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.

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 fan blade having an opening on one side exposing one or more cavities, and a composite cover that fits over the opening, is provided. The composite cover has a variable thickness resulting from the layering of cover plies having different shapes, and is designed to achieve a lightweight fan blade having an optimal level of stiffness.

Abstract: A fan blade includes a blade body, a composite segment and a cover. The blade body extends from a blade root to an opposed blade tip along a longitudinal axis. The blade body defines a leading edge and a trailing edge. A first airfoil surface extends from the leading edge to the trailing edge. A pocket is defined between the leading edge, the trailing edge, the blade root and the blade tip. The pocket has a bottom surface that opposes the first airfoil surface across the blade body. The composite segment is disposed in the pocket. The cover is mounted to the composite segment and to the blade body to form a second airfoil surface opposed to the first airfoil surface.

Abstract: Disclosed is a fan blade for a gas turbine engine, including: an airfoil, a cavity formed in the airfoil, a cover configured to cover the cavity, the cover when secured to the airfoil encloses the cavity in the airfoil, a conduit extending from the cavity to an exterior surface of the fan blade, and a check valve located in the conduit, the check valve configured to regulate an internal pressure of the cavity when the cover is secured to the airfoil.

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: A turbomachine airfoil element includes an airfoil that has pressure and suction sides spaced apart from one another in a thickness direction and joined to one another at leading and trailing edges. The airfoil extends in a radial direction a span that is in a range of 17.2-18.2 inches (436-462 mm). A chord length extends in a chordwise direction from the leading edge to the trailing edge at 50% span is in a range of 10.0-11.0 inches (255-281 mm). The airfoil element includes at least two of a first mode with a frequency of 51±10% Hz, a second mode with a frequency of 147±10% Hz, a third mode with a frequency of 267±10% Hz, a fourth mode with a frequency of 350±10% Hz, a fifth mode with a frequency of 454±10% Hz and a sixth mode with a frequency of 619±10% Hz.

Abstract: An insulin analogue comprises a B-chain polypeptide containing a cyclohexanylalanine substitution at position B24 and optionally containing additional amino-acid substitutions at positions A8, B28, and/or B29. A proinsulin analogue or single-chain insulin analogue contains a B domain containing a cyclohexanylalanine substitution at position B24 and optionally contains additional amino-acid substitutions at positions A8, B28, and/or B29. 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. A method of semi-synthesis using an unprotected octapeptide by means of modification of an endogenous tryptic site by non-standard amino-acid substitutions.

Abstract: A two-chain insulin analogue contains Aspartic Acid at position B10 and penta-fluoro-Phenylalanine at position B24, optionally Histidine or Glutamic Acid at position A8, optionally additional substitutions or modifications at positions A13 and/or A14 and/or B28 and/or B29. The analogue may be an analogue of a mammalian insulin, such as human insulin, may optionally include (i) N-terminal deletion of one, two or three residues from the B chain, (ii) a mono-peptide or dipeptide C-terminal extension of the B-chain containing at least one acidic residue, and (iii) other modifications known in the art to enhance the stability of insulin. Formulations of the above analogues at successive strengths U-100 to U-1000 in soluble solutions at at least pH value in the range 7.0-8.0 in the absence or presence of zinc ions at a molar ratio of 0.00-0.10 zinc ions per insulin analogue monomer.

Abstract: Disclosed is a fan blade for a gas turbine engine, including: an airfoil, a cavity formed in the airfoil, a cover configured to cover the cavity, the cover when secured to the airfoil encloses the cavity in the airfoil, a conduit extending from the cavity to an exterior surface of the fan blade, and a check valve located in the conduit, the check valve configured to regulate an internal pressure of the cavity when the cover is secured to the airfoil.

Abstract: A fan of a gas turbine engine includes a plurality of fan blades secured to a rotor, each of the plurality of fan blades having an airfoil secured to the rotor at one end, wherein the airfoil comprises pockets filled with an elastomeric composite.

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 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 fan blade includes first and second portions that are secured to one another and provide a cavity. The first and second portions form an exterior airfoil surface that extends in a radial direction from a root to a tip and in a chord-wise direction from a leading edge to a trailing edge. Radial ribs extend in a radial direction from the root toward the tip and are spaced apart from one another in the chord-wise direction. First and second angled ribs intersect one another at a first apex. The radial ribs intersect at least one of the first and second angled ribs. The first and second angled ribs are at an angle relative to one of the radial ribs. The angle is in a range of 45°+/?30°.

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: An insulin analogue comprises an insulin B-chain polypeptide containing a Trp substitution at position B26 relative to the sequence of wild-type insulin. The insulin analogue may additionally comprise an OrnB29 substitution, a C-terminal extension of one or two basic amino acids such as Arg-Arg, a GlnB13 substitution, a GlyA21 substitution, a HisA8 or ArgA8 substitution, or a combination thereof. The insulin analogue may be formulated in the presence of zinc ions at a molar ratio of 2.2-10 zinc ions per six insulin analogue monomers. The molecular design is believed to stabilize the dimer interface of insulin (and its stable formulation as a zinc insulin hexamer) by means of aromatic amino-acid substitutions at position B26 of the B chain. The insulin analogs of the present invention may have two chains (A and B) as in mammalian insulins or may be engineered with a C domain (4-12 amino acids in length) to provide a single-chain.

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: 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.

Abstract: A two-chain insulin analogue contains Aspartic Acid at position B10 and penta-fluoro-Phenylalanine at position B24, optionally Histidine or Glutamic Acid at position A8, optionally additional substitutions or modifications at positions A13 and/or A14 and/or B28 and/or B29. The analogue may be an analogue of a mammalian insulin, such as human insulin, may optionally include (i) N-terminal deletion of one, two or three residues from the B chain, (ii) a mono-peptide or dipeptide C-terminal extension of the B-chain containing at least one acidic residue, and (iii) other modifications known in the art to enhance the stability of insulin. Formulations of the above analogues at successive strengths U-100 to U-1000 in soluble solutions at at least pH value in the range 7.0-8.0 in the absence or presence of zinc ions at a molar ratio of 0.00-0.10 zinc ions per insulin analogue monomer.

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.