; forming the second powder/binder mixture into a core; covering the core with an outer surface layer of the first powder/binder mixture, to obtain a green compact; sintering the green compact at a temperature, T1, and in a wet reducing or inert atmosphere, to obtain an artefact precursor; cooling the precursor to a temperature, T2, at which no further sintering takes place, while maintaining the wet reducing or inert atmosphere; while maintaining the precursor at about T2, exposing it to an oxidizing environment, so as to oxidize at least some of the solid substance and render it into gaseous form, so that it is thereby substantially removed from the body, thereby to obtain an artefact comprising a sintered body having an outer surface layer, with the outer surface layer having a surface area of at least 1,5 m2/g, with the spaces which were occupied by the solid substance thus being micropores interspersed throughout the surface layer and having a maximum dimension of up to about 150 μnm. 28. A method according to claim 27, wherein the powdered calcium phosphate-based material is hydroxyapatite, with the hydroxyapatite particles having a narrow size distribution and a mean particle size of about 1 μm. 29. A method according to claim 28, wherein the powdered solid substance is carbon, with the carbon particles having a narrow size distribution and a mean particle size of about 5 μm. 30. A method according to claim 29, wherein the formation of the core and the covering thereof with the outer surface layer is effected by pressing, moulding or extruding the powder/binder mixture; and/or wherein the temperature, T1, is above 1100° C.; and/or wherein the atmosphere in which the sintering is effected is a combination of a 5% hydrogen in nitrogen mixture, and steam; and/or wherein the temperature, T2, is about 900° C.; and/or wherein the oxidizing environment is air; and/or wherein the mass proportion of carbon to hydroxyapatite in the powder/binder mixture is about 1:3. 31. A method according to claim 27, wherein the granulation of the powder/binder mixtures is effected by crushing or milling the mixtures, and sieving them to the required granule or particle size. 32. A method according to claim 27, wherein the mixing of the powder components is effected by homogenizing the components in a ball mill for an extended period of time. 33. A method according to claim 27, wherein fugitive phase particles which have sizes of 100 to 2000 microns and which are heat decomposable, are mixed with the first powder/binder mixture and/or with the second powder/binder mixture, with the green compact, prior to sintering, being heated to above the decomposition temperature of the fugitive phase particles, thereby to form macropores. 34. A method according to claim 33, wherein the fugitive phase particles are stearic acid particles which are substantially spherical, with the stearic acid particles having a size range of 500 to 1000 microns. 35-36. (canceled) |
Myoelectrically activated respiratory leak sealing |
The method and system are for sealing/unsealing (regulating) airway leaks occuring between the ventilator circuit and respiratory airways during lung ventilatory support in response to myoelectrical activity of diaphgram. Myolectrical activity of a patient's respiratory-related muscle is sensed to detect respiratory effort, and to produce a myoelectrical signal representative of the sensed muscle myoelectrical activity. Respiratory flow and pressure can also be measured to produce respective respiratory pressure and respiratory flow signals. A logic trigger sealing/unsealing of airway leaks in relation to the myoelectrical signal, respiratory flow signal and/or respiratory pressure signal to assist respiration of the patient. The amplitude of the myoelectrical signal Is compare to a given threshold, and airway leaks are sealed when the amplitude of the myoelectrical signal is higher than this threshold. Increment of myoelectrical signal amplitude can be also detected to trigger the airway leak regulating device to seal the airway leaks, while decrement of the myoelectrical signal amplitude can be detected to unseal the airway leaks and thus permit air evacuation from the patient's lungs. |
1. A method for controlling an air seal between a ventilator air circuit and a patient's respiratory airways, comprising: sensing myoelectrical activity of a respiratory-related muscle of the patient so as to yield at least one myoelectrical signal representative of respiratory effort of the patient; comparing said at least one myoelectrical signal to a predetermined value, so as to determine the highest value therebetween; and modifying the seal according to the highest value so as to control said leak. 2. A method for controlling an air seal is recited in claim 1, wherein said respiratory-related muscle is taken from the group consisting of diaphragm, parasternal intercostal muscles, sternocleidomatoids, scalenes, and alae nasi. 3. A method for controlling an air seal as recited in claim 2, wherein said respiratory-related muscle is the diaphragm. 4. A method for controlling an air seal as recited in claim 3, wherein said myoelectrical activity is sensed in the electrically active region of said diaphragm (DDR). 5. A method for controlling an air seal as recited in claim 4, wherein said myoelectrical activity is sensed near the centre of the DDR. 6. A method for controlling an air seal as recited in claim 5, further comprising: sensing at least one signal above said DDR and at least one signal below said DDR, and subtracting these two signals to yield at least one myoelectrical signal representative of the respiratory effort of the patient. 7. A method for controlling an air seal as recited in claim 1, further comprising filtering from said at least one myoelectrical signal at least one of the following disturbances: motion artefacts, electrocardiogram (ECG), electrical interference, and high frequency noise. 8. A method for controlling an air seal as recited in claim 1, wherein said predetermined value is a predetermined threshold; said air seal being modified so as to: (a) seal the patient's respiratory airways when said at least one myoelectrical signal is said highest value, thereby avoiding gas leaks during respiratory effort of the patient, and (b) unseal the patient's airways when said threshold is the highest value, thereby allowing gas leaks during relaxation of the respiratory effort of the patient. 9. A method for controlling an air seal as recited in claim 8, wherein two different thresholds are used in (a) and in (b). 10. A method for controlling an air seal as recited in claim 8, wherein said threshold is predetermined by manual adjustment using visual feedback. 11. A method for controlling an air seal as recited in claim 8, wherein said threshold is predetermined automatically by letting the level be relative to a predetermined noise level. 12. A method for controlling an air seal as recited in claim 1, further comprising multiplying a current sample of said at least one myoelectrical signal by a predetermined constant to produce a multiplied sample; wherein said predetermined value corresponds to a prior sample of said at least one myoelectrical signal; said air seal being modified so as to: (a) seal the patient's respiratory airways when said current sample is said highest value, thereby avoiding gas leaks during respiratory effort of the patient, and (b) unseal the patient's airways when said prior sample of said at least one myoelectrical signal is the highest value, thereby allowing gas leaks during relaxation of the respiratory effort of the patient. 13. A method for controlling an air seal as recited in claim 1, further comprising detecting the level of noise in said at least one myoelectrical signal; and determining whether the respiratory-related muscle of the patient is active in relation to the detected level of noise. 14. A system for controlling an air seal between a ventilator air circuit and a patient's respiratory airways, comprising: a controller; a myoelectrical sensor connected to said controller, said sensor being configured to sense at least one myoelectrical signal representative of the respiratory effort of the patient; and a respiratory sealing device connected to said controller and configured to modify the air seal according to the at least one sensed myoelectrical signal. 15. A system for controlling an air seal as recited in claim 14, wherein said respiratory sealing device is in the form of a sealing balloon. 16. A system for controlling an air seal as recited in claim 15, wherein said sealing balloon is mounted on a ventilatory assist tube of the ventilator air circuit; said ventilatory assist tube including a first lumen in the form of an air passage from the ventilatory air circuit, and a second lumen in the form of a fluid passage for fluid communication between said sealing balloon and a balloon inflation device and pressure control of said balloon. 17. A method for controlling an air seal as recited in claim 16, wherein two different thresholds are used in (a) and in (b). 18. A system for controlling an air seal as recited in claim 14, wherein said respiratory sealing device is in the form of a face mask including a seal pressure lumen. 19. A system for controlling an air seal as recited in claim 14, wherein said myoelectrical sensor is in the form of an array of electrodes. 20. A system for controlling an air seal as recited in claim 19, wherein said array of electrodes is provided with a constant inter-electrode distance. 21. A system for controlling an air seal as recited in claim 19, wherein said array of electrodes includes nine electrodes. 22. A system for controlling an air seal as recited in claim 14, wherein said myoelectrical sensor is mounted on the free end of a catheter. 23. A system for controlling an air seal as recited in claim 22, wherein said myoelectrical sensor includes a steel wire wound around said catheter. 24. A system for controlling an air seal as recited in claim 23, wherein said wound steel wire is smoothed out by solder. 25. A system for controlling an air seal as recited in claim 22, wherein said catheter is an oesophageal catheter. 26. A system for controlling an air seal as recited in claim 14, wherein said myoelectrical sensor is mounted on the free end of a nasogastric tube. 27. A system for controlling an air seal as recited in claim 19, further comprising at least one differential amplifier connected to both said electrodes and said controller. 28. A system for controlling an air seal as recited in claim 27, wherein said at least one amplifier includes single-ended amplifiers, allowing monopolar readings. 29. A system for controlling an air seal as recited in claim 27, wherein said at least one amplifier is connected to said electrodes via electric wires. 30. A system for controlling an air seal as recited in claim 27, comprising a differential amplifier for each pair of electrodes. 31. A system for controlling an air seal as recited in claim 27, wherein said at least one isolation amplifier is configured for sampling said at least one myoelectrical signal to form signal segments. 32. A system for controlling an air seal as recited in claim 14, wherein said controller is in the form of a personal computer. 33. A system for controlling an air seal between a ventilator air circuit and a patient's respiratory airways, comprising: means for sensing myoelectrical activity of a respiratory-related muscle of the patient; means for modifying the air seal; and means for controlling the air seal modifying means depending on the sensed myoelectrical activity. 34. A system as recited in claim 29, further comprising means for filtering from said at least one myoelectrical signal at least one of the following disturbances: motion artefacts, ECG, electrical interference, and high frequency noise. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Inherent to methods of administrating ventilatory support via delivering inspiratory flow, volume, and/or pressure to the airways is the influence of airway leaks occurring between the ventilator circuit and respiratory airways. A poor seal between the device used for administration of ventilatory support (e.g., endotracheal tube, face/nasal mask) and the patient (e.g., airway, airway opening) introduces difficulties to deliver appropriate gas flow, volume, or pressure into the airway system in order to inflate the lungs. |
<SOH> SUMMARY OF THE INVENTION <EOH>A present invention relates to a method and system for sealing/unsealing airway leaks between the patient's airways and a ventilatory support apparatus in response to a respiratory effort via the use of myoelectrical activity of the diaphragm (or other muscles associated with respiratory effort). Methods and systems according to the present invention allow synchronizing the activation of the seal between the respiratory airways and ventilator circuit with the neural activation of inspiratory muscles. Methods and systems according to the present invention further allow to reduce the problems related to the interface and the leaks occurring between the respiratory airways and ventilator circuit during the entire (or parts of) the period of neural inspiratory activation, which help to ensure adequate delivery of gas flow, volume and/or pressure into the lungs. Methods and systems according to the present invention also allow synchronizing the deactivation of the, seal between the respiratory airways and ventilator circuit with the neural deactivation of inspiratory muscles. More specifically, according to the present invention, there is provided a method for controlling an air seal between a ventilator air circuit and a patient's respiratory airways, comprising: sensing myoelectrical activity of a respiratory-related muscle of the patient so as to yield at least one myoelectrical signal representative of respiratory effort of the patient; comparing the at least one myoelectrical signal to a predetermined value, so as to determine the highest value therebetween; and modifying the seal according to the highest value so as to control the leak. According to another aspect of the present invention, there is provided a system for controlling an air seal between a ventilator air circuit and a patient's respiratory airways, comprising: a controller; a myoelectrical sensor connected to the controller, the sensor being configured to sense at least one myoelectrical signal representative of the respiratory effort of the patient; and a respiratory sealing device connected to the controller and configured to modify the air seal according to the at least one sensed myoelectrical signal. According to still another aspect of the present invention, there is provided a system for controlling an air seal between a ventilator air circuit and a patient's respiratory airways, comprising: means for sensing myoelectrical activity of a respiratory-related muscle of the patient; means for modifying the air seal; and means for controlling the air seal modifying means depending on the sensed myoelectrical activity. Other objects, advantages and features of the present invention will become more apparent upon reading the following non-restrictive description of preferred embodiments thereof, given by way of example only with reference to the accompanying drawings. |
Photodynamic stimulation device and methods |
A treatment device which uses a light radiation of multiple wavelengths and pulse-shaped electromagnetic fields for the photodynamic stimulation of cells, especially cells of human tissue, and also for the activation and stimulation of light sensitive substances (PTD). The device produces energy radiation by the use of semiconductor and/or laser diodes, which emit light in several separate wavelengths due to a special operation mode and the use of tuneable diodes. The equipment consists of a stand, with which machine applicators are connected via a jointed arm. The stand is freely moveable on wheels and includes a control mechanism whereby the various parameters for therapy can be adjusted and switched on and off. The stand is also connected to a hand applicator for treatment of small tissue-areas, e.g., acupuncture points. Photodynamic substances are introduced into the tissue with a special hand applicator. |
1. A device for the (PDT) photodynamic therapy and electromagnetic field stimulation of light sensitive substances and human cells, comprising: light sources with suitable strength, suitable wavelength, a light conductor, an applicator, an optic lens, a polarization filter, an electromagnetic field transmitter coil, and a control and power unit, characterized by the following: the light source consists of at least one semiconductor diode and/or at least one laser diode, the wavelength of the light source is adjustable to correspond with the light sensitive substance and the indication type, the supply of the light sources are adjustable and selectable in modes like a continuous and a pulsed mode, wherein the frequency, pulse-length and amplitude of the current pulses are selected to correspond with the type of indication and/or light sensitive substance, the frequency, pulse-shape and amplitude of the electromagnetic field pulses are adjustable to correspond with the type of indication and the light sensitive substance, wherein the light sensitive substances is are introduced to the tissue to be treated by help of a hand applicator of the inventive device using a method of air-pressure and/or iontophoresis and/or photophoresis. 2. A device according to claim 1, wherein the light source contains at least one adjustable laser diode. 3. A device according to claim 1, wherein the light source contains at least one semiconductor diode, which produces light of different wavelengths. 4. A device according to claim 1, wherein the light-source contains several semiconductor and/or laser diodes, which emit light of different wavelengths. 5. A device according to claim 1, wherein the light sources are individually selected—switched ON or OFF. 6. A device according to claim 1, wherein the applicator contains a feedback photosensor for the light reflected from the skin surface. 7. A device according to claim 1, wherein the applicator contains a feedback sensor measuring the temperature changes of the treated tissue. 8. A device according to claims 4, 5 or 6, wherein the light sources and sensors are located on a printed circuit board. 9. A device according to claim 8, wherein the electromagnetic field transmitter coil is placed in the same printed circuit board on which the light sources are placed. 10. A device according to claim 1, wherein the at least one applicator is mounted to the control unit by means of a movable jointed arm. 11. A device according to claim 10, wherein the at least one applicator comprises several single applicators hinged together so as to be adjustable at angles with respect to one another. 12. A device according to claim 11, wherein the radiation outlet is covered by a polarization filter. 13. A device according to claim 11, wherein the at least one applicator contains sensors connected to the control mechanism for measurement of reflected light for feedback control and automatic adjustment. 14. A device according to claim 11, wherein the printed circuit board, on which the light sources is located, is moved linearly and/or rotated by help of a scan mechanism. 15. A device according to claim 11, wherein at least one of the applicators is mounted with a light source emitting a fluorescent light for photo diagnosis (PD). 16. A device according to claim 15, wherein the applicator contains an optic system with magnifier for photo diagnostic (PD). 17. A device according to claim 1, further comprising a hand-held applicator containing at least one second light source connected to said pulse generator and at least one light outlet. 18. A device according to claim 17, wherein the hand-held applicator is equipped with a shaft and a head and a printed circuit board equipped with semiconductor diodes. 19. A device according to claim 17, wherein the at least one light outlet is equipped with a mounted lens and a polarization filter. 20. A device according to claim 1, further comprising a hand-held applicator containing four selective light sources and a conductor for a light fibre cable. 21. A device according to claim 20 wherein: on the circular printed circuit board four different light sources are placed at 90° intervals; there is at least one light source emitting a fluorescent light for the photodiagnosis (PD); the head comprises a light conductor rotatable in four steps to selectively conduct light for photo diagnosis (PD) or one of the three selectable and adjustable light sources of suitable wavelengths for therapy to said at least one light outlet. 22. A device according to claim 21, wherein the conductor mounted with an expander includes a fibre optic cable suitable for dental use. 23. A device according to claim 21, wherein the conductor is mounted with an expander with a flexible fibre cable for internal medical treatment. 24. A device according claim 1, wherein the hand-held applicator is formed as a rectangle with a handle at the upper part equipped with a start/stop switch. 25. A device according claim 1, wherein the applicator has a circular housing containing at least one light source equipped with a lens. 26. A device according claim 25, wherein the applicator housing is equipped with a self-adhesive pad for placing the applicator on the patient's skin when radiating acupuncture points. 27. A device according claim 1, wherein the applicator is formed as a rectangular tube containing the printed circuit boards with light sources placed at all four inner walls for intensive radiation of the blood in the inner rectangular tube. 28. A device according to claim 1, wherein the applicator for whole body treatment is made of a lower part like a bed with a hinged upper part. 29. A device according to claim 28, wherein the printed circuit boards mounted with multiple light sources are placed in a housing formed like a normal round light tube in the length of 2.15 m. 30. A device according claim 28, wherein the light tubes containing the multiple light sources are favourably produced in the form of a flat oval tube in the length of 2.15 m. 31. A device according to claim 28, wherein the light tubes containing the multiple light sources, including the electromagnetic transmitter coils, can also be built as a separate unit also containing the control unit. 32. A device according to claim 28, wherein both under and upper parts are equipped with a multiple number of light tubes of 2.15 m length containing a multiple number of said light sources of which every second could be mounted with normal UV light tubes. 33. A device according to claim 1 for introducing light sensitive substances into the tissues, comprising: a pressurized air-supply system connected by an air-supply tube to a hand applicator a chamber containing the light-sensitive substances, which is integrated in the hand applicator. 34. A device according to claim 33, wherein the air pressure can be regulated and displayed on an instrument. 35. A device according to claim 33, wherein the length of the air impulses can be regulated by means of an electronic or manual valve-system. 36. A device according to claim 33, wherein the hand applicator contains a mechanical or electrical switch system to activate the treatment. 37. A device according to claim 33, wherein the hand applicator contains a valve by the air inlet. 38. A device according to claim 33, where the treatment head is exchangeable to suit the treatment area. 39. A device according to claim 33, where the treatment head is equipped with a skin contact sensor system to protect from excessive treatment. 40. A device according to claim 33, wherein the treatment head contains a valve-system which opens up automatically upon skin contact. 41. A device according to claim 33, wherein a chamber containing the light sensitive substance is integrated in the side of the treatment head. 42. A device according to claim 33, wherein the hand applicator contains a dosage pump for the light-sensitive substance. 43. A device according to claim 33, where the housing of the hand applicator is made of insulating material and the treatment head is made of a conducting material. 44. A device according to claim 33, where the treatment head is connected to the iontophoresis generator in the control mechanism and used as an iontophoresis electrode. 45. A device according to claim 33, where the patient, during the iontophoresis treatment, holds an electric conductor handle in his hand. 46. A device according to claim 33, where the iontophoresis amplitude and frequency can be regulated on the control mechanism. 47. A device according to claim 33, wherein the hand applicator contains at least one second light source connected to said pulse generator and at least one light outlet 48. A device according claim 33, wherein the hand applicator contains a printed circuit board equipped with semiconductor diodes and a feedback sensor. 49. A device according to claim 33, wherein the at least one light outlet is equipped with a mounted lens and/or polarization filter. 50. A method of treating tissue, comprising the steps of: introducing a photosensitive substance to the tissue; determining when the tissue has absorbed a predetermined level of the photosensitive substance; and irradiating the tissue with a device according to claim 1. 51. A method according to claim 50, wherein the photosensitive substance is one of photofrin, 5-aminolevulan acid, hematoporphyrin, verteporfin, chlorins, phthaldodyanines, phenothiazine, benzoporphyrin-derivative mono acid-A (A TMPn), L-Phenylalanin. 52. A method according to claim 50, wherein the step of determining when the tissue has absorbed a predetermined level of the photosensitive substance consists in observing that the tissue undergoes a predetermined colour change when viewed under a predetermined illumination. 53. A method according to claim 52, wherein the predetermined illumination consists of an optic system and a fluorescent light source. 54. A device according to claim 28, wherein the printed circuit boards mounted with multiple light sources are placed in a housing formed like a normal round or oval light bulb. |
<SOH> BACKGROUND OF THE INVENTION <EOH> |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention provides a device with changeable applicators using a light and/or laser radiation of several wavelength ranges suited for the photodynamic stimulation of the cell energy in living cells, in particular human cells of both surface and underlying tissue. The light and/or laser radiation especially enhances vesicular respiration, most particularly stimulation of the ATP production in cells, thus increasing the therapeutic capabilities of the device. Furthermore, it is also possible to stimulate the activity of the cytochromes and the enzyme activity of the cells. The device consists of a stand, to which machine applicators are connected by means of a jointed arm. The stand, freely moveable on wheels, consists of a control mechanism, on which the desired therapy data can be adjusted and the device can be switched ON and OFF. The plain surface applicators can consist of several applicators placed side by side and flexibly connected with each other through hinges, whereby the applicators are suitable for the treatment of large-area tissues such as the human back. The applicators contain printed circuit boards mounted with semiconductor diodes and/or laser diodes (in large numbers), and the diodes are mounted with reflectors, which collect the radiation and bundle them in front of the applicator. The applicators also contain one or more transmitter coils for the emission of pulse-shaped electromagnetic radiation. The applicators are also equipped with an adjustable scan system, which permits an even and gap-free radiation of the surface with the multiple wavelengths of light. A diagnostic system (PD) containing a fluorescent light source and optics for photodiagnosis during the treatment is also included in the applicator. At least one of the applicator elements is equipped with feedback sensors for controlling the patient's response to the therapy, and via an automatic regulation system in the control mechanism it is possible to optimise the therapy results. The applicator contains a polarization filter, which is placed directly in front of the diodes. The control mechanism is also connected with a hand applicator, which is constructed for treatment of small tissue areas, e.g. acupuncture points and trigger points (pain points). The hand applicator includes a cylindrical shaft to which a headpiece is connected. A printed circuit board is fastened to the headpiece, mounted with semiconductor diodes or laser diodes. The light radiation is emitted from an axial opening in the front, equipped with a polarization filter and a lens for the focusing of the light rays. A second version hand applicator, which is especially invented for dental and/or invasive treatment, including (PD) diagnosis, contains at the front end of its shaft a printed circuit board, where 4 light and/or laser diodes of different wavelengths are placed at 90° intervals. One of these radiation sources can be selected as a fluorescent light for diagnostic purposes (PD) related to PDT therapy using light reactive biopharmaceuticals. The headpiece in front of the printed circuit board can be rotated in steps of 90° so that the expander, which is connectable with various types of optical fibres, can be positioned in front ofeither radiation source. The applicator may selectively emit blue light for the bonding and hardening of composite plastic fillings or infrared light for the treatment of dental pain, gingivitis, and wounds. In order to optimise bonding with the blue light, the output of the hand applicator is supplied at 25% of full power for the first ten seconds of the radiation time, and then is switched to full power. Acupuncture applicators made as small heads mounted on self-adhesive pads connected to the control mechanism, allow a certain number of applicators to be connected corresponding with the usual number of points utilised in classical acupuncture. The control mechanism can be programmed for a randomised acupuncture programme with changing frequency, modulation and amplitude instead of a programme with classical needling and Moxa treatment. Two applicator types are made for the stimulation of blood, either of venous blood or integrated in a heart/lung-machine. The first applicator allows radiation of blood passing the applicators' radiation sources in a 5 mm infusion lead, and the second version provides an intensive radiation of a quadrant tube, where the blood passes and receives radiation from 4 sides from light and/or laser diodes mounted on print-boards also containing transmitter coils radiating pulse-shaped electromagnetic emission. The applicators can also be designed as standard 2 meter and 15 cm long light tubes of the type commonly used in sun-beds for whole body therapy. Here it is advantageous to make the applicator in the form of a flat oval tube in order to achieve a better radiation surface. The tube applicators contain print-boards mounted with a suitable number of semiconductor light and/or laser-diodes as well as transmitter coils for the emission of pulse-shaped electromagnetic fields. The applicators are then mounted in a large body treatment arrangement like a sun-bed, where the patient lies on the lower part beneath a top part covering the whole body. Applicators of this type could be useful for treating office workers suffering from SAD disorders caused by too little exposure to natural light. The invention provides multiple wavelength stimulation that is also effective in conjunction with photodynamic therapy (PDT) chemicals. Such chemicals are applied or injected into or onto tissue to be treated, and subsequent photo-stimulation of them causes reactions in them that result in treatment of the tissue. Irradiation at multiple wavelengths enhances the effects of PDT chemicals while reducing discomfort to the patient. The present invention provides an apparatus including a semiconductor light source including a hand applicator. The hand applicator can selectively emit light of various wavelengths and introduce the light-sensitive substances into the tissue by means of air-pressure and electrical impulses (iontophoresis). The absorption time, depending on the type of light-reactive substances, may vary from 1 to 24 hours without this technique. Other advantages with the described technique are that the light-sensitive substances can be applied very precisely and the absorption dose can be improved and more accurately regulated. Other advantages of the invention will become evident from the following description of the invention and from the appended drawings, wherein: |
Miniature precision bearings for minisystems or microsystems and method for assembling such systems |
The aim of the invention is to obtain a cost-effective solution for providing a microsystem with bearings, which have sufficiently high precision and long-term stress resistance. The invention proposes a method for manufacturing, adapting or adjusting a bearing portion in a fluidal microcomponent (M) comprising a stator (30) and a rotor (40,2). Said rotor is rotatably supported on the at least one bearing portion (L10,L11) relative to said stator. Said rotor (40,2) is rotatably supported by a sleeve (10, 11) inserted into said stator (30), for forming said bearing portion, the at least one sleeve being inserted in said stator as a bearing sleeve and comprising an inner surface and an outer surface (10i, 10a; 11i, 11a). Before being inserted in said stator, said bearing sleeve (10, 11) is a separate bearing component comprising an inner surface (10i, 11i) as an inner bearing surface, which is mechanically micro-finished before being inserted into said stator (30). The outer surface (10a, 11a) of said bearing component (10, 11) is mechanically permanently connected with said stator (30). |
1. Method for at least one of manufacturing, adapting and adjusting at least one bearing portion in a fluidal mini to micro component (M), said component comprising a stator (30) and at least one rotor (40,2), said rotor being supported at said at least one bearing portion (L10,L11) relative to said stator to be rotatable and rotatably supported; characterized in that (a) said rotor (40,2) is rotatably supported by a sleeve (10,11) inserted in said stator (30), for forming said bearing portion, said at least one sleeve is inserted in said stator as a bearing sleeve and comprises an inner surface and an outer surface (10i,10a; 11i,11a); (b) said bearing sleeve (10,11), prior to inserting in said stator, is a separate bearing component, comprising an inner bearing surface as said inner surface (10i,11i), and said bearing sleeve is mechanically micro-finished on at least said surface prior to inserting in said stator (30); (c) said outer surface (10a,11a) of said bearing component (10,11) is brought into a mechanically permanent connection with said stator (30). 2. The method of claim 1, wherein said outer surface (10a,11a) of said bearing component (10,11) is inserted by friction setting into a receiving portion (30i,30i′) of said stator, said receiving portion having a smaller inner dimension, whereby a particularly radial displacement of a surface portion of a softer material of said stator is effected by said bearing sleeve (10,11), for providing a mechanically permanent connection with said stator (30). 3. The method of claim 1, wherein said outer surface (10a,11a) of said bearing component (11,10) is inserted into a receiving portion of said stator (30), said receiving portion having a larger inner dimension, and a gap (13) or an irregular interspace between said bearing component and said receiving portion is provided with a hardenable filling material (12), said filling material hardening after being filled in, for a mechanically permanent connection of said bearing component (10,11) with said stator (30). 4. The method of claim 3, wherein said hardening is obtained by one of cooling down, particularly when a solder is used as filling material, and a chemical reaction, particularly when an adhesive substance is used as filling material (12). 5. The method of claim 1, wherein at least two axially spaced bearing portions (L10,L11; 10,11) are provided in said stator (30), one of said bearing portions being formed by a first sleeve (10) and the other of said bearing portions being formed by a further sleeve (11), said first sleeve being fixed and said second sleeve being fixed to said stator (30) and relative to each other. 6. The method of claim 1, wherein said mechanical micro-finishing of said inner surface (10i,11i) of said bearing component is one of grinding, honing, and lapping. 7. The method of claim 2, wherein during the entire inserting operation, said bearing component is guided and supported (50) by a mechanical contact, to result in an accurately positioned bearing component in said stator (30) during said friction setting. 8. The method of claim 3, wherein said bearing component (10,11) is supported in an accurate position during hardening, for obtaining an accurately positioned alignment of said supported bearing component in said stator (30) after said hardening. 9. The method of claim 1, wherein said bearing portion is a unilateral bearing, particularly being positioned in said stator (30) as housing, such that said bearing portion is closer to a drive than said microsystem (M). 10. The method of claim 1, wherein said at least one bearing component (10,11) has a cylindrical shape, particularly also an outer cylindrical shape. 11. The method of claim 1, wherein a first and a second bearing body (10,11) each being shaped as a sleeve, and each defining an axis (100,101), said two sleeves being mounted in a housing (30,31) as stator, to have eccentric or radially offset (dr) axes relative to each other, and to be axially offset, for obtaining a bearing support at an axial distance (dL) or non-identical axial positions (L11,L10) for a shaft (40) and a bearing support for an outer rotor (2) as two rotors. 12. The method of claim 1, wherein two bearing components are inserted into said stator, into two axially spaced portions (30i,30i′) of an inner opening (31) of said stator (30), and wherein said two portions of said opening (31) are designed eccentrically with respect to each other, for attributing each of two rotors to one of said two bearing components for being rotatably supported. 13. The method of claim 1, wherein at least two axially spaced bearing portions (L10,L11; 10,11) are provided in said stator (30), one of said bearing portions being formed by a first sleeve (10) and the other of said bearing portions being formed by a further sleeve (11), said first sleeve being fixed and said second sleeve being fixed relative to said stator (30) and relative to each other; and wherein two bearing components are inserted into said stator, into two axially spaced portions (30i,30i′) of an inner opening (31) of said stator (30), and wherein said two portions of said opening (31) are designed eccentrically with respect to each other, for attributing each of two rotors to one of said two bearing components for being rotatably supported; and wherein said first bearing component (10) is provided for supporting said shaft (40), and said second bearing component (11) is provided for supporting said rotor (2). 14. The method of claim 12, wherein said first bearing component (10) has an outer diameter of an outer surface (10a) with a first diameter (d10a), and said second bearing component has an inner diameter of an inner bearing surface (11i) with an inner diameter (d11i), said inner diameter being smaller than said outer diameter, for an axial supporting surface (10c) between said bearing bodies (10,11) in a difference portion; for an axial bearing surface (b,10b) within said inner diameter. 15. The method of claim 1, wherein said at least one bearing component is a freely shaped bearing body, having an inner surface (11i,10i) suitable for a bearing support. 16. The method of claim 11, wherein said radial offset (dr) and said inner diameter and said outer diameter (d10a,d11i) are coordinated such that said two bearing bodies contact each other circumferentially continuously at a face end, at a support surface ring (10c). 17. The method of claim 1, wherein a first and a second bearing body (10,11) each being shaped as a sleeve, and each defining an axis (100,101), said two sleeves being mounted in a housing (30,31) as stator, to have eccentric or radially offset (dr) axes relative to each other, and to be axially offset, for obtaining a bearing support at an axial distance (dL) or non-identical axial positions (L11,L10) for a shaft (40) and a bearing support for an outer rotor (2) as two rotors; and wherein two bearing components are inserted into said stator, into two axially spaced portions (30i,30i′) of an inner opening (31) of said stator (30), and wherein said two portions of said opening (31) are designed eccentrically with respect to each other, for attributing each of two rotors to one of said two bearing components for being rotatable supported; and wherein said first bearing component (10) has an outer diameter of an outer surface (10a) with a first diameter (d10a), and said second bearing component has an inner diameter of an inner bearing surface (11i) with an inner diameter (d11i), said inner diameter being smaller than said outer diameter. for an axial supporting surface (10c) between said bearing bodies (10,11) in a difference portion; for an axial bearing surface (b,10b) within said inner diameter; and wherein said radial offset (dr), said inner diameter, and said outer diameter of a respective sleeve are coordinated such that a circumferentially extending face end or strip portion (10c,10b,b) is provided, as one of an axial support when permanently fixing said second bearing body and an operational bearing (b) of at least one rotatable part of said microsystem (M), particularly of one of said outer rotor and said inner rotor. 18. The method of claim 17, wherein said strip portion as a face end surface (10b) does not have a constant width (b) along its circumferential extension. 19. The method of claim 1, wherein the bearing portion is constructed of one of hardened steel, ceramic, and hard metal. 20. Microsystem with a fluidal flow, said microsystem comprising a first portion for one of an inlet and an outlet of a fluid (F) and a second portion having at least one bearing portion (10,11), wherein (a) a rotor (40,2) is rotatably supported relative to a stator (30) by at least one bearing body (10,11), said bearing body being prefabricated of a hard material; (b) said stator (30) comprises an inner surface portion (30i,30i′) receiving said bearing body (10,11), said inner surface portion being made of a softer material than said bearing body. 21. The microsystem of claim 20, wherein two bearing bodies (10,11) are made of said hard material and positioned in said stator. 22. The microsystem of claim 21, wherein two bearing bodies are radially offset relative to each other and are arranged in said stator such that a respective center axis (100,101) of a respective bearing body (10,11) has a radial distance from the other (dr) axis. 23. The microsystem of claim 20, comprising two axially offset (dL), but closely neighboring bearing positions as separate bearing bodies (10,11) in said stator (30). 24. The microsystem of claim 20, wherein said stator (30) comprises as an inner portion an initially not fitting receiving portion (30i′, 30i) for said bearing body (10,11). 25. The microsystem of claim 24, wherein, when inserting said bearing body into said not fitting portion, said initially not fitting portion and said at least one bearing body (10,11) form a gap, said gap having a width of larger than zero, and a hardening filling material is introduced into said gap (13), for fixing said bearing body relative to said stator after a hardening of said filling material (12). 26. The microsystem of claim 20, wherein said initially not fitting portion is an undersize of said receiving portion (30i′,30i) of said stator, into which a bearing body (10,11) is mechanically pressed by friction setting, said bearing body being radially larger than said receiving portion and made of a harder material, thus displacing part of said receiving portion of said stator (30), but at least modifying said receiving portion with respect to its surface structure. 27. Method for at least one of manufacturing, adapting and adjusting at least one bearing portion in a fluidal mini to micro system (M), said system comprising a stator (30) and at least one rotor (40,2), said rotor being rotatably supported at said at least one bearing portion (L10,L11) to be rotatable relative to said stator, characterized in that (a) said stator, prior to inserting at least one separate bearing body, comprises a portion (30i,30i′) not suitable for a bearing support, said portion being made of a softer material than said bearing body (10,11) (as a non-fitting portion or misfit); (b) said non-fitting portion, by inserting, particularly by pressing in or gluing in, said bearing body made of a harder material with respect to the material of said stator, is provided as a mechanical assembly and adjusting portion, for spatially-geometrically, high-precisely determining an inner surface (11i,10i) defined by said bearing body as a bearing surface for rotatably supporting said rotor (40,2). 28. The method of claim 27, wherein said pressing in is effected by displacing, but at least by modifying an inner surface (30i) of said bearing body. 29. The method of claim 28, wherein a hardening material (12) is introduced into one of a gap and, subsequently to said mechanical displacement, the remaining interspaces, for obtaining a mechanical fixing and a spatial/geometrical positioning of said bearing body as a bearing portion after hardening of said filling material (12). 30. The method of claim 1, wherein said bearing component (10,11) has at least one of an outer diameter of less than 15 mm, particularly less than 10 mm, and an inner diameter of less than 5 mm, particularly less than 2 mm, for supporting an outer rotor (2), particularly a shaft (40). 31. The method of claim 27, wherein two bearing portions (L10,L11) are determined successively, one by friction setting (10a,10i) and a further one by soldering, gluing in (11a,11i) or friction setting. 32. The method of claim 31, wherein initially friction setting and thereafter gluing in takes place. 33. The method of claim 27; wherein two bearing portions (L10,L11) are determined successively, one by friction setting (10a,10i) and a further one by soldering, gluing in (11a,11i) or friction setting; and wherein initially friction setting and thereafter gluing in takes place; and wherein said first bearing portion inserted by friction setting is used as an auxiliary bearing portion determined relatively to said stator (30), for spatially/geometrically positioning said second bearing portion (L11) prior to fixing/locating it by said hardening material (12). 34. The method of claim 27, wherein two bearing portions (L10,L11) are determined successively, one by friction setting (10a,10i) and a further one by soldering, gluing in (11a,11i) or friction setting; and wherein said first bearing portion inserted by friction setting is used as an auxiliary bearing portion determined relatively to said stator (30), for spatially/geometrically positioning said second bearing portion (L11) prior to fixing/locating it by said hardening material (12); and wherein said second bearing portion (11;11a,11i) is positioned in at least one of an axial (10b) and a radial (10i,11i) direction, supported by said first bearing portion (10). 35. Method for manufacturing a first and a second bearing portion for two rotating bodies (2,40) and forming a joint system of a stator and rotors, rotatable relative to said stator, wherein said mechanically precise joint system is obtained from two bearing portions (L10,L11) and corresponding two rotors (2,40) by simple, but mechanically/geometrically precise bodies (10,11) and a stator (30) not precise enough for a bearing support, and by a permanent connecting technology, permanently fixing said precise bodies with respect to each other and with respect to said stator; by subsequently inserting and bearingly supporting said two rotors (2,40) in said stator (30;10,11) adapted for a bearing support by said connecting technology and said precise bodies (10,11). |
Vectors capable of imparting herbicide resistance and viral cross protection and methods |
A nucleic acid vector for concurrently imparting herbicide resistance to a plant and cross protecting the plant. The vector includes sufficient potyvirus nucleic acid sequence to permit viral replication and spread. The vector further includes mutations which attenuate symptoms of viral infection in the plant and which abolish transmission of the virus by an insect vector. The vector further includes an additional nucleic acid sequence encoding a protein which imparts resistance to an herbicide when expressed in the infected plant. Further disclosed is a method of concurrently imparting herbicide resistance to a plant and cross protecting the plant against at least one potyvirus comprising inoculating at least a portion of the plant with the vector. Further disclosed are plant cells treated according to the method and virions derived from the vector. |
Subsets and Splits