Abstract: The present invention concerns compositions and methods for the introduction of specific genetic changes in endogenous genes of the cells of an animal. The genetic changes are effected by oligonucleotides or oligonucleotide derivatives and analogs, which are generally less than about 100 nucleotides in length. The invention provides for macromolecular carriers, optionally incorporating ligands for clathrin coated pit receptors. In one embodiment the ligand is a lactose or galactose and the genetic changes are made in hepatocytes. By means of the invention up to 40% of the copies of a target gene have been changed in vitro. Repair of mutant genes having a Crigler-Najjar like phenotype and Hemophilia B phenotype were observed.

Abstract: The present invention provides a method for treating a subject infected with a mammalian pathogenic fungus which uses melanin in virulence, by administering to the subject an amount of glyphosate effective to treat the infection. The present invention further provides a method for inhibiting proliferation of a mammalian pathogenic fungus which uses melanin in virulence, by contacting the fungus with an amount of glyphosate effective to inhibit the proliferation of the fungus. Additionally, the present invention further provides a method for inhibiting melanogenesis in a microorganism which produces melanin, by contacting the microorganism with an amount of glyphosate effective to inhibit melanogenesis in the microorganism.

Abstract: The present invention provides novel nucleoside-analogue compounds that are effective inhibitors of purine nucleoside phosphorylase (PNP), purine phosphoribosyltransferases (PPRT), and/or nucleoside hydrolases. Also provided are tautomers, esters, prodrugs, and pharmaceutically-acceptable salts of the compounds disclosed herein. The present invention further provides the use of these compounds as pharmaceuticals. The present invention also discloses pharmaceutical compositions containing these compounds. Finally, the present invention provides processes for preparing these compounds.

Abstract: The invention provides a method and vectors to express a gene or genes, derived from a virus, which block allograft rejection. One class of genes blocks the intracellular transport and/or intracellular maturation within the cells of proteins called MHC class I products. Without limitation as to theory, it is believed that blocking the appearance of this class of proteins on the transplanted cell's surface, prevents the host's immune system from rejecting the graft. Another class of proteins acts to permit TNF &agr;-mediated cell cytolysis. In one embodiment, the invention is directed towards engrafting the cells that secrete insulin, which are called alternatively, pancreatic &bgr;-cells and islet cells, and thereby provide a treatment of diabetes mellitus.

Abstract: The method provided by the present invention sets forth a novel combination of methods and principles which allows for the rapid and accurate isolation and identification of a large number of differentially expressed mRNAs.

Abstract: The present invention provides a method for treating a demyelinating condition in a subject in need of treatment, by administering to the subject an amount of a Ca2+-channel blocker effective to treat the demyelinating condition. The present invention is also directed to a method for treating a demyelinating condition in a subject in need of treatment, by administering to the subject a Ca2+-channel blocker in combination with a glutamate inhibitor, in amounts effective to treat the demyelinating condition. Also disclosed is a pharmaceutical composition comprising a Ca2+-channel blocker, a glutamate inhibitor, and a pharmaceutically-acceptable carrier. Additionally, the present invention provides a method for treating a demyelinating condition in a subject in need of treatment, by administering to the subject a Ca2+-channel blocker in combination with a hypertensive agent, in amounts effective to treat the demyelinating condition.

Abstract: The present invention provides for peptide conjugate compositions, methods of using the peptide conjugate compositions, and pharmaceutical compositions comprising the peptide conjugate compositions. The peptide conjugate compositions comprise peptides with amino acid sequences similar to the gp120 principal neutralizing domain (PND) of HIV, gp41, and Nef (p27) of HIV and carriers which enhance immunogenicity. The peptide conjugate compositions of the present invention may comprise a multivalent cocktail of several different peptide conjugates. Also provided by present invention is a method for reducing the level of HIV titers in a mammal by administering to the mammal a peptide composition of the present invention in an amount effective to reduce the level of HIV titers. The peptide conjugate compositions of the present invention induce prolonged antibody response in serum, a high level of antibody in the mucosa, and the production of cytotoxic lymphocytes.

Abstract: An animal, e.g., transgenic mouse, in which the MSH5 gene is misexpressed. The animal is useful for screening treatments for a number of conditions. Methods for identifying contraceptive agents are also described.

Abstract: The present invention provides a method for detecting chitin-containing organisms on an area of a person of animal by contacting the particular area with a dye that is capable of binding or conjugating to chitin and emitting fluorescence upon exposure to light. If a chitin-containing organism is present in the treated area, the chitin of the organism will bind or conjugate the dye and, upon exposure to light, the chitin-containing organisms may be visualized and removed. Also provided by the present invention are solutions and suspensions that contain a dye capable of binding or conjugating to a chitin-containing organism and emitting fluorescence upon exposure to light. The solutions and suspensions provided herein may be in the form of a shampoo, cream, lotion or detergent for the detection of chitin-containing organisms present in body hair, on the skin, clothing or the fur of animals.

Abstract: Disclosed is a recombinant slow-growing mycobacterium comprising at least one mycobacterial gene containing an unmarked mutation, where an “unmarked mutation” is a mutated nucleotide sequence introduced into a mycobacterium where the introduced mutated nucleotide sequence does not contain a selectable marker, such as a gene conferring antibiotic resistance to the recombinant mycobacterium incorporating the mutated nucleotide sequence. Also disclosed is a method for preparing a recombinant slow-growing mycobacterium comprising at least one mycobacterial gene containing an unmarked mutation, as well as a vaccine comprising a recombinant slow-growing mycobacterium having at least one mycobacterial gene containing an unmarked mutation dispersed in a physiologically acceptable carrier. Further disclosed is a method of treating or preventing tuberculosis in a subject comprising administering the vaccine of the present invention in an amount effective to treat or prevent tuberculosis in the subject.

Abstract: The present invention provides a method of identifying novel agents that increase glucose dependent insulin secretion in pancreatic islet cells as well as methods of treating diabetes using the agents which have an inhibitory effect on the activity of pancreatic islet cell phosphodiesterases (“PDE”) enzyme, namely PDE1C. The methods described herein are based upon the inventor's surprising discovery that inhibition of PDE1C increases glucose dependent insulin secretion. Specifically, the present invention provides for a method of identifying therapeutic agents that act to increase the release of insulin from pancreatic islet cells. The method of identification provided herein is used to determine the effects of isozyme specific phosphodiesterase inhibitors on insulin secretion from cultured pancreatic &bgr;-cells. Also provided are agents that have an inhibitory effect on the activity of PDE1C in pancreatic cells.

Abstract: This invention relates to a method for treating a subject with irritable bowel syndrome (“IBS”) which comprises long-term administration of an opioid receptor antagonist at an appropriately low dose which will selectively antagonize excitatory opioid receptor functions, but not inhibitory opioid receptor functions, in myenteric neurons in the intestinal tract as well as in neurons of the central nervous system (“CNS”). The administration of the opioid receptor antagonist at a low dose enhances the potency of the inhibitory effects of endogenous opioid peptides present in the intestinal tract and the CNS, thereby reducing abdominal pain and stool frequency resulting from abnormally supersensitized excitatory opioid receptor functions. The invention also relates to a composition for treating a subject with IBS, which comprises an effective dose of an opioid receptor antagonist, and a pharmaceutically acceptable carrier.

Abstract: The present invention provides a purified and isolated nucleic acid encoding a sodium/iodide symporter. The present invention also provides purified sodium/iodide symporter, a vector comprising nucleic acid encoding sodium/iodide symporter, a host cell transformed with the vector, and a method for producing recombinant sodium/iodide symporter. In addition, the present invention provides nucleic acid probes and mixtures thereof specific for sodium/iodide symporter nucleic acid and antibodies immunoreactive with sodium/iodide symporter. The present invention also provides a method for diagnosing and treating thyroid disorders associated with non-functional sodium/iodide symporter. Furthermore, the present invention provides a method for the selective ablation of tissue. The present invention also provides a method for identifying an iodide transport protein in non-thyroid tissue. Finally, the present invention provides a non-human, transgenic model for a thyroid disorder.

Abstract: The present invention provides a purified and isolated nucleic acid encoding mycobacterial isocitrate lyase, as well as mutated forms of the nucleic acid. Further provided are purified and isolated isocitrate lyase proteins and mutated isocitrate lyase proteins. Additionally, the present invention provides vectors which comprises nucleic acid sequences encoding mycobacterial isocitrate lyase and mutated forms of this nucleic acid, as well as host cells containing these vectors. Also provided is a mycobacterium containing one or more mutations in its isocitrate lyase gene. Further provided by the present invention are agents that inhibit the activity or expression of a mycobacterial lyase protein, a method of identifying these, and a method of producing them. Finally, the present invention also provides a method of identifying genes required for persistence of mycobacteria.

Abstract: The invention relates to a method of detecting and/or assaying nucleoside hydrolases or nucleoside phosphorylases using a chromogenic substrate. Preferred chromogenic substrates have formula (I) where X is OH, or H, and Y is the residue of Y—OH where Y—OH is a chromophore or a compound readily converted to a chromophore and the substrates are hydrolyzed by the nucleoside hydrolase to yield ribose or 2-deoxyribose plus Y—OH. Alternatively, those substrates may be phosphorylysed by nucleoside phosphorylase to yield ribose-1-phosphate plus Y—OH. The methods may be used to detect and/or assay parasites in biological samples.

Abstract: Recombinant mycobacterial vaccine vehicles capable of expressing DNA of interest which encodes at least one protein antigen for at least one pathogen against which an immune response is desired and which can be incorporated into the mycobacteria or stably integrated into the mycobacterial genome. The vaccine vehicles are useful for administration to mammalian hosts for purposes of immunization. A recombinant vector which replicates in E. coli but not in mycobacteria is also disclosed. The recombinant vector includes 1) a mycobacterial gene or portions thereof, necessary for recombination with homologous sequences in the genome of mycobacteria transformed with the recombinant plasmid; 2) all or a portion of a gene which encodes a polypeptide or protein whose expression is desired in mycobacteria transformed with the recombinant plasmid; 3) DNA sequences necessary for replication and selection in E coli; and 4) DNA sequences necessary for selection in mycobacteria (e.g., drug resistance).

Abstract: This invention relates to a method for selectively enhancing the analgesic potency of a bimodally-acting opioid agonist such as morphine and simultaneously attenuating anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects associated with the administration of the bimodally-acting opioid agonist. The method of the present invention comprises administering to a subject an analgesic or sub-analgesic amount of a bimodally-acting opioid agonist such as morphine and an amount of an excitatory opioid receptor antagonist such as naltrexone or nalmefene effective to enhance the analgesic potency of the bimodally-acting opioid agonist and attenuate the anti-analgesia, hyperalgesia, hyperexcitability, physical dependence and/or tolerance effects of the bimodally-acting opioid agonist.

Abstract: This invention relates to methods of isolating hepatoblasts utilizing panning techniques and fluorescence activated cell sorting. This invention further relates to isolated hepatoblasts and to a method of treating liver dysfunction as well as to methods of forming artificial livers.

Abstract: This invention relates to a method for increasing the usefulness, sensitivity and specificity of tests that measure memory and facets of memory, including learning, retention, recall and/or recognition. Specifically, the sensitivity and specificity of such tests are enhanced by selectively weighting the value of specific items recalled by the test subject, either by weighting such items within any specific testing trial or across numerous testing trials. Also disclosed are various methods of reducing ceiling effects in memory tests. The invention also provides improved tests which employ item-specific weighting for the diagnosis of Alzheimer's Disease and other dementia characterized by memory impairment, as well as a method of screening for and evaluating the efficacy of potential therapeutics directed to the treatment of such dementia.

Abstract: This invention relates to mycobacterial species-specific reporter mycobacteriophages (reporter mycobacteriophages), methods of producing said reporter mycobacteriophages and the use of said reporter mycobacteriophages for the rapid diagnosis of mycobacterial infection and the assessment of drug susceptibilities of mycobacterial strains in clinical samples. In particular, this invention is directed to the production and use of luciferase reporter mycobacteriophages to diagnose tuberculosis. The mycobacterial species-specific reporter mycobacteriophages comprise mycobacterial species-specific mycobacteriophages which contain reporter genes and transcriptional promoters therein. When the reporter mycobacteriophages are incubated with clinical samples which may contain the mycobacteria of interest, the gene product of the reporter genes will be expressed if the sample contains the mycobacteria of interest, thereby diagnosing mycobacterial infection.