Abstract: The instant invention provides a method for establishing safety profiles for chemical compounds, as well as pharmacological profiling said method comprising (A) testing the effects of said chemical compounds on the amount and/or post-translational modifications of two or more macromolecules in intact cells; (B) constructing a pharmacological profile based on the results of said tests; and (C) comparing said profile to the profile(s) of drugs with established safety characteristics. Additionally, the invention is also directed to a composition comprising an assay panel, said panel comprising at least one high-content assay for the amount and/or post-translational modification of a protein and at least one high-content assay for the amount and/or subcellular location of a protein-protein interaction.

Abstract: The invention features a method for treating a patient having a cancer or other neoplasm, by administering to the patient one of the following drugs or a metabolite or analog thereof: cinnarizine; desipramine; fenofibrate; flunarizine; isoreserpine; nicardipine; promazine; promethazine; suloctidil; terfenadine; atorvastatin; mebeverine; sertraline; albendazole; bepridil; bergaptene; clomiphene; dichlorophene; droperidol; mebendazole; meclocycline; metergoline; ramiphenazone; sanguinarine; dipyrone; nicardipine; or 4-dimethylaminoantipyrine.

Abstract: The present invention describes a method of expressing PCA interacting partners in plant material comprising: (A) transforming said material with: (1) a first construct coding for a first fusion product comprising (a) a first fragment of a first molecule whose fragments can exhibit a detectable activity when associated and (b) a first protein-protein interacting domain; and (2) a second construct coding for a second fusion product comprising (a) a second fragment of said first molecule and (b) a second protein-protein interacting domain that can bind (1)(b); (B) culturing said material under conditions allowing expression of said PCA interacting partners; and (C) detecting said activity.

Abstract: The present invention describes an assay method comprising: (A) generating (1) at least a first fragment of a reporter molecule linked to a first interacting domain and at least a second fragment of a reporter molecule linked to a second interacting domain, or (2) nucleic acid molecules that code for (A)(1) and subsequently allowing said nucleic acid molecules to produce their coded products; then, (B) allowing interaction of said domains; and (C) detecting reconstituted reporter molecule activity, where said reporter molecule can react with a penicillin- or a cephalosporin-class substrate.

Abstract: The present invention provides methods for performing pharmacological profiling of a chemical compound, in particular to improve drug safety and efficacy at an early stage in the drug development process. The chemical compound may be a test compound, drug lead, known drug or toxicant. The compound is profiled against a panel of assays. Preferred embodiments of the invention include high-content assays for protein-protein interactions. The compositions and methods of the invention can be used to identify pathways underlying drug efficacy, safety, and toxicity; and to effect attrition of novel compounds with undesirable or toxic properties. The compositions and methods of the invention can also be used to identify new uses of therapeutic agents, to screen libraries of chemical compounds, to perform lead optimization, and to perform studies of structure-activity relationships in the context of intact cells.

Abstract: The invention presents a method for selectively slowing the motion of acoustically active particles immersed in a flowing fluid, eventually stopping their motion, holding them in place by pushing them against a surface or against the flow of said flowing fluid, and/or breaking up said acoustically active particles into smaller particles and/or dissolving them. The invention also relates to various systems that utilize this method.

Abstract: The present invention describes a rapid and efficient in vivo library-versus-library screening strategy for identifying optimally interacting pairs of heterodimerizing polypeptides. It allows for the screening of a protein library against a second protein library, rather than against a single bait protein, and thus has numerous applications in the study of protein-protein interactions. Additionally, it allows for the application of different selection stringencies. Two leucine zipper libraries, semi-randomized at the positions adjacent to the hydrophobic core, were genetically fused to either one of two designed fragments of the enzyme murine dihydrofolate reductase (mDHFR), and cotransformed into E. coli. Interaction between the library polypeptides was required for reconstitution of the enzymatic activity of mDHFR, allowing bacterial growth.

Abstract: The present invention describes a method for detecting biomolecular interactions said method comprising: (a) selecting an appropriate reporter molecule selected from the group consisting of a protein, a fluorescent protein, a luminescent protein and a phosphorescent protein; (b) effecting fragmentation of said reporter molecule such that said fragmentation results in reversible loss of reporter function; (c) fusing or attaching fragments of said reporter molecule separately to other molecules; followed by (d) reassociation of said reporter fragments through interactions of the molecules that are fused to said fragments; and (e) detecting said biomolecular interactions by reconstitution of activity of the reporter molecule with the proviso that said protein is not ubiquitin.

Abstract: The present invention describes a rapid and efficient in vivo library-versus-library screening strategy for identifying optimally interacting pairs of heterodimerizing polypeptides. It allows for the screening of a protein library against a second protein library, rather than against a single bait protein, and thus has numerous applications in the study of protein-protein interactions. Additionally, it allows for the application of different selection stringencies. Two leucine zipper libraries, semi-randomized at the positions adjacent to the hydrophobic core, were genetically fused to either one of two designed fragments of the enzyme murine dihydrofolate reductase (mDHFR), and cotransformed into E. coli. Interaction between the library polypeptides was required for reconstitution of the enzymatic activity of mDHFR, allowing bacterial growth.

Abstract: Protein Fragment Complementation Assays (PCA) are done in plant material using enzyme fragment constructs, for example, dihydrofolate reductase (DHFR) fragment constructs. Plant material is transformed with at least two different constructs that form different products capable of interacting to reconstitute enzymatic activity in the plant material. Detection of the activity can be done using a substrate for the enzyme in the culture medium which, when reacted with the enzyme, is converted to a detectable product. One embodiment uses a substrate that can be enzymatically converted to a detectable fluorescent product. An inducer such as rapamycin or salicylic acid can be added to the culture medium to increase the level of detectable product.

Abstract: The present invention describes an assay method comprising: (A) generating (1) at least a first fragment of a reporter molecule linked to a first interacting domain and at least a second fragment of a reporter molecule linked to a second interacting domain, or (2) nucleic acid molecules that code for (A)(1) and subsequently allowing said nucleic acid molecules to produce their coded products; then, (B) allowing interaction of said domains; and (C) detecting reconstituted reporter molecule activity, where said reporter molecule can react with a penicillin- or a cephalosporin-class substrate.

Abstract: The present invention provides protein fragment complementation assays for drug discovery, in particular to identify compounds that activate or inhibit cellular pathways. Based on the selection of an interacting protein pair combined with an appropriate PCA reporter, the assays may be run in high-throughput or high-content mode and may be used in automated screening of libraries of compounds. The interacting pair may be selected by cDNA library screening; by gene-by-gene interaction mapping; or by prior knowledge of a pathway. Fluorescent and luminescent assays can be constructed using the methods provided herein. The selection of suitable PCA reporters for high-throughput or high-content (high-context) assay formats is described for a diversity of reporters, with particular detail provided for examples of monomeric enzymes and fluorescent proteins.

Abstract: The invention relates to impression compositions based on vulcanizable polyether materials, which are characterized in that the ready-mixed pastes comprise a) approx. 30 to 70 wt. % of aziridino-polyether, b) approx. 5 to 20 wt. % of a triacyl glyceride of non-animal origin which has a stearoyl content of ≧70 wt. %, based on the acyl content of the triacyl glyceride, or, in the case of a lower stearoyl content and if this adversely influences the storage stability of the impression composition, has been esterified in itself beforehand, and c) approx. 10 to 65 wt. % of customary catalysts, auxiliaries and additives, in each case based on the total weight of the composition. The impression compositions are distinguished by consistently good mechanical properties of the polymerized materials, have a comparatively low proportion of aziridino-polyether, which has a favorable effect on their preparation costs, and can easily be mixed.

Abstract: The invention relates to impression compositions based on vulcanizable pother materials, which are characterized in that the ready-mixed pastes comprisea) approx. 30 to 70 wt. % of aziridino-polyether,b) approx. 5 to 20 wt. % of a triacyl glyceride of non-animal origin which has a stearoyl content of .gtoreq.70 wt. %, based on the acyl content of the triacyl glyceride, or, in the case of a lower stearoyl content and if this adversely influences the storage stability of the impression composition, has been esterified in itself beforehand, andc) approx. 10 to 65 wt. % of customary catalysts, auxiliaries and additives,in each case based on the total weight of the composition.The impression compositions are distinguished by consistently good mechanical properties of the polymerized materials, have a comparatively low proportion of aziridino-polyether, which has a favourable effect on their preparation costs, and can easily be mixed.

Abstract: In a film tube containing a flowable substance, a fold 11 is formed in the film, which fold is so shaped that it abruptly decreases the cross-section at this location of the tube. The fold 11 may be fixed by a V-shaped weld 12. When the film tube is compressed, maximum stress is exerted on the area of the film close to the apex 13 of the V-shaped weld 12, so that the tube starts to rupture and form a dispensing opening at this location.

Abstract: Dental composites are provided on the basis of customary polymerizable monomers, initiators, fillers and other auxiliaries, which additionally contain the plaque-inhibiting addition of salts of acid-functional polymers having mono- or polyvalent cations.

Abstract: A device for emptying a film tube 15 containing a pasty substance comprises a cap structure 11 including a transverse wall 12 supporting the front of the tube, a cylindrical flange 13 formed on the wall for receiving the front end of the tube, and a dispensing pipe 17. The pipe 17 extends from a recess 16 formed in the wall 12 and having an at least partially circular-cylindrical shape, with a spike 18 being integrally formed at the center of the recess and extending parallel to the axis of the tube. The tip 19 of the spike is retracted from the plane of the wall 12. When dispensing pressure is exerted on the tube 15, the portion of the tube film overlying the recess 16 will bulge into the recess, until its central part is scratched by the tip 19 of the spike and thus caused to burst. The content of the tube can then flow into the recess 16 surrounding the spike 18 and out through the pipe 17.

Abstract: A device suited for dispensing a dental substance comprises a cartridge 20 or receiving the substance, with a curved dispensing nozzle 22 disposed at the front end and a flange 21 of octagonal cross-section provided at the rear end of the cartridge. The flange 21 serves to engage a slide-in socket 16 of an applicator 10 which includes a piston rod 12 for advancing a dispensing piston 23 disposed in the cartridge 20. In the retracted position of the piston rod 12, the cartridge 20 may be laterally inserted into the slide-in socket 16 of the applicator 10. The socket has two parallel walls spaced by a distance which is between the largest and the smallest diameter of the octagonal flange 21.

Abstract: An addition-crosslinking polyether impression material is described which ntains(a) at least one polyether which has at least two optionally substituted vinyl and/or allyl end-groups,(b) an SiH component,(c) at least one platinum catalyst,(d) optionally usual additives, and(e) an organopolysiloxane with at least two alkenyl groups.The impression material has in at least two-part form of administration in which the components (b) and (c) are spatially separated from each other a particularly satisfactory storage stability and has good mechanical properties in the cured state.