Abstract: Methods and compositions which are useful in the treatment of amyloidosis. In particular, methods and compositions are provided for inhibiting, preventing and treating amyloid deposition, e.g., in pancreatic islets, wherein the amyloidotic deposits are islet amyloid polypeptide (IAPP)-associated amyloid deposition or deposits. The methods of the invention involve administering to a subject a therapeutic compound which inhibits IAPP-associated amyloid deposits. Accordingly, the compositions and methods of the invention are useful for inhibiting IAPP-associated amyloidosis in disorders in which such amyloid deposition occurs, such as diabetes.

Abstract: Human antibodies, preferably recombinant human antibodies, that specifically bind to human tumor necrosis factor &agr; (hTNF&agr;) are disclosed. These antibodies have high affinity for hTNF&agr; (e.g., Kd=10−8 M or less), a slow off rate for hTNF&agr; dissociation (e.g., Koff=10−3 sec−1 or less) and neutralize hTNF&agr; activity in vitro and in vivo. An antibody of the invention can be a full-length antibody or an antigen-binding portion thereof. The antibodies, or antibody portions, of the invention are useful for detecting hTNF&agr; and for inhibiting hTNF&agr; activity, e.g., in a human subject suffering from a disorder in which hTNF&agr; activity is detrimental. Nucleic acids, vectors and host cells for expressing the recombinant human antibodies of the invention, and methods of synthesizing the recombinant human antibodies, are also encompassed by the invention.

Abstract: 13-substituted methacycline compounds, methods of treating tetracycline responsive states, and pharmaceutical compositions containing the 13-substituted methacycline compounds are described.

Abstract: A method useful for regulating cytokine production by a hematopoietic cell by regulating an MEKK/JNKK-contingent signal transduction pathway in such a cell is disclosed. Methods of identifying compounds capable of specifically regulating an MEKK/JNKK-contingent signal transduction pathway in hematopoietic cells, a kit for identifying cytokine regulators, methods to treat diseases involving cytokine production, and cells useful in such methods are also set forth.

Abstract: The invention relates to methods and compositions of WW-domains as phosphoserine and phosphothreonine binding modules. The WW-domain containing polypeptides of the invention can be used, for example, to regulate cell growth; to treat neurodegenerative diseases; to screen for substances that modulated interactions between WW-domain containing polypeptides and phosphorylated ligands; as drug targeting vehicles; to direct protein degradation; and in the treatment of certain diseases or conditions characterized by aberrant WW-domain containing polypeptides or their ligands.

Abstract: Disclosed are synthetic oligonucleotides complementary to a transcript of the marORAB operon which inhibit expression of a gene in the operon. Also disclosed are methods of reducing bacterial resistance to antibiotics, and pharmaceutical formulations containing marORAB-specific oligonucleotides of the invention.

Abstract: Novel cyclic ether vitamin D3 compounds having a cyclic ether side chain are disclosed. These compounds were first identified as metabolites of 3-epi vitamin D3 produced via a tissue-specific metabolic pathway which catalyzes the formation of a cyclic ether structure. Also disclosed are 1&agr;(OH) 3-epi vitamin D3 compounds, which are produced via the epimerization of a 3-&bgr;-hydroxyl group of 1&agr;(OH) vitamin D3 precursor in vivo. The vitamin D3 compounds of the present invention can be used as substitutes for natural and synthetic vitamin D3 compounds.

Abstract: Inhibitors of phosphoserine- or posphothreonine-specific peptidyl prolyl isomerases are described. Such inhibitors include molecules that mimic the structure and conformation of the pSer/pThr-Pro peptide moiety of the isomerase substrate when the substrate is bound into the active site of the isomerase. For example, a protein, peptide or peptide mimetic including xSer/ThrY where x is a negatively charged tetra or pentavalent moiety and Y is a Pro or a Pro analog. Methods of inhibiting cell growth and methods of identifying phosphoserine- or phosphothreonine-proline specific peptidyl-prolyl isomerase inhibitors are also included in the invention.

Abstract: Aryl alkenamides derivatives of Formula I or a pharmaceutically acceptable salt thereof are novel MCP-1 antagonists and are thus useful in the treatment of inflammation, atherosclerosis, restenosis, and immune disorders such as arthritis and transplant rejection where V═O,S, NH or a bond; Ar can be unsubstituted or substituted benzimidazole, phenyl, biphenyl, pyridyl, naphthyl, quinoline or isoquinoline. The other meanings for the terms are recited in the specification below.

Abstract: A method of cleaning or protecting surfaces by treatment with compositions comprising N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL) blocking compounds and/or N-butyryl-L-homoserine lactone (BHL) analogs, either in combination or separately.

Abstract: The invention relates to methods and compositions for manipulating bacterial resistance to non-antibiotic antibacterial compositions, disinfectants and organic solvents. The invention provides methods for rendering bacterial cells susceptible to non-antibiotic antibacterial compositions. Also provided are methods to reduce the selection of bacterial mutants having an multiple antibiotic resistance phenotype by non-antibiotic antibacterial compositions. The invention also provides methods for testing the ability of non-antibiotic antibacterial compositions to select for or induce a multiple antibiotic resistance phenotype in bacteria. Also provided are methods for increasing or decreasing bacterial tolerance to organic solvents by increasing or decreasing the activity of bacterial organic solvent efflux pumps. Compositions useful in the foregoing methods are also provided.

Abstract: Therapeutic compounds and methods for modulating amyloid deposition in a subject, whatever its clinical setting, are described. Amyloid deposition is modulated by the administration to a subject of an effective amount of a therapeutic compound comprising a phosphonate group and a carboxylate group, a congener thereof, or a pharmaceutically acceptable salt or ester thereof. In preferred embodiments, an interaction between an amyloidogenic protein and a basement membrane constituent is modulated.

Abstract: The invention relates to novel oxazinones designed to bind to the penicillin receptor, methods of synthesizing the compounds, and the use of the compounds as antibacterial agents. The compounds have the general formula (I) Preferably the compounds have a carboxyethyl or a substituted carboxymethyl substituent at the 2-position and a hydroxyl group at the 5-position and have a molecular shape suitable for binding to and reacting with the active site of a pencillin-recognizing enzyme. The compounds are synthesized by condensing a carboxyl-protected N-hydroxy amino acid with a 3-hydroxyprotected-4-bromobutanoic acid to form a a doubly protected N-hydroxy N-acylamino acid, which is cyclized with an organic base to yield a doubly protected 1,2-oxazin-3-one. The protecting groups are then removed to provide an antibacterial agent.

Abstract: An isolated and cloned region of a bacterial chromosome containing a multiple antibiotic resistance operon is disclosed. A description of the structure and function of the operon is provided as are assorted recombinant DNA constructs involving the operon or fragments thereof. The diagnostic, therapeutic and experimental uses of these constructs are also disclosed. Methods of evaluating the antibiotic effectiveness of compositions are disclosed and methods of treatment employing effective compositions are provided.

Abstract: The instant methods and compositions represent an advance in controlling drug resistance in microbes. AcrAB-like efflux pumps have been found to control resistance to drugs, even in highly resistant microbes. Accordingly, methods of treating infection, methods of screening for inhibitors of AcrAB-like efflux pumps, and methods of enhancing antimicrobial activity of drugs are provided. Pharmaceutical composition comprising an inhibitor of an AcrAB-like efflux pump and an antimicrobial agent are also provided.

Abstract: Autoinducer compounds which enhance gene expression in a wide variety of microorganisms, therapeutic compositions and therapeutic methods wherein gene expression within microorganisms is regulated are disclosed.

Abstract: The present invention provides for the use of aminoguanidines for prophylactic and/or therapeutic treatments of undesirable cell growth, e.g. tumors. The present invention provides methods of using aminoguanidines, optionally in combination with a hyperplastic inhibitory agent, to inhibit the growth of undesirable cells in a subject. The present invention is based, at least in part, on the discovery that aminoguanidines inhibit cell growth. The present invention further pertains to compositions for inhibiting undesirable cell growth in a subject. The compositions of the present invention include an effective amount of the aminoguanidine in a pharmaceutically acceptable carrier. Other aspects of the invention include a packaged aminoguanidine. The packaged compound includes instructions for using the aminoguanidine compound for inhibiting undesirable cell growth in a patient or instructions for using the compound in selected quantities, in a pharmaceutically acceptable carrier.

Abstract: An iterative and regenerative method for sequencing DNA is described. This method sequences DNA in discrete intervals starting at one end of a double stranded DNA segment. This method overcomes problems inherent in other sequencing methods, including the need for gel resolution of DNA fragments and the generation of artifacts caused by single-stranded DNA secondary structures. A particular advantage of this invention is that it can create offset collections of DNA segments and sequence the segments in parallel to provide continuous sequence information over long intervals. This method is also suitable for automation and multiplex automation to sequence large sets of segments.

Abstract: The present invention relates to the use of creatine compounds such as, for example, creatine, creatine phosphate or analogs of creatine, such as creatine-pyruvate, creatine-ascorbate, cyclocreatine, 3 guanidinopropionic acid, guanidinoacetate, homocyclocreatine, guanidino benzoates as energy generating systems and antioxidants for preservation of skin against adverse aging effects and damage secondary to insults such as harmful sun radiations, stress and fatigue. The creatine compounds which can be used in the present method include (1) creatine, creatine phosphate and analogs of these compounds which can act as substrates or substrate analogs for creatine kinase; (2) molecules that mimic the biological activity of creatine (3) molecules that modulate the creatine kinase system.

Abstract: A nonhuman animal having somatic and germ cells in which at least one allele of an endogenous SLP-76 gene is functionally disrupted is provided. The animal may be heterozygous or, more preferably, homozygous for the SLP-76 gene disruption and is preferably a mouse. In homozygous animals, the percentage of peripheral T cells is substantially decreased compared to wildtype animals, whereas the percentage of B cells and macrophages in the periphery is substantially normal, indicating that SLP-76 disruption causes a profound block in T cell development. The animals of the invention can be used, for example, as controls to evaluate the efficacy of SLP-76 inhibitors and to identify disease conditions that can be treated with SLP-76 inhibitors. A transgenic nonhuman animal having a functionally disrupted endogenous SLP-76 gene but which has been reconstituted with an exogenous SLP-76 transgene (e.g., a human SLP-76 gene or a SLP-76 gene whose expression in targeted to a particular cell population) is also provided.