Abstract: One aspect of the invention relates to compounds that inhibit the activity of p97, such as by binding covalently to a cysteine residue in the active site. In certain embodiments, the invention relates to the treatment of disease, such as cancer, comprising administering a compound of the invention.

Abstract: Hypoxia, a state of lower than normal tissue oxygen tension, has recently been implicated in a host of human diseases, including cancer, heart disease, and neurological disorders. Novel associations between p97 and other proteins, including UBX-domain-containing proteins (UBX-polypeptides), HIF1?, and a variety of E3 ligases are provided herein. The disclosure provides complexes comprising UBX-domain-containing polypeptides (UBX-polypeptides) and other polypeptides involved in the degradation of ubiquitinated proteins. In addition, the disclosure provides uses for active agents that modulate protein-protein complex formation between an UBX-polypeptide and its complementary-binding substrate. For example, the disclosure provides methods for treating or preventing hypoxia-related disorders or conditions in a patient or a cell by administration of an active agent that modulates the activity of an UBX-polypeptide and/or its complementary binding-substrate.

Abstract: A hybrid electric propulsion system for a vehicle. The system includes an internal combustion engine (12); a flywheel (14) operatively connected to the engine (12), the flywheel (14) having a horizontal rotation axis parallel to a rotation axis of the wheels of the vehicle, the flywheel (14) having a main disk being rotatable in an opposite direction (RFES) with respect to a rotation of the wheels (RT) of the vehicle when the vehicle is travelling forward so as to inhibit a rollover effect of the vehicle when the vehicle is turning; an electric generator (18) operatively connected to the flywheel (14); an electric motor (22) operatively connected to the electric generator (18); and a controller for controlling operation of the engine (12), the flywheel (14), the electric generator (18) and the electric motor (22).

Abstract: One aspect of the invention relates to compounds that inhibit the activity of p97, such as by binding covalently to a cysteine residue in the active site. In certain embodiments, the invention relates to the treatment of disease, such as cancer, comprising administering a compound of the invention.

Abstract: Hypoxia, a state of lower than normal tissue oxygen tension, has recently been implicated in a host of human diseases, including cancer, heart disease, and neurological disorders. Novel associations between p97 and other proteins, including UBX-domain-containing proteins (UBX-polypeptides), HIF1?, and a variety of E3 ligases are provided herein. The disclosure provides complexes comprising UBX-domain-containing polypeptides (UBX-polypeptides) and other polypeptides involved in the degradation of ubiquitinated proteins. In addition, the disclosure provides uses for active agents that modulate protein-protein complex formation between an UBX-polypeptide and its complementary-binding substrate. For example, the disclosure provides methods for treating or preventing hypoxia-related disorders or conditions in a patient or a cell by administration of an active agent that modulates the activity of an UBX-polypeptide and/or its complementary binding-substrate.

Abstract: The present invention is based on the discovery that a polypeptide containing the JAB subunit or the JAM domain has peptidase activity, e.g., isopeptidase activity. The present invention provides polypeptides and crystalline polypeptides containing the JAM domain and methods of using such polypeptides to screen for agents capable of affecting the peptidase activity of the polypeptides. The present invention also provides methods of using the JAM domain for rational drug design or identifying agents capable of affecting the peptidase activity of the JAM domain.

Abstract: The disclosure provides compositions and methods for blocking the proteasome pathway, as well as compounds that block mitotic cell cycle progression. Compounds disclosed include a family of molecules that bind to a multiubiquitin chain attached to a protein and thereby inhibit degradation of that protein by the proteasome pathway. According to another aspect of the disclosure, compounds are provided that inhibit cell cycle progression. Compounds disclosed herein may be formulated for pharmaceutical use and employed in methods for treating cancers or other hyperproliferative disorders.

Abstract: The present invention is based on the discovery that a polypeptide containing the JAB subunit or the JAM domain has peptidase activity, e.g., isopeptidase activity. The present invention provides polypeptides and crystalline polypeptides containing the JAM domain and methods of using such polypeptides to screen for agents capable of affecting the peptidase activity of the polypeptides. The present invention also provides methods of using the JAM domain for rational drug design or identifying agents capable of affecting the peptidase activity of the JAM domain.

Abstract: The present invention is based on the discovery that a polypeptide containing the JAB subunit or the JAM domain has peptidase activity, e.g., isopeptidase activity. The present invention provides polypeptides and crystalline polypeptides containing the JAM domain and methods of using such polypeptides to screen for agents capable of affecting the peptidase activity of the polypeptides. The present invention also provides methods of using the JAM domain for rational drug design or identifying agents capable of affecting the peptidase activity of the JAM domain.

Abstract: The present invention is based on the discovery that a polypeptide containing the JAB subunit or the JAM domain has peptidase activity, e.g. isopeptidase activity. The present invention provides polypeptides and crystalline polypeptides containing the JAM domain and methods of using such polypeptides to screen for agents capable of affecting the peptidase activity of the polypeptides. The present invention also provides methods of using the JAM domain for rational drug design or identifying agents capable of affecting the peptidase activity of the JAM domain.

Abstract: The present invention is based on the discovery that a polypeptide containing the JAB subunit or the JAM domain has peptidase activity, e.g., isopeptidase activity. The present invention provides polypeptides and crystalline polypeptides containing the JAM domain and methods of using such polypeptides to screen for agents capable of affecting the peptidase activity of the polypeptides. The present invention also provides methods of using the JAM domain for rational drug design or identifying agents capable of affecting the peptidase activity of the JAM domain.

Abstract: A method is provided for identifying an compound that affects an activity of a polypeptide subunit of a SCF complex. The method includes contacting a sample comprising a chimeric SCF complex assembled from subunits derived from Saccharomyces cerevisiae or human and another species and a CDC34p polypeptide with the compound under conditions that allow the components to interact, and adding to these components an E1 enzyme, ubiquitin and ATP, and a SCF substrate. The ubiquitination of the SCF substrate is measured. A chimeric in vitro assay system is provided for measuring CDC53p or CUL1p activity, comprising a CDC4p, CDC34p, and a SKP1p polypeptide, and either a CDC53p or CUL1p polypeptide. In this assay the CDC4p, CDC34p, and SKP1p polypeptide are either a yeast polypeptide or a polypeptide from another species, and at least one of the CDC4p, CDC34p, and SKP1p polypeptides is a yeast polypeptide and at least one of the CDC4p, CDC34p, and SKP1p polypeptides is a polypeptide from another species.