Abstract: The present invention relates to methods for identifying one or more reporter genes for a particular biological pathway of interest. The reporter genes of this invention are particularly useful for analyzing the activity of particular biological pathways of interest, and may be further used in the design of drugs, drug therapies or other biological agents (e.g., insecticides, herbicides, fungicides, antibiotics, or antivirals) to target a particular biological pathway. The present invention also relates to methods for identifying one or more target genes for a particular biological pathway of interest. Target genes of the invention are useful as specific targets for drugs which may be designed to enhance, inhibit, or modulate a particular biological pathway. Methods to identify genes which modify the function or structure of a member (e.g., compound or gene product) of a particular biological pathway are provided.

Abstract: A method for fluorophore bias removal in microarray experiments in which the fluorophores used in microarray experiment pairs are reversed. Further, a method for calculating the individual errors associated with each measurement made in nominally repeated microarray experiments. This error measurement is optionally coupled with rank based methods in order to determine a probability that a cellular constituent is up or down regulated in response to a perturbation. Finally, a method for determining the confidence in the weighted average of the expression level of a cellular constituent in nominally repeated microarray experiments.

Abstract: The present invention relates to methods of identifying genes whose expression is indicative of activation of a particular biochemical or metabolic pathway or a common set of biological reactions or functions in a cell (“regulon indicator genes”) The present invention provides an example of such an indicator gene. The present invention also relates to methods of partially characterizing a gene of unknown function by determining which biological pathways, reactions or functions its expression is associated with, thereby placing the gene within a functional genetic group or “regulon”. These partially characterized genes may be used to identify desirable therapeutic targets of biological pathways of interest (“regulon target genes”) The present invention provides examples of such target genes. Methods for identifying effectors (activators and inhibitors) of regulon target genes are provided. The present invention also provides examples of regulon target gene inhibitors.

Abstract: The present invention provides methods of screening for a molecule that inhibits the expression or activity of a protein encoded by a target gene which affects the fitness of a cell. The methods are based on a co-culture assay, and entail culturing together two cell populations, each of which is a population of identical cells, of the same species that differs substantially only in the expression or activity of the gene to be targeted or its encoded protein and the presence or absence of a reporter gene. The screen can be applied to cultured cells, unicellular and multicellular organisms. Manipulating the expression or activity of the target gene sensitizes the host to a molecule which inhibits the target gene or its encoded protein such that the cell or organism comprising the manipulated target gene grows at a different rate from the cell or organism comprising the unmanipulated gene in response to exposure to the molecule.

Abstract: A system, method, and computer program product for enhanced computer-aided analysis of biological response data is disclosed. In a preferred embodiment, biological datasets are graphically selected by a user from a first active biological viewer window on a user computer display and projected onto one or more other active biological viewers on the display. The selected data is highlighted in the destination biological viewers using contrast or color differentiation from other data appearing in the destination windows. In another preferred embodiment, hierarchical cluster trees from biological signal profiles are presented in a hyperbolic display fashion. In another preferred embodiment, biological menu and submenu items utilized by the user computer are not stored in the user computer, but rather are stored a central biological response database.

Abstract: The present invention provides methods for enhanced detection of biological response patterns. In one embodiment of the invention, genes are grouped into basis genesets according to the co-regulation of their expression. Expression of individual genes within a geneset is indicated with a single gene expression value for the geneset by a projection process. The expression values of genesets, rather than the expression of individual genes, are then used as the basis for comparison and detection of biological response with greatly enhanced sensitivity. In another embodiment of the invention, biological responses are grouped according to the similarity of their biological profile. The methods of the invention have many useful applications, particularly in the fields of drug development and discovery. For example, the methods of the invention may be used to compare biological responses with greatly enhanced sensitivity.

Abstract: A system, method, and computer program product for enhanced computer-aided analysis of biological response data is disclosed. In a preferred embodiment, biological datasets are graphically selected by a user from a first active biological viewer window on a user computer display and projected onto one or more other active biological viewers on the display. The selected data is highlighted in the destination biological viewers using contrast or color differentiation from other data appearing in the destination windows. In another preferred embodiment, hierarchical cluster trees from biological signal profiles are presented in a hyperbolic display fashion. In another preferred embodiment, biological menu and submenu items utilized by the user computer are not stored in the user computer, but rather are stored a central biological response database.

Abstract: A method for fluorophore bias removal in microarray experiments in which the fluorophores used in microarray experiment pairs are reversed. Further, a method for calculating the individual errors associated with each measurement made in nominally repeated microarray experiments. This error measurement is optionally coupled with rank based methods in order to determine a probability that a cellular constituent is up or down regulated in response to a perturbation. Finally, a method for determining the confidence in the weighted average of the expression level of a cellular constituent in nominally repeated microarray experiments.

Abstract: The present invention relates to methods of identifying genes in Saccharomyces cerevisiae which are essential for germination and proliferation of S. cerevisiae and using the identified genes or their encoded proteins as targets for highly specific antifungal agents, insecticides, herbicides and anti-proliferation drugs. The present invention also provides a method to systematically analyze the S. cerevisiae genome to identify essential genes for use as targets for antifungal agents, insecticides, herbicides and anti-proliferation drugs. The present invention provides antisense molecules and ribozymes comprising sequences complementary to the sequences of mRNAs of essential genes that function to inhibit the essential genes. The present invention also provides neutralizing antibodies to proteins encoded by essential genes that bind to and inactivate the essential gene products.

Abstract: The present invention provides methods for determining the level of protein activity in a cell by: (i) measuring abundances of cellular constituents in a cell in which the activity of a specific protein is to be determined so that a diagnostic profile is thus obtained; (ii) measuring abundances of cellular constituents that occur in a cell in response to perturbations in the activity of said protein to obtain response profiles and interpolating said response profiles to generate response curves; and (iii) determining a protein activity level at which the response profile extracted from the response curves best fits the measured diagnostic profile, according to some objective measure. In alternative embodiments, the present invention also provides methods for identifying individuals having genetic mutations or polymorphisms that disrupt protein activity, and methods for identifying drug activity in vivo by determining the activity levels of proteins which interact with said drugs.

Abstract: This invention provides methods for detecting and predicting drug interaction. In one embodiment of the invention, a plurality of cellular constituents in a biological sample is monitored as the sample is subject to various drug treatments. The response of the cellular constituents are analyzed to detect interactions. This method is particularly useful for predicting drug interaction using a model organism. It is also useful for analyzing interaction between any perturbations to a biological system.

Abstract: This invention features high-density electrode arrays for use in electroporation. These arrays contain a plurality of electrode pairs where the electrodes in each electrode pair are flat and parallel to each other.

Abstract: A method for fluorophore bias removal in microarray experiments in which the fluorophores used in microarray experiment pairs are reversed. Further, a method for calculating the individual errors associated with each measurement made in nominally repeated microarray experiments. This error measurement is optionally coupled with rank based methods in order to determine a probability that a cellular constituent is up or down regulated in response to a perturbation. Finally, a method for determining the confidence in the weighted average of the expression level of a cellular constituent in nominally repeated microarray experiments.

Abstract: This invention relates to methods and systems for characterizing the actions of drugs in cells. In particular, the invention provides methods for identifying multiple primary targets through which a drug, drug candidate, or other compound of interest acts on a cell. Thus, the invention also relates to methods for drug development based on the disclosed methods for identifying multiple primary targets of a drug. The methods of the invention involve: (i) measuring responses of cellular constituents to graded exposures of the cell to a drug of interest; (ii) identifying an “inflection concentration” of the drug for each cellular constituent measured; and (iii) identifying “expression sets” of cellular constituents from the distribution of the inflection drug concentrations. Each expression set corresponds to a particular primary target of the drug. The invention also provides computer systems which identify multiple targets of a drug by executing the disclosed methods.

Abstract: This invention relates to methods and systems for characterizing the actions of drugs in cells. In particular, the invention provides methods for identifying multiple primary targets through which a drug, drug candidate, or other compound of interest acts on a cell. Thus, the invention also relates to methods for drug development based on the disclosed methods for identifying multiple primary targets of a drug. The methods of the invention involve: (i) measuring responses of cellular constituents to graded exposures of the cell to a drug of interest; (ii) identifying an “inflection concentration” of the drug for each cellular constituent measured; and (iii) identifying “expression sets” of cellular constituents from the distribution of the inflection drug concentrations. Each expression set corresponds to a particular primary target of the drug. The invention also provides computer systems which identify multiple targets of a drug by executing the disclosed methods.

Abstract: The present invention provides methods for monitoring disease states in a subject, as well as methods for monitoring the levels of effect of therapies upon a subject having one or more disease states. The methods involve: (i) measuring abundances of cellular constituents in a cell from a subject so that a diagnostic profile is obtained, (ii) measuring abundances of cellular constituents in a cell of one or more analogous subjects so that perturbation response profiles are obtained which correlate to a particular disease or therapy, and (iii) determining the interpolated perturbation response profile or profiles which best fit the diagnostic profile according to some objective measure.

Abstract: This invention provides methods for determining drug specificity, therapeutic index and effective doses for individual patients. According to the methods of the invention, graded levels of drug are applied to a biological sample or a patient. A plurality of cellular constituents are measured to determine the activity of the drug on a target pathway and at least one off-target pathway. A drug specificity is determined by comparing the target and off target activities of the drug. A therapeutic concentration (or dose) is defined as a concentration (or dose) of the drug that induces certain response in the target pathway. A toxic concentration (or dose) is defined as a concentration (or dose) of the drug that induces certain response in the off target pathway. Therapeutic index is the ratio of the toxic concentration over therapeutic concentration. Methods are also provided to determine an effective dose of a drug for a patient by measuring the activity of the drug on the particular patient.

Abstract: The present invention relates to methods and kits for amplification of mRNA using a primer in PCR that contains an RNA polymerase promoter. The invention provides methods for amplification and detection of RNA derived from a population of cells, preferably eukaryotic cells and most preferably mammalian cells, which methods preserve fidelity with respect to sequence and transcript representation, and additionally enable amplification of extremely small amounts of mRNA, such as might be obtained from 106 mammalian cells. In typical embodiments of the invention, an RNA polymerase promoter (RNAP) is incorporated into ds cDNA by priming cDNA amplification by polymerase chain reaction (PCR) with an RNAP-containing primer. Following less than 20 cycles of PCR, the resultant RNAP-containing ds cDNA is transcribed into RNA using an RNA polymerase capable of binding to the RNAP introduced during cDNA synthesis.

Abstract: The present invention relates to anti-heteronucleic acid antibodies and their uses for detection of RNA-DNA duplexes on arrays. The invention provides a method for detection of total cellular RNA hybridization on microarrays, thus obviating the need for isolation of the poly(A)+ fraction.

Abstract: The present invention relates to genes in Saccharomyces cerevisiae which are essential for germination and proliferation of S. cerevisiae and using the identified genes or their encoded proteins as targets for highly specific antifungal agents, insecticides, herbicides and anti-proliferation drugs. The present invention provides antisense molecules and ribozymes comprising sequences complementary to the sequences of mRNAs of essential genes that function to inhibit the essential genes. The present invention also provides neutralizing antibodies to proteins encoded by essential genes that bind to and inactivate the essential gene products. The present invention further provides pharmaceutical compositions for treating fungal and proliferative diseases, as well as methods of treatment of fungal and proliferative diseases.