Abstract: A method and compositions are provided for increased cerebral bioavailability of blood-born compositions by administering the composition of interest while increasing brain NO levels. This increase in NO levels may be accomplished by stimulating increased production of NO by eNOS, especially by administering L-arginine, by administering agents that increase NO levels independent of ecNOS, or by any combination of these methods. As NO is increased, cerebral blood flow is consequently increased, and drugs in the blood stream are carried along with the increased flow into brain tissue. By increased flow, the site of action will be exposed to more drug molecules. By stimulating increased NO production, administration of drugs that are not easily introduced to the brain may be facilitated and/or the serum concentration necessary to achieve desired physiologic effects may be reduced.

Abstract: The present invention is based at least in part on the discovery of polymorphisms within the 5-lipoxygenase gene which are included in a haplotype. Accordingly, the invention provides nucleic acid molecules having a nucleotide sequence of an allelic variant of a 5-LO gene. The invention also provides methods for identifying specific alleles of polymorphic regions of a 5-LO gene, methods for determining whether a patient has a more or less severe phenotype of an inflammatory disease or disorder such as asthma, methods for determining whether a patient will be more or less responsive to treatment with 5′LO inhibitors, forensic methods based on detection of polymorphisms within the 5-LO gene, and kits for performing such methods.

Abstract: Compounds which are active against viruses have the following Formulas: wherein B is a purine or pyrimidine heterocyclic ring and is preferably selected from the group consisting of 6-aminopurine (adenine), 2,6-diaminopurine, 2-amino-6-azidopurine, 2-amino-6-cyclopropylaminopurine, 6-hydroxypurine (hypoxanthine), 2-amino-6-halo substituted purines, 2-amino-6-alkoxy substituted purines, 2-amino-6-hydroxypurine (guanine), 3-deazapurines, 7-deaza-purines, 8-azapurines, cytosine, 5-halo substituted cytosines, 5-alkyl substituted cytosines, thymine, uracil and 6-azapyrimidines; X is O; and, R1 and R2 are alkyl or aryl groups. The compounds of the present invention also include the R- and S-enantiomers of the above compounds. The R1X and/or R2X can also be amino acid residues with X as NH.

Abstract: A method for regulating expression of a tet operator-linked gene in a cell of a subject is disclosed. In one embodiment, the method involves introducing into the cell a nucleic acid molecule encoding a tetracycline-controllable transactivator (tTA), the tTA comprising a Tet repressor operably linked to a polypeptide which directly or indirectly activates transcription in eucaryotic cells; and modulating the concentration of a tetracycline, or analogue thereof, in the subject. Alternatively, in another embodiment, the method involves obtaining the cell from the subject, introducing into the cell a first nucleic acid molecule which operatively links a gene to at least one tet operator sequence, introducing into the cell a second nucleic acid molecule encoding a tTA, to form a modified cell, administering the modified cell to the subject, and modulating the concentration of a tetracycline, or analogue thereof, in the subject. The first and second nucleic acid molecule can be within a single molecule (e.g.

Abstract: A method of making a set of labelled compounds by the use of a preferably particulate support, comprises dividing the support into lots, performing a different chemical reaction on each lot of the support, e.g. to couple a chemical moiety to that lot of the support, tagging a fraction of each lot of the support with a different label, and combining the said lots of the support. The steps are repeated several times, preferably to build up oligomer molecules carrying labels which identify the nature and position of a monomer unit of the oligomer, and which are releasable from the support. Preferred labels, which are releasable from the compounds by cleavage to provide charged groups for analysis by mass spectrometry, are groups of the trityl (trimethylphenyl) family. Also claimed are libraries of these labels and their use in assays and nucleic acid analysis methods.

Abstract: The complete sequence of the canine von Willebrand Factor cDNA and deduced amino acid sequence is provided. The mutation which causes von Willebrand's Disease in Scottish Terriers, Doberman pinschers, Shetland sheepdogs, Manchester terriers and Poodles are also provided. Methods for detecting carriers of the defective vWF gene are also provided.

Abstract: The complete sequence of the canine von Willebrand Factor cDNA and deduced amino acid sequence is provided. The mutation which causes von Willebrand's Disease in Scottish Terriers, Doberman pinschers, Shetland sheepdogs, Manchester terriers and Poodles are also provided. Methods for detecting carriers of the defective vWF gene 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: Tumor cells modified to express one or more T cell costimulatory molecules are disclosed. Preferred costimulatory molecules are B7-2 and B7-3. The tumor cells of the invention can be modified by transfection with nucleic acid encoding B7-2 and/or B7-3, by using an agent which induces or increases expression of B7-2 and/or B7-3 on the tumor cell or by coupling B7-2 and/or B7-3 to the tumor cell. Tumor cells modified to express B7-2 and/or B7-3 can be further modified to express B7. Tumor cells further modified to express MHC class I and/or class II molecules or in which expression of an MHC associated protein, the invariant chain, is inhibited are also disclosed. The modified tumor cells of the invention can be used in methods for treating a patient with a tumor, preventing or inhibiting metastatic spread of a tumor or preventing or inhibiting recurrence of a tumor.

Abstract: Provided are compositions and methods useful for modulating the activity of autoinducer synthase catalysts. A method for identifing modulators of the autoinducer synthesis reaction is also provided. Such modulators are useful for controlling bacterial growth and can be used for therapeutic treatment of bacterial infections particularly in immunocompromised subjects. They are also useful in treating disease states associated with autoinducer synthesis and biofilm development.

Abstract: Isolated ligands which bind a molecule expressed on the surface of T cells and induce antigen specific apoptosis in activated T cells are disclosed. Preferably, the T cell surface molecule is CTLA4 and the ligand is a monoclonal anti-CTLA4 antibody that binds to an epitope of CTLA4 distinct from the binding sites of B7-1 and B7-2. Upon binding of the antibody to CTLA4 on an activated T cell, in the presence of an antigenic signal, antigen specific apoptosis is induced. The invention also describes a novel natural CTLA4 ligand, distinct from B7-1 and B7-2, which mediates induction of apoptosis. Pharmaceutical compositions of anti-CTLA4 antibodies or other isolated CTLA4 ligands which can be administered to subjects to induce T cell apoptosis, thereby clonally deleting antigen specific. T cells, such as alloreactive T cells in transplantation situations or autoreactive T cells in autoimmune disorders, are also disclosed.

Abstract: Liquid pharmaceutical compositions comprising at least one thyroid hormone, ethanol, a pH adjusting agent, and water are disclosed. The compositions may be delivered by a metered dosage delivery system such as an aerosol or pump-action spray, and are useful in the treatment of disorders associated with an impairment of thyroid hormone function in animals including human beings.

Abstract: Antibodies that bind to a 40 kDa protein which is expressed on tumors, but is not expressed on normal adult hemopoietic cells are disclosed. Also disclosed are methods for production and the use of such antibodies.

Abstract: A rodenticidal composition comprises a carrier together with a rodenticidally effective amount of a compound having formula (I) wherein R1, R2, R3, R4, R5, R6, R7 and R8 are the same or different halogen selected from F, Cl and Br atoms. The preferred compound is bis(2,3,5,6-tetrafluoro-4-pyridyl)amine. The compounds of formula (I) are toxic to rodents, particularly rats, and yet have smell and taste acceptable to rodents.

Abstract: The method of immunotherapy of the present invention involves the regulation of the T cell immune response through the activation or suppression/inactivation of the CD28 pathway. Induction of activated T cell lymphokine production occurs upon stimulatory binding of the CD28 surface receptor molecule, even in the presence of conventional immunosuppressants. Inhibition of CD28 receptor binding to an appropriate stimulatory ligand or inactivation of the CD28 signal transduction pathway through other means down-regulates CD28-pathway related T cell lymphokine production and its resulting effects.

Abstract: The invention provides shuttle vectors, and methods of using shuttle vectors, capable of expression in, at least, a mammalian cell. Furthermore, the shuttle vectors are capable of replication in at least yeast, and optionally, bacterial cells. Also provided is a method wherein yeast are transformed with a shuttle vector as provided herein. Heterologous nucleic acids flanked by 5′ and 3′ ends identical to a homologous recombination site within the shuttle vector are introduced to the transformed yeast and allowed to homologously recombine with the shuttle vector such that they are inserted into the vector by the yeast organism. The shuttle vector is then recovered and transferred to a mammalian cell for expression.

Abstract: Methods for modulating T cell responses by manipulating intracellular signals associated with T cell costimulation are disclosed. The methods involve inhibiting or stimulating the production of at least one D3-phosphoinositide in a T cell. Production of D3-phosphoinositides can be manipulated by contacting a T cell with an inhibitor or activator of phosphatidylinositol 3-kinase. Inhibitors of phosphatidylinositol 3-kinase for use in the methods of the invention include wortmannin and quercetin, or derivatives or analogues thereof. The methods of the invention can further comprise modulating other intracellular signals associated with costimulation, such as protein tyrosine phosphorylation, for example by modulating the activity of a protein tyrosine kinase or a protein tyrosine phosphatase in the T cell.

Abstract: The present invention is directed to novel exocytotic polypeptides, such as Exo1 and Exo2 polypeptides and related molecules, which have an inhibitory effect on exocytosis and to nucleic acid molecules encoding those polypeptides. Also provided herein are vectors and host cells comprising those nucleic acid sequences, chimeric polypeptide molecules comprising the polypeptides of the present invention fused to heterologous polypeptide sequences, antibodies which bind to the polypeptides of the present invention and to methods for producing the polypeptides of the present invention. Further provided by the present invention are method for identifying novel compositions which mediate exocytotic polypeptide bioactivity, and the use of such compositions in diagnosis and treatment of disease.

Abstract: Novel structural forms of T cell costimulatory molecules are described. These structural forms comprise a novel structural domain or have a structural domain deleted or added. The structural forms correspond to naturally-occurring alternatively spliced forms of T cell costimulatory molecules or variants thereof which can be produced by standard recombinant DNA techniques. In one embodiment, the T cell costimulatory molecule of the invention contains a novel cytoplasmic domain. In another embodiment, the T cell costimulatory molecule of the invention contains a novel signal peptide domain or has an immunoglobulin variable region-like domain deleted. The novel structural forms of T cell costimulatory molecules can be used to identify agents which stimulate the expression of alternative forms of costimulatory molecules and to identify components of the signal transduction pathway which results in costimulation of T cells.

Abstract: The present invention provides for the use of G protein binding agents for prophylactic and/or therapeutic treatment of septic shock. The present invention provides methods of using agents which bind G protein to treat a subject having or susceptible to septic shock. The present invention further pertains to compositions for treating a subject for septic shock. The composition includes an effective amount of a G protein binding agent such as mastoparan and, optionally, an antibiotic and a pharmaceutically acceptable carrier. Other aspects of the invention include packaged agents which bind G proteins for treating septic shock.