The present invention provides methods, compositions, and systems for distributing molecules and complexes into reaction sites. In particular, the methods, compositions, and systems of the present invention result in loading of polymerase enzyme complexes into a predetermined number of reaction sites, including nanoscale wells.

The present invention provides a formulation to link protein to a solid support that comprises one or more proteins, Oligo-dT and one or more non-volatile, water-soluble protein solvents, solutes or combination thereof in an aqueous solution. Further provided is a method of attaching a protein to a surface of a substrate. The formulations provided herein are contacted onto the substrate surface, printed thereon and air dried. The substrate surface is irradiated with UV light to induce thymidine photochemical crosslinking via the thymidine moieties of the Oligo-dT.

A frequency of somatic mutations in a biological sample (e.g., plasma or serum) of a subject undergoing screening or monitoring for cancer, can be compared with that in the constitutional DNA of the same subject. A parameter can derived from these frequencies and used to determine a classification of a level of cancer. False positives can be filtered out by requiring any variant locus to have at least a specified number of variant sequence reads (tags), thereby providing a more accurate parameter. The relative frequencies for different variant loci can be analyzed to determine a level of heterogeneity of tumors in a patient.

Fiducial markers are provided on patterned arrays of the type that may be used for molecular analysis, such as sequencing. The fiducial markers may have configurations that enhance their detection in image or detection data, that facilitate or improve processing, that provide encoding of useful information, and so forth. Examples of the fiducial markers may include features and materials that are provided on or in the support of a patterned array and that return at least a portion of incident light by reflection. The fiducial markers may form gratings or other encoding configurations that assist in image processing, alignment, or other aspects of processing of the patterned array.

A device for synthesis of macromolecules is disclosed. In one aspect, the device comprises an ion-releaser having a synthesis surface comprising an array of synthesis locations arranged for synthesis of the macromolecules. The ion-releaser also includes an ion-source electrode, which is arranged to contain releasable ions and is arranged to be in contact with each of the synthesis locations of the synthesis surface, thereby release ions to the synthesis locations. The ion-releaser further comprises activating electrodes, which are arranged to be in contact with the ion-source electrode, wherein each one of the activating electrodes is arranged in association with one of the synthesis locations via the ion-source electrode. The ion-releaser is arranged to release at least a portion of the releasable ions from the ion-source electrode to one of the synthesis locations, by activation of the activating electrode associated with the synthesis location.

An integrated circuit includes an interconnection structure, first and second sensing pixels over the interconnection structure, and an isolation layer over the first and second sensing pixels. Each of the first and second sensing pixels includes a bio-sensing device, a temperature-sensing device, one or more heating elements adjacent to the bio-sensing device and the temperature-sensing device, and a sensing film over the bio-sensing device. The isolation layer includes a first opening configured to expose the sensing film of the first sensing pixel without exposing the sensing film of the second sensing pixel and a second opening configured to expose the sensing film of the second sensing pixel without exposing the sensing film of the first sensing pixel.

A system includes a synthesizer unit having a fluid input to receive fluids and a communication input to receive commands to synthesize data-encoded DNA sequences and cleave the DNA. A first flexible chemistry reaction chamber module may be fluidically coupled to the synthesizer unit to receive the data-encoded DNA sequences and amplify the sequences. A deposition unit may be fluidically coupled to the first flexible chemistry reaction chamber module to receive the amplified DNA sequences and encapsulate the amplified DNA sequences into one or more wells in a storage plate for storage and retrieval to and from a plate storage unit. Retrieved DNA may be processed and read by further units.

The invention relates to a method for analyzing molecular properties and/or reaction conditions, comprising a step of providing a first store having a first surface, wherein a specific selection of sample molecules is directly or indirectly bonded to the surface in a defined arrangement, a step of producing at least two transfer stores, wherein at least two additional surfaces are provided, and a reaction step, selected from the group comprising a transfer reaction, an amplification reaction, and/or a derivatization reaction, whereby product molecules can arise and said product molecules and/or the sample molecules bond to the surfaces, wherein there is a clear spatial association between the sample molecules of the first store and the product molecules and/or sample molecules of the transfer stores and the first store, the transfer stores, the sample molecules, the product molecules, the transfer reaction, the amplification reaction, and/or the derivatization reaction is analyzed.

A rigid mask protects selective portions of a chip including a plurality of wells for biochemical reactions. The rigid mask includes a supporting portion and a plurality of legs, where each leg is provided with a rigid stem and a plate. The plurality of legs are arranged and fixed with respect to the supporting portion in a way aligned to the spatial arrangement of the wells, and are configured in such a way that, when each leg is inserted into the corresponding well, the respective plate covers at least in part the bottom of the well, protecting it during a chemical/physical treatment of side walls of the wells.

Disclosed herein are methods for producing high density cellular arrays. In some embodiments, the methods comprise: providing a sample comprising a plurality of cells; and introducing the plurality of cells in the sample into microwells of a microwell array to produce a cellular array, wherein the microwell array comprises 500 or more microwells per inch.sup.2, and wherein 25% or more of the microwells of the cellular array comprise a single cell. The disclosed methods can be used for producing a high density synthetic particle array and a high density reagent array.