Abstract: A method for obtaining a eukaryotic cell transfected with an episome involves transfecting the cell with the episome under conditions wherein cells survive that are successfully transfected with the episome. The resulting cells express both a first protein whose expression causes cell death and a second protein whose expression prevents cell death resulting from expression of the first protein.

Abstract: A method for photoeluting photocleavable linker-attached chemical compounds, and an apparatus suitable for implementing the method, are disclosed. According to the method, photocleavable linker-attached library compounds are photoeluted from solid support media under conditions of controlled light exposure and controlled temperature. An apparatus suitable for carrying out the present photoelution method includes means for substantially evenly illuminating the photocleavable linker, means for controlling illumination time and intensity, and means for controlling sample temperature.

Abstract: A method for determining the level of tyrosine kinase activity in a biological sample is disclosed. The method employs an anti-phosphotyrosine antibody as both the capture agent and the detecting agent. The detecting antibody is labeled with a lanthanide ion, such as europium, as the signal generating entity. The method is particularly well suited to high throughput screening, for example, for compounds which modulate tyrosine kinase activity.

Abstract: A computer-implemented method and apparatus are provided for planning the generation of combinatorial chemical libraries produced by a series of chemical reaction stages, each stage involving a multiplicity of simultaneous chemical reactions utilizing a set of potential synthons. The disclosed method and apparatus involve enumerating the members of the proposed library and determining which of the members meet desired criteria.

Abstract: An article for dispensing very small volumes of liquid via non touch-off transfer. The article includes a rotator that drives a liquid dispensing system in circular motion at constant rotational speed. The liquid dispensing system has a delivery system that is operatively connected to a dispensing element A small volume of liquid is advanced by the delivery system to the dispensing element. As a consequence of the circular motion, energy is imparted to the liquid causing it to forcibly issue from the dispensing element.

Abstract: Flow-regulation means for improving the operation of a liquid dispenser, and liquid dispensers incorporating the same, are disclosed. In some embodiments, the flow-regulation means includes a conduit for receiving a pressurized fluid, wherein a flow restriction restricts the flow of the pressurized fluid into the conduit. The flow restriction has a smaller flow area than the outlet of the dispensing valve. As a result, fluid is re-supplied to the conduit more slowly than it is dispensed through the dispensing valve. In further embodiments, at least a portion of the conduit is elastic. A dynamic pressure sensor is used to sense pressure in the elastic region. In an additional embodiment, the flow-regulation means includes a resilience-adjustment means operable to adjust the resilience or elasticity of an elastic portion of the conduit. Such adjustable resilience provides an additional measure of control over the dispensing process.

Abstract: A reagent is described for incorporating phosphorylation sites into compounds, particularly into proteins and peptides. The reagent has the structure A—B—C wherein A is a moiety that is specifically reactive with a reactive side chain in the compound, B is a linking moiety, and C is a peptide sequence that contains a kinase substrate.

Abstract: Compounds of Formula I are disclosed as inhibitors having activity against the aspartyl proteases, plasmepsin and cathepsin D. The compounds are therefore useful for treatment of diseases such as malaria and Alzheimer's disease. In preferred compounds of Formula I, Y is an dialkoxyphosphonate, or &agr;-hydroxyamide group and Z is an acyl or &agr;-ketocarbamate functionality. Intermediates in the solid phase synthesis of compounds of Formula I, in which compounds are attached to a solid support, are also disclosed.

Abstract: In some embodiments, the present invention provides a method and an article for segregating solid support media or other solids, from liquid, while at the same time maintaining such solids and liquid in intimate contact as may be required for various processing or chemical operations. In an illustrative embodiment, the present article comprises a filter pocket plate consisting of a plate with a plurality holes. A foraminous material projects through each hole in the plate such that a “pocket” is formed within each hole. In use, the aforedescribed filter pocket plate engages a vessel having one or more wells suitable for retaining liquid and for receiving the filter pockets. The filter pockets contain a solid material that is to be exposed to the liquid in the well. After exposure is complete, the solid material is readily removed from the liquid by simply disengaging the filter pocket plate, which retains the solid support media, from the vessel, which retains the liquid.

Abstract: A substrate for solid phase synthesis comprising a solid phase-linker combination of the formula I is disclosed. Also disclosed are processes for preparing the substrate and chemical intermediates useful therein. Among the novel intermediates are compounds of the formula II wherein R1 is —NO2 or —CHO; R2 is —OCH3, —CHO or —H; R3 is chosen from the group consisting of hydroxyl, the residue of a solid support having a plurality of amino groups, and the residue of an ester, and n=1 or 3. A substrate of solid phase synthesis of the formula III is also disclosed.

Abstract: Techniques for high throughput parallel separation, filtration and plate-to-plate transfer are described. Cells, proteins, chemical compounds and the like are being developed in multi-well, small volume well plates, such as 1536-well plates having wells of a volume on the order of 1 &mgr;l. A mechanism for clamping such plates together so that the wells will be aligned allows rapid separation or transfer by simply centrifuging the assembly. A membrane may be clamped between the plates. Alternatively, a membrane may replace one of the plates. Centrifuge dependent and independent designs are described.

Abstract: Combinatorial chemical libraries of the Formula [S]—C(O)—L′—Z containing dihyroxy amides and hydroxyphosphonate amides are disclosed, in which [S] represents a solid support and —L′—Z is a linker/ligand residue. In these libraries, Z is and Y is —P(O)(OR6)(OR7), —CH(OH)—COR8, —CH,CH═CH2—CH2CH(OH)CH2OH, —CH2CHO, —CH2CH2OH, —CH2CH2OC(O)NHR26, —CH2CH2NR27R28, or The combinatorial libraries are optionally encoded with tags. The use of these libraries in assays to discover biologically active compounds is also disclosed.

Abstract: A combinatorial chemical library comprising a plurality of members of the Formula [S]—C(O)—L′-Z containing hydroxyamides is disclosed, in which [S] represents a solid support and L′-Z is a linker/compound residue. In this library, Z is and Y is —NR3R4 or —OR9. R3 and R4 are independently selected from the group consisting of H, alkyl, aralkyl, heteroarylalkyl, heterocycloalkyl, —CH(R5)CH(R6)OH, —CH(R5)C(O)NHR6 and —CH(R5)C(O)NHCH(R6)C(O)NHR7. R3 and R4 together are wherein X=O or NR8 and R9 is aryl, aralkyl or R7CH═CH(CH2){overscore (n)}. The combinatorial library can be optionally encoded with identifiers T′-L, which are covalently attached to the solid support. The methods of synthesizing such a library are described. The use of such library in assays to discover biologically active compounds is also disclosed.

Abstract: A U-valve apparatus including a bidirectional check valve for controlling the flow of liquid from a vessel while preventing inadvertent discharge from the vessel. The check valve allows passage of a fluid such a gas into the vessel, for purposes of agitating the liquid or for other purposes, and also permits the evacuation of the liquid from the vessel. The U-valve apparatus is advantageously included in a universal fluid exchange device including upper and lower reaction vessel supports which include pressure sealed injection and evacuation ports for each supported reaction vessel. Reaction vessels matingly engage through the injection and evacuation ports with fittings which are connected through flexible tubing to respective supplying and receiving vessels. Each of one or more reaction vessels may suitably be connected by a U-valve apparatus including a check valve to a corresponding receiving vessel.

Abstract: Combination chemical libraries of Formula I and methods for preparation are disclosed. The libraries allow one to screen large numbers of compounds for a desired biological activity with relative ease. The libraries may be tagged or untagged. In preferred libraries, Y is the residue of an N-acylated amino acid, a substituted 4-aminoproline or substituted piperazinealkanoic acid. The use of the libraries to discover biologically active compounds is also disclosed.

Abstract: An article comprising a Z-axis positioning stage is disclosed. The Z-axis positioning stage includes at least one collapsible/expandable cell or cavity that is defined within a region bounded by a lower and a movable upper surface and a side wall depending therefrom. Means for collapsing/expanding the cavity is operatively connected to the cavity. During collapse of the cavity, the upper surface drops towards the lower surface. During expansion of the cavity, the upper surface rises away from lower surface. The upper surface thus functions as a movable stage, which is capable of moving an object placed thereon in a vertical direction (i.e., along the z-axis).

Abstract: An improved centrifugation bucket providing two axes of rotation for a pair of multi-well plates. The centrifugation bucket is adapted to be used with a centrifuge in order to effect material transfer between a pair of microwell plates. The centrifugation bucket comprises a yoke adapted to be attached to a rotor arm of a centrifuge, and a platform attached to the yoke. The yoke is adapted to be attached to the centrifuge by a hinge or hinges providing a primary axis of rotation and the platform is attached to the yoke by hinges or other connectors providing a secondary axis of rotation. Multi-well plates may be secured to the platform to allow transfer of materials between the plates. The primary axis of rotation is parallel to the direction of travel of the centrifugation bucket during centrifugation and the secondary axis of rotation is perpendicular to the direction of travel of the centrifugation bucket during centrifugation.

Abstract: Compounds of Formula I are disclosed as inhibitors having activity against the aspartyl proteases, plasmepsin and cathsepsin D. The compounds are useful for treatment of diseases such as malaria and Alzheimer's disease. In preferred compounds of Formula I, Y is a heterocycle, amide, sulfonamide or carbamate and Z is an acyl or a functionalized acyl. Intermediates in the solid phase synthesis of compounds of Formula I, in which compounds are attached to a solid phase support, are also disclosed.

Abstract: An incremental positioner is disclosed. In one embodiment, the incremental positioner includes a motor, a drive shaft, a motion converter and a rack. The motion converter engages the rack and, impelled by the motor and drive shaft, causes the rack to move. The motion converter transmits and converts the continuous rotary motion of the motor to a linear intermittent motion of the rack. To generate such intermittent motion, the motion converter is physically configured so that even though the motion converter is in constant motion, it urges the rack to move on a periodic basis. In other words, during each revolution of the motion converter, the rack “dwells” (i.e., does not move) during a first portion of the cycle, and advances during a second portion of the cycle. Each time the rack advances, it does so by a characteristic incremental distance.

Abstract: A high throughput chemical synthesis system utilizing cylindrical reaction vessels is disclosed. Reaction vessels are utilized which include a tubular member adapted for placement of electronically readable identifying indicia thereon. The identifying indicia are representative of reaction conditions within the tubular member and of one or more reagents utilized in a reaction within the tubular members. A method of performing chemical synthesis on solid phase reactive material within a plurality of reaction vessels using a plurality of reaction stages resulting in final products and employing identifying indicia representing the reaction stages is also disclosed. The method includes reading the identifying indicia located on the reaction vessels, reacting one or more reagents within the reaction vessels under particular reaction conditions which may be determined by reading the identifying indicia, thereby synthesizing chemical compounds within the reaction vessels.