Abstract: A two-chain insulin analogue is provided containing (a) a B chain modified by the addition of a C-terminal diol element in combination with (b) a glucose-binding element attached to the A chain at or near its N terminus, optionally linked to a D-amino acid. A “flipped” set of insulin analogues wherein the A chain is modified by addition of an N-terminal diol element whereas the glucose-binding element is attached at or near the C terminus of the B chain is also provided. Compositions comprising such insulin analogues are used in methods of treating a patient with diabetes mellitus.

Abstract: A glucagon analogue containing a lactam bridge between a Lysine introduced at position 13 and a Glutamic Acid introduced at position 17, optionally including C-terminal extensions and optionally including a second side-chain/side-chain staple beginning at or C-terminal to residue 20. The second staple may also be an (i, i+4) lactam bridge, an (i, i+3) disulfide bridge between D-Cysteine and L-Cysteine or an (i, i+7) disulfide bridge between L-Cysteine and L-Cysteine. A fusion protein containing an N-terminal lactam-stabilized glucagon analogue as above and a C-terminal single-chain insulin (SCI) analogue wherein the C domain of the SCI contains 4-11 residues is also disclosed herein. A method of treating a patient with diabetes mellitus comprises the subcutaneous, intraperitoneal, or oral administration of a physiologically effective amount of the glucagon analogue or glucagon-SCI fusion protein is also provided.

Abstract: A single-chain insulin analogue comprises the insulin B-chain polypeptide sequence, the insulin A-chain polypeptide sequence, and a connecting polypeptide sequence of 5-11 amino acids linking the C-terminal amino acid of the B-chain polypeptide to the N-terminal amino acid of the A-chain polypeptide. The analogue comprises an acetylated Lys at a location selected from the group consisting of any of the amino acids in the connecting polypeptide, B0-B3, B28-B29 or A14, relative to wild type insulin, or comprises an acetylated amino acid at the N-terminal amino acid of the single-chain insulin analogue. The single-chain insulin analogue may be acylated with a C6-C21 fatty acid, which may be attached to the e-amino group of a unique Lysine residue or the a-amino group of the N-terminal amino acid of the single-chain insulin analogue. The insulin analogue may be used to lower the blood sugar of a patient in need thereof.

Abstract: A two-chain insulin analogue is provided containing (a) a B chain modified by a C-terminal diol element such that one hydroxyl group substitutes for the C-terminal carboxylate function in combination with (b) a glucose-binding element attached to the A chain at or near its N terminus. Compositions comprising such insulin analogs are used in methods of treating a patient with diabetes mellitus.

Abstract: A pharmaceutical composition comprises an effective amount of an insulin analogue comprising modified A-chain and B-chain polypeptides. The modified A chain comprises one or more substitutions relative to wild-type human insulin A-chain selected from a Gln, His or Glu substitution at position A8, a Glu or Ala substitution at position A14, and an Ala, Gln, Gly, or Thr substitution at position A21. The modified B-chain polypeptide comprises one or more modifications relative to wild-type human insulin B-chain selected from a deletion of the amino acid or amino acids at position B1, B1 and B2, or B1-B3, an Ala or Glu substitution at position B2, a Glu or Ala substitution at position B3, an Ala substitution at position B4; and a Glu or Lys substitution at position B29. The composition comprises one or more of iloprost, citrate, EDTA and a polyphosphate compound. The composition may be used to treat diabetes.

Abstract: A premixed acidic solution contains two single-chain insulin analogues. One has isoelectric point between 6.5 and 8.0 (SCI-A) and the other has isoelectric point between 4.5 and 6.0 (SCI-B), such that biphasic basal and prandial insulin activity is provided on subcutaneous injection. Each protein is an analogue of a mammalian insulin, such as human insulin, with insertion of engineered C domain of length 5-11 residues; the respective C domains of SCI-A and SCI-B may be different. SCI-A contains a Glycine, Alanine, Serine or Glutamine substitution at position A21 and may contain a basic residue at position A8 and Glutamine at position B13. SCI-B may contain a non-beta-branched substitution at position A8, either Alanine or Glutamic Acid at position A14, and substitutions at positions B28 and/or B29 to confer rapid action. A method of treating a patient comprises administering the insulin analogue or a physiologically acceptable salt thereof to a patient.

Abstract: A single-chain insulin analogue containing (i) diverse amino-acid substitutions at position A14; (ii) wild-type or variant residues at positions A8 and A14; and (ii) an engineered C-domain segment of lengths 4-6 containing a specific set of Alanine substitutions and/or deletions derived from the prototype C-domain sequence Glu-Glu-Gly-Pro-Arg-Arg. The analogue may otherwise be an analogue of a mammalian insulin, such as human insulin, may optionally include standard or non-standard modifications that (i) augment the stability of insulin, (ii) cause a shift in the isoelectric point to enhance or impair the solubility of the protein at neutral pH or (iii) reduce cross-binding of the protein to the Type I IGF receptor. Formulations of the above analogues at successive strengths U-100 to U-1000 in soluble solutions under acidic or neutral pH values (e.g., pH 3.0-4.2 and 6.5-7.8, respectively) and optionally in the presence of zinc ions at a molar ratio of 2.2-10 zinc ions per six insulin analogue monomers.

Abstract: A fan blade includes a metallic body, a first composite cover, and a second composite cover. The metallic body may have a first side, a second side, a plurality of first retention slots, and a plurality of second retention slots, in accordance with various embodiments. The first and second retention slots may extend from the first side to the second side of the metallic body. The first composite cover may be coupled to the first side of the metallic body and may include a plurality of first fingers that extend through the first retention slots and are coupled to the second side of the metallic body. The second composite cover may be coupled to the second side of the metallic body and may include a plurality of second fingers that extend through the second retention slots and are coupled to the first side of the metallic body.

Abstract: Disclosed herein are insulin analogues containing a pairwise substitution of cysteine at positions A6 and A11 with selenocysteine residues such that a diselenide bridge forms between these positions. The disleenide bridge of the [SecA6, SecA11] insulin analogues stabilizes the analogue relative to its [CysA6, CysA11] parent structure, providing formulations with extended shelf life at or above room temperature. Also provide are methods of treating diabetes mellitus using the [SecA6, SecA11] insulin analogue.

Abstract: A two-chain insulin analogue contains a modified A-chain polypeptide and a modified B-chain polypeptide. The A-chain polypeptide comprises one or more of: a His or Glu substitution at position A8, a Glu substitution at position A14; and a Gln or Arg substitution at position A17. The B-chain polypeptide comprises one or more of: a deletion of the amino acids at position B1, B1-B2, B1-B3, B30 or a combination thereof; an Ala or Glu substitution at position B2; a Glu substitution at position B3. The analogue exhibits thermodynamic stability in a zinc-free solution, decreased self-association, maintains biological potency, and no increased mitogenicity. The analogue exhibits resistance to chemical degradation and physical degradation. A method of treating a patient with diabetes mellitus or obesity comprises administering a physiologically effective amount of the insulin analogue or a physiologically acceptable salt thereof to a patient.

Abstract: A rotor blade is provided for a turbine engine. This rotor blade includes an airfoil extending longitudinally between a leading edge and a trailing edge. The airfoil extends spanwise to a tip. The airfoil is configured with a plurality of projections arranged longitudinally along the tip.

Abstract: A single-chain insulin analogue containing an engineered C-domain segment of lengths 4-11 conforming to the sequence pattern [Asp/Glu]-Ala-An-Ala-Xaa where An designates a sub-segment of 0-7 Alanine residues and where Xaa designates an amino-acid residue selected from the amino acids Alanine, Arginine, Asparagine, Aspartic Acid, Glutamic Acid, Histine, Lysine and Serine. The analogue may be an analogue of a mammalian insulin, such as human insulin, may optionally include standard or non-standard modifications that (i) augment the stability of insulin, (ii) cause a shift in the isoelectric point to enhance or impair the solubilty of the protein at neutral pH or (iii) reduce cross-binding of the protein to the Type I IGF receptor. A method of treating a patient with diabetes mellitus comprising the administration of a physiologically effective amount of the protein or a physiologically acceptable salt thereof to a patient.

Abstract: A two-chain insulin analogue contains a modified A-chain polypeptide and a modified B-chain polypeptide. The A-chain polypeptide comprises one or more of: a His or Glu substitution at position A8, a Glu substitution at position A14; and a Gln or Arg substitution at positon A17. The B-chain polypeptide comprises one or more of: a deletion of the amino acids at position B1, B1-B2, B1-B3, B30 or a combination thereof; an Ala or Glu substitution at position B2; a Glu substitution at position B3. The analogue exhibits thermodynamic stability in a zinc-free solution, decreased self-association, maintains biological potency, and no increased mitogenicity. The analogue exhibits resistance to chemical degradation and physical degradation. A method of treating a patient with diabetes mellitus or obesity comprises administering a physiologically effective amount of the insulin analogue or a physiologically acceptable salt thereof to a patient.

Abstract: The present invention provides rapid-acting insulin and insulin analogue formulations. The invention further provides delivery devices, particularly infusion sets, which allow for the rapid absorption of insulin and insulin analogues, as well as other active agents. Methods of using the insulin and insulin analogue formulations as well as the insulin delivery devices for treating subjects with diabetes mellitus are also provided.

Abstract: A single-chain insulin analogues may comprise an insulin B-chain polypeptide sequence connected by a connecting polypeptide (or C-domain) sequence to an insulin A-chain polypeptide sequence. The connecting polypeptide sequence may be Glu-Xaa-Gly-Pro-Arg-Arg where Xaa is Glu or Ala. The insulin analogues may additionally comprise Glu or His substitutions at the position corresponding to A8 of human insulin and/or a Glu substitution at the position corresponding to A14 of human insulin. In some embodiments, the insulin analogues may additionally comprise either a Pro or Glu at the positions corresponding to B28 and B29 of wild-type insulin. Additional substitutions may comprise Phe or Trp at the position corresponding to A13 of wild type insulin and/or Gln, Arg, Phe, or Glu at the position corresponding to A17 of wild type insulin. In some embodiments, a Glu substitution at the position corresponding to B16 of wild type insulin may be present.

Abstract: An airfoil for a gas turbine engine according to an example of the present disclosure includes, among other things, an airfoil body defining a recessed region and including at least one rib dimensioned to loop about a respective pocket within a perimeter of the recessed region. At least one cover skin is welded to the airfoil body along the at least one rib to enclose the recessed region. The at least one cover skin is welded to the at least one rib along a respective weld path. The weld path defines a weld width, the at least one rib defines a rib width, and a ratio of the weld width to the rib width is equal to or greater than 3:1 for each position along the weld path. A method of forming a gas turbine engine component is also disclosed.

Abstract: A single-chain insulin analogue comprises a B-chain insulin polypeptide connected to an A-chain insulin polypeptide by a C-domain polypeptide. The B-chain insulin polypeptide contains a Cysteine substitution at position B4. The A-chain insulin polypeptide contains a Cysteine substitution at position A10. The C-domain polypeptide is 4 to 11 amino acids long. The analogue mitigates the unfavorable activity of this 4th disulfide bridge in conventional two-chain insulin analogues resulting in a duration of insulin signaling similar to that of wild-type insulin. A method of treating a patient with diabetes mellitus comprises the administration of a physiologically effective amount of the protein or a physiologically acceptable salt thereof to a patient. Use of a single-chain insulin analogue of the present invention in an insulin delivery device (such as a pump or pen) or as part of a high-temperature polymer-melt manufacturing process.

Abstract: A single-chain insulin comprises a C-domain of 6 to 11 amino acid residues comprising at least two acidic residues at the N-terminal side of the C-domain and at least two basic residues at the C-terminal side of the C-domain peptide, a basic amino acid residue at the position corresponding to A8 of human insulin, and an acidic amino acid residue at the position corresponding to A14 of human insulin. The C-domain may contain a 2 to 4 amino acid joint region between the acidic and basic residues. Residues C1 and C2 may have a net negative charge of ?1 or ?2; and the remaining C-domain segment may culminates with two basic residues. A pharmaceutical composition comprises the single-chain insulin, formulated at a pH within the range 7.0 to 8.0, and may be formulated at a concentration of 0.6 mM to 5.0 mM and/or at a strength of U-100 to U-1000.

Abstract: A rotor blade is provided for a turbine engine. This rotor blade includes an airfoil extending longitudinally between a leading edge and a trailing edge. The airfoil extends spanwise to a tip. The airfoil is configured with a plurality of projections arranged longitudinally along the tip.

Abstract: An insulin analogue comprises an insulin A-chain polypeptide and an insulin B-chain polypeptide. The A-chain polypeptide contains a Glu substitution at a position corresponding to position A8, and an Ala, Glu, Gln, His, Tyr, Phe or Trp substitution at a position A13, relative to wild type insulin. The B-chain polypeptide contains a cyclohexanylalanine substitution at position B24, relative to wild type insulin. The analogue may be an analogue of a mammalian insulin, such as human insulin. A nucleic acid encoding such an insulin analogue is also provided. A method of lowering the blood sugar of a patient comprises administering a physiologically effective amount of the insulin analogue or a physiologically acceptable salt thereof to a patient.