Abstract: The efficient regulation of cholesterol synthesis, metabolism, acquisition, and transport is an essential component of lipid homeostasis. The farnesoid X receptor (FXR) is a transcriptional sensor for bile acids, the primary product of cholesterol metabolism. Accordingly, the development of potent, selective, small molecule agonists, partial agonists, and antagonists of FXR would be an important step in further deconvoluting FXR physiology. In accordance with the present invention, the identification of novel potent FXR activators is described. Two derivatives of invention compounds, bearing stilbene or biaryl moieties, contain members that are the most potent FXR agonists reported to date in cell-based assays. These compounds are useful as chemical tools to further define the physiological role of FXR as well as therapeutic leads for the treatment of diseases linked to cholesterol, bile acids and their metabolism and homeostasis.

Abstract: The present invention provides compositions comprising the ligand binding domain (LBD) of a farnesoid X receptor (FXR) in crystalline form. In alternative embodiments, the LBD of FXR is complexed with a ligand therefor. There are provided high resolution structures of FXR complexed with a novel high affinity agonist, fexaramine. The discovered structure of a FXR LBD provides the first three-dimensional view of the structural basis for FXR ligand binding. The present invention further provides a computer for producing a three-dimensional representation of FXR or a complex thereof, and a computer for determining at least a portion of the structure coordinates of FXR or a complex thereof. The present invention further provides methods of using this structural information to predict molecules capable of binding to FXR; to identify compounds with agonist, antagonist or partial agonist activity for FXR; and to determine whether a test compound is capable of binding to the LBD of FXR.

Abstract: The efficient regulation of cholesterol synthesis, metabolism, acquisition, and transport is an essential component of lipid homeostasis. The farnesoid X receptor (FXR) is a transcriptional sensor for bile acids, the primary product of cholesterol metabolism. Accordingly, the development of potent, selective, small molecule agonists, partial agonists, and antagonists of FXR would be an important step in further deconvoluting FXR physiology. In accordance with the present invention, the identification of novel potent FXR activators is described. Two derivatives of invention compounds, bearing stilbene or biaryl moieties, contain members that are the most potent FXR agonists reported to date in cell-based assays. These compounds are useful as chemical tools to further define the physiological role of FXR as well as therapeutic leads for the treatment of diseases linked to cholesterol, bile acids and their metabolism and homeostasis.

Abstract: A shaft seal assembly for use with a reciprocating or rotating shaft includes a shaft seal, a lubricant-storing ring, and a retainer. The retainer and ring can be formed as a subassembly and then combined with a shaft seal. The seal includes an annular body portion, a first sealing lip portion, and a first pocket portion. The first sealing lip portion has a substantially uniform axial dimension and is adapted to sealingly engage a shaft. The first pocket portion includes a plurality of pockets, each having an opening toward the first sealing lip portion. The plurality of pockets are each adapted to collect a working fluid when the shaft axially displaces in a first direction and to dispense the working fluid when the shaft axially displaces in a second direction. The assembly provides a lubricated shaft and seal that improves the effective life of the shaft seal.

Abstract: The efficient regulation of cholesterol synthesis, metabolism, acquisition, and transport is an essential component of lipid homeostasis. The farnesoid X receptor (FXR) is a transcriptional sensor for bile acids, the primary product of cholesterol metabolism. Accordingly, the development of potent, selective, small molecule agonists, partial agonists, and antagonists of FXR would be an important step in further deconvoluting FXR physiology. In accordance with the present invention, the identification of novel potent FXR activators is described. Two derivatives of invention compounds, bearing stilbene or biaryl moieties, contain members that are the most potent FXR agonists reported to date in cell-based assays. These compounds are useful as chemical tools to further define the physiological role of FXR as well as therapeutic leads for the treatment of diseases linked to cholesterol, bile acids and their metabolism and homeostasis.

Abstract: The present invention relates to the identification, isolation, sequencing and characterization of a new member of the histone deacetylase family, as well as its transcripts, gene products, associated sequence information, and related genes. The present invention also relates to methods for detecting and diagnosing carriers of normal and mutant alleles of these genes, methods for detecting and diagnosing diseases, methods of identifying genes and proteins related to or interacting with such genes and proteins, methods of screening for potential therapeutics for diseases, methods of treatment for diseases, and to cell lines and animal models useful in screening for and evaluating potentially useful therapies for diseases. In a particular aspect of the present invention, a novel family member, HDAC7, is described and its interaction with SMRT/N-CoR and mSin3A, its biochemical properties and subcellular localization are characterized.

Abstract: A radial shaft seal for use on a shaft, said radial shaft seal including a rigid insert generally having a L-shaped cross section. The shaft seal including a circumferential seal body molded around the insert. The shaft seal further including an exclusion lip integral with the seal body, the exclusion lip having a venting mechanism. The venting mechanism allows fluid transfer into the primary sealing lip.