Untitled record

Description Ankle

Background deception

The present application claims the benefit of US Provisional Application No. 205336/62, filed on August 14, 2015 and having the same title, which is incorporated herein by reference.

Current NGS (next generation sequencing) based sequencing systems

<p dir="rtl">5 The basis of sequencing-by-synthesis (SBS) is complex, expensive, and bulky. Baltasch, new detection methods are required for synthesis tools by succession.</p>

US Patent 120090208957 relates to new systems and methods that provide new multi-ligand constructs and marking strategies, including fluorescence-based, non-fluorescence-based and non-optical-based labeling, for example, for use with

<p dir="rtl">10 monomolecular straight.</p>

European Patent 1544310 2 describes methods and systems for characterizing a polymer in a sample. In current methods, any labeled polymer sample includes at least one nanopore in contact with a nanopore under conditions such that it is positioned within the nanopore.

US Patent 28252910 provides modular nucleotide structures.

<p dir="rtl">15 Compositions and methods for making and using these compositions, which use a template method to add functional groups to nucleotide analogs.</p>

Working description of the invention

In one embodiment, the method of synthesis is provided by series including providing a detector including an array of magnetically-responsive sensors. Each

<p dir="rtl">20 Of sensors responding magnetically near a given vacuum corresponding to detecting a magnetic property thereof. The detector also includes a set of template strands of nucleic acid placed in corresponding designated spaces. The method also includes performing a plurality of synthesis events by succession to give a complementary strand by input</p>

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Nucleotides along each template strand. At least some of the nucleotides are attached to corresponding magnetic particles that have corresponding magnetic properties. Each set of synthesis events involves detecting changes in electrical resistance at magnetically responsive sensors caused by magnetic properties.

<p dir="rtl">5 properties corresponding to magnetic particles. The method also includes determining genetic properties of complementary strands based on detected changes in electrical resistance.</p>

In one embodiment, the synthesis method is provided by respectively including providing a detector including an array of magnetically responsive sensors. Each of the magnetically responsive sensors is placed near a corresponding blank to detect a magnetic property of it. A detector is also included

<p dir="rtl">10 A group of DNA template strands arranged in corresponding specific spaces. The method also includes supplying a set of reactants to the designated blanks. The reactants include a nucleotide and a rice polymerase, where at least one of the nucleotides or rice polymer has magnetic particles attached thereto. The method also includes detecting changes in electrical resistance at magnetically responsive sensors during a set of synthesis events by series, which includes</p>

<p dir="rtl">15 All synthesis occurs by successive growth of a complementary strand by insertion of a single nucleotide into the complementary strand. The changes in electrical resistance when magnetic particles are placed in the corresponding designated spaces during the set of synthesis events are achieved by series. The method also includes determining genetic properties of complementary strands based on detected changes in electrical resistance.</p>

In one embodiment, the synthesis method is provided by respectively including providing a detector including

<p dir="rtl">20 Magnetically responsive array of sensors. Each of the magnetically responsive sensors is placed near a corresponding blank to detect a magnetic property of it. The detector also includes a plurality of nucleic acid template strands placed in corresponding designated spaces. The method also includes performing a plurality of synthesis cycles in succession to give a complementary strand along each die strand. Each cycle of synthesis involves (a) attaching nucleotides to the designated spaces and permitting</p>

<p dir="rtl">25 By adding nucleotides to complementary strands; (b) Delivering magnetic particles to designated spaces, magnetic particles captured by nucleotides; (c) Detecting changes in resistance</p>

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Electrophysiology of magnetically responsive sensors, changes caused by the magnetic properties of magnetic particles; and (d) removing magnetic particles from designated spaces. The method also includes determining genetic properties of complementary strands based on detected changes in electrical resistance. In one embodiment, the method of synthesis is provided by series including providing a detector including

<p dir="rtl">5 Magnetically responsive array of sensors. Each of the magnetically responsive sensors is placed near a corresponding blank to detect a magnetic property of it. The detector also includes a plurality of nucleic acid template strands placed in corresponding designated spaces. The method also includes performing a plurality of synthesis cycles in succession to give a complementary strand along each die strand. Each cycle of synthesis involves (a) attaching nucleotides to the designated spaces and permitting</p>

<p dir="rtl">10 By adding nucleotides to complementary strands. Nucleotides include at least first, second, and third nucleotides. The first, second, and third nucleotides contain different bases. Each cycle of sequential synthesis also includes (b) delivering magnetic particles to the designated spaces, where the magnetic particles are captured by the first nucleotide and by the second nucleotide, and (c) detecting changes in electrical resistance at the magnetically responsive sensors. Each cycle includes Synthesis by</p>

<p dir="rtl">15 Also respectively (d) removal of magnetic particles from the first nucleotide; (e) delivery of magnetic particles to designated spaces, where the magnetic particles are captured by the third nucleotide; and (f) detection of changes in electrical resistance at magnetically responsive sensors. The method also includes determining genetic properties of complementary strands based on detected changes in electrical resistance.</p>

<p dir="rtl">20 In one embodiment, the synthesis method is provided by respectively including providing a detector including an array of magnetically responsive sensors. Each of the magnetically responsive sensors is placed near a corresponding blank to detect a magnetic property of it. The detector also includes a plurality of nucleic acid template strands placed in corresponding designated spaces. The method also includes performing a plurality of synthesis cycles in succession to give a complementary strand along each template strand.</p>

<p dir="rtl">25 Each cycle of synthesis by sequence (a) includes attaching at least the first and second nucleotides to the designated spaces to extend the complementary strands. The first and second nucleotides contain different bases, which include:</p>

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The first and second nucleotides are magnetic particles attached to them. Each cycle of synthesis by series also includes (b) detecting changes in electrical resistance at magnetically responsive sensors, whereby the magnetic particles held by the first nucleotide result in a different change in electrical resistance than the magnetic particles held by the second nucleotide.

<p dir="rtl">5 Determining genetic properties of complementary strands based on revealed changes in electrical resistance.</p>

In one embodiment, the synthesis method is provided by respectively. The method includes providing a detector

Includes an array of magnetically responsive sensors. Each of the responding sensors is placed

Magnetically near a given blank to detect the magnetic property of it. The detector also includes a plurality of nucleic acid template strands placed in corresponding designated spaces. Method 10 also includes performing a plurality of synthesis cycles by successively to give a complementary strand along each template strand. Each cycle of synthesis by sequence (a) includes attaching at least the first and second nucleotides to the designated spaces to extend the complementary strands. The first and second nucleotides have different bases, with the first and second single-molecule magnets (SMMs), respectively, attached to them. Both the first and second SMMs have 15 different magnetic states that respond to different light frequencies. Each cycle of synthesis by series also includes (b) modifying the magnetic state of the first monomolecular magnets by shining a first light frequency and (c) detecting changes in electrical resistance at the magnetically responsive sensors, where the changes are produced by the magnetic state of the first monomolecular magnets. . Each cycle of synthesis involves successively (d) modifying the magnetic state of the first monomolecular magnets 20 by applying a second light frequency; (e) modifying the magnetic state of the second monomolecular magnets by applying a third light frequency; and (f) detecting changes in electrical resistance In magnetically responsive sensors, the changes are produced by the magnetic state of the second monomolecular magnets. The method also includes determining genetic properties of the complementary strands based on the detected changes

About electrical resistance.

<p dir="rtl">25 In one embodiment, the synthesis method is provided by respectively. The method includes providing a detector that includes an array of magnetically responsive sensors. Each of the responding sensors is placed</p>

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Magnetically near a given blank to detect the magnetic property of it. The detector also includes a plurality of nucleic acid template strands placed in corresponding designated spaces. The method also includes performing a plurality of synthesis cycles in succession to give a complementary strand along each template strand. Each cycle of synthesis by sequence (a) includes the delivery of at least the first and second nucleotides to

<p dir="rtl">5 A thousand designated spaces for extending the complementary strands. The first and second nucleotides contain different bases</p>

The first and second nucleotides have single-molecule magnets attached to them. The first and second nucleotides have a number of different monomolecular magnets attached to them. Single-molecule magnets involve magnetic states that respond to different frequencies of light. Each cycle of synthesis also includes (b) modification of the magnetic state of the monomolecular magnets by the application of a first light frequency; (c) detection

<p dir="rtl">10 About changes in electrical resistance at magnetically responsive sensors; and (d) modifying the magnetic state of single-molecule magnets by shining a second light frequency. The method also includes determining genetic properties of complementary strands based on detected changes in electrical resistance.</p>

In one embodiment, the synthesis method is provided by respectively. The method includes providing a detector that includes an array of magnetically responsive sensors. Each of the responding sensors is placed

<p dir="rtl">15 Magnetically near a given blank to detect the magnetic property of it. The detector also includes a plurality of nucleic acid template strands placed in corresponding designated spaces. The method also includes performing a set of synthesis events by sequentially giving a complementary strand by adding nucleotides along each template strand using a rice polymerase. The rice polymer includes corresponding magnetic particles attached thereto that exhibit corresponding magnetic properties, where each event includes synthesis by</p>

<p dir="rtl">20 Respectively detecting changes in electrical resistance at magnetically responsive sensors. The changes detected are caused by the presence of magnetic particles at the specific gaps when the rice polymer adds nucleotides. The method also includes determining genetic properties of complementary strands based on detected changes in electrical resistance.</p>

In one embodiment, the synthesis method is provided by respectively. The method includes providing a detector

<p dir="rtl">25 Includes an array of magnetically responsive sensors. Each of the magnetically responsive sensors is placed near a corresponding blank to detect a magnetic property of it. Detector included</p>

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Also a set of DNA template strands arranged in corresponding specific spaces. The method also includes performing a plurality of synthesis cycles in succession to give a complementary strand along each die strand. Each set of synthesis cycles by series involves (a) delivering a first nucleotide and a rice polymer to the designated spaces. The rice polymer includes magnetic particles attached to it. Each synthesis cycle includes

<p dir="rtl">5 Also by series (b) detecting changes in electrical resistance at magnetically responsive sensors. Changes in electrical resistance are produced by the presence of magnetic particles at the specific spaces when the rice polymer adds the first nucleotide to the complementary strand. Each cycle involves synthesis by series (c) Delivery of a second nucleotide and a rice polymer to the designated spaces. The rice polymer has magnetic particles attached to it. Each cycle of synthesis by the sequence also includes (d) detection of changes in</p>

<p dir="rtl">10 Electrical resistance at magnetically responsive sensors. Changes in electrical resistance are caused by the presence of magnetic particles at specific gaps when the corresponding rice polymer adds the second nucleotide to the complementary strand. The method also includes determining genetic properties of complementary strands based on detected changes in electrical resistance.</p>

In one embodiment, the synthesis method is provided by respectively. The method includes providing a detector

<p dir="rtl">15 Includes an array of magnetically responsive sensors. Each of the magnetically responsive sensors is placed near a corresponding blank to detect a magnetic property of it. The detector also includes a plurality of nucleic acid template strands placed in corresponding designated spaces. The method also includes performing a plurality of synthesis events by successively to give a complementary strand along each template strand. Each of the set of synthesis events by sequence (a) includes the delivery of at least nucleotides</p>

<p dir="rtl">20 First, second, and cedar polym to the designated thousand argat. The first and second nucleotides contain different bases. Polymers have magnetic particles attached to them. Each sequence synthesis event also involves (b) detecting changes in electrical resistance at magnetically responsive sensors. Changes in electrical resistance are produced by the presence of magnetic particles at the designated spaces when the rice polymer adds the first nucleotide or the second nucleotide to the complementary strand. Includes nucleotides</p>

<p dir="rtl">25 The first and second have different input rates. The method also includes determining genetic properties of complementary strands based on detected changes in electrical resistance.</p>

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In one embodiment, the synthesis system is provided by a detector including an array of magnetically responsive sensors. Each magnetically responsive sensor includes at least two ferromagnetic layers and a non-magnetic layer that separates the two ferromagnetic layers. Each of the 5 magnetically responsive sensors constitutes at least one giant magnetoresistance (GMR) sensor or tunnel magnetoresistance (TMR) sensor. Magnetically responsive sensors are placed next to corresponding designated spaces in a room and configured to detect magnetic particles from the corresponding designated spaces. The system also includes a readout circuit that is connected to the magnetically responsive sensors. The reading circuit is configured to emit signals that respond

<p dir="rtl">10 For electrical resistors of magnetically responsive sensors. The detector also includes a fluidic-control system configured to flow reagent agents through the chamber to carry out the synthesis protocol by series. Detectors include a set of nucleotide types, where the readout circuit is configured to emit signals after each input event.</p>

In one embodiment, the detector has an array of magnetically responsive art sensors. Each magnetically responsive Art 15 sensor includes at least two ferromagnetic layers and a non-magnetic layer that separates the two ferromagnetic layers. Each of the magnetically responsive sensors constitutes at least one of a massive magnetoresistance sensor or a tunnel magnetoresistance sensor. Magnetically responsive sensors are placed next to corresponding designated spaces in a room and configured to detect magnetic particles from the corresponding designated spaces. The detector may include a circuit

20 A reading device that is connected to magnetically responsive sensors.

In one embodiment, the series synthesis system includes a readout arm and a magnetically responsive sensor attached to the arm. The magnetically responsive sensor includes at least one sensor

Massive magnetoresistance or tunnel magnetoresistance sensor. The responding sensor is initialized

Magnetically detecting magnetic particles. The system also includes a sample substrate having a substrate surface. Surface

25 The substrate is configured to include a plurality of nucleic acid template strands positioned in specified spaces along the surface of the substrate, where at least one of the reading beds and the sample substrate are configured to move relative to the other

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To position the magnetically responsive sensor near the designated spaces in an operational relationship. The system also includes a readout circuit that is communicatively coupled to the magnetically responsive sensor. The read circuit is configured to broadcast

Signals that respond to the electrical resistance of the magnetically responsive sensor when positioned at one of the specified spaces.

In one embodiment, the synthesis method is provided by respectively including providing a reading arm having an arm and a magnetically responsive sensor attached to the arm. The magnetically responsive sensor includes at least one of a massive magnetoresistance sensor or a tunneling magnetoresistance sensor. The sensor is initialized

Magnetically transponder detecting magnetic particles. The method includes providing a sample substrate having a plurality of die strands positioned at specified intervals along the surface of the substrate. The method also includes

<p dir="rtl">10 Carrying out a set of synthesis cycles in succession to give complementary strands by inserting nucleotides along each of the template strands. At least some of the nucleotides are labeled with corresponding magnetic particles that exhibit corresponding magnetic properties. For each of the series synthesis cycles, the method includes placing the magnetically responsive sensor adjacent to designated voids along the surface of the substrate and detecting electrical resistance at the magnetically responsive sensors. The method also includes determining genetic characteristics</p>

<p dir="rtl">15 of complementary strands based on detected changes in electrical resistance.</p>

In one embodiment, the synthesis method is provided by respectively including providing a detector including an array of magnetically responsive sensors. Each of the magnetically responsive sensors is placed near a specific area corresponding to detecting a magnetic property of it. The detection device also includes a rice polymer transported to the designated areas. Polymer rice is prepared to hold the braid of a corresponding template. The method includes

<p dir="rtl">20 Also perform a set of synthesis events by successively to give a complementary strand by inserting nucleotides along a corresponding template strand. Nucleotides are attached to corresponding magnetic particles that have corresponding magnetic properties. Each of the series synthesis events involves detecting changes in electrical resistance at the magnetically responsive sensors produced by the corresponding magnetic properties of the magnetic particles as nucleotides are added to the complementary strand.</p>

<p dir="rtl">25 The method also includes determining genetic properties of complementary strands based on detected changes in electrical resistance.</p>

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In one embodiment, the synthesis method is provided by respectively including providing a detector including

Magnetically responsive array of sensors. Each of the responsive sensors is positioned magnetically

Near a certain area corresponding to detecting the magnetic property thereof. A detector is also included

Rice bulk transported to designated areas. The rice polymer is prepared to be attached to the corresponding die strands. Includes

<p dir="rtl">5 The method also performs a set of synthesis events by sequentially giving complementary strands along the template strands. Each synthesis event by stranding involves (a) delivering nucleotides to designated regions and allowing the addition of nucleotides to complementary strands. Each synthesis event by stranding also involves (b) delivering magnetic particles to designated regions. The magnetic particles are captured by</p>

Nucleotides. Magnetic particles provide a corresponding external magnetic field. Every synthesis event

<p dir="rtl">10 By succession also including (c) detecting changes in electrical resistance at magnetically responsive sensors and (d) removing magnetic particles from designated areas. The method also includes</p>

Determining genetic properties of complementary strands based on revealed changes in electrical resistance.

In one embodiment, the synthesis method is provided by respectively including providing a detector including an array of magnetically responsive sensors. Each of the responsive sensors is positioned magnetically

<p dir="rtl">15 Near a certain area corresponding to detecting the magnetic property thereof. The detection device also includes a rice polymer transported to the designated areas. The rice polymer is prepared to be attached to the corresponding mold strands. The method also includes performing a plurality of synthesis events by sequentially giving complementary strands along the template strands. Each synthesis event by sequence (a) involves delivering nucleotides to designated regions and allowing the addition of nucleotides to complementary strands. Nucleotides include at least first nucleotides,</p>

<p dir="rtl">20 A second, and a third. The first, second, and third nucleotides contain different bases. Each sequence synthesis event also includes (b) the delivery of magnetic particles to designated areas, the magnetic particles captured by the first nucleotide and by the second nucleotide. Each sequence synthesis event also includes (c) the detection of changes in electrical resistance at the responding sensors. Magnetically; (d) removing magnetic particles from the first nucleotides; (e) connecting particles</p>

<p dir="rtl">25 Magnetic to designated regions, magnetosomes are specific to the third nucleotide; (f) Detecting changes in electrical resistance at magnetically responsive sensors. The method also includes</p>

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Determining genetic properties of complementary strands based on revealed changes in electrical resistance.

In one embodiment the method of synthesis is disclosed by respectively. The method includes providing a detector comprising an array of magnetically responsive sensors, each of the magnetically responsive sensors placed in the vicinity of a corresponding blank to detect a magnetic property thereof, the detector also

<p dir="rtl">5 Including a set of DNA template strands arranged in corresponding specific spaces. The method also includes performing a plurality of synthesis events by sequence to give a complementary strand by introducing nucleotides along each template strand, at least some of the nucleotides attached to corresponding magnetic particles having corresponding magnetic properties, wherein each plurality of synthesis events by sequence includes detecting changes in The electrical resistance at the magnetically responsive sensor 10 is generated by the corresponding magnetic properties of the magnetic particles. The method also includes determining genetic properties of complementary strands based on detected changes in electrical resistance.</p>

In one embodiment, the magnetically responsive sensor includes a magnetically resistive sensor

.magnetoresistive sensor

In one embodiment, the magnetically responsive sensors include a massive magnetoresistance sensor, 15 the changes in electrical resistance caused by changes in current flow through layers of

Huge magnetic resistance sensor.

In one embodiment, the magnetically responsive sensors include a tunneling magnetoresistance sensor, changes in electrical resistance resulting from changes in tunneling electron current through insulative layers of the tunneling magnetoresistance sensor.

<p dir="rtl">20 In one embodiment, each of the magnetically responsive sensors includes a first and second ferromagnetic layer and a nonmagnetic layer separating the first and second ferromagnetic layer.</p>

In one embodiment, determining the genetic property of complementary strands includes analyzing detected changes in electrical resistance to determine whether signals based on the detected changes form a particular pattern.

<p dir="rtl">25 In one embodiment, determining genetic properties includes determining complementary strand sequences, the complementary strand sequences being based on the detected changes in electrical resistance that occur at the sensors</p>

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Magnetically responding to each of the set of synthesis events by respectively.

In one embodiment, determining complementary strand sequences includes determining whether changes in electrical resistance have occurred at the magnetically responsive sensors.

In one embodiment, determining complementary strand sequences includes determining the magnitudes of changes in electrical resistance 5 at the magnetic response sensors.

In one embodiment, the nucleotides include multiple types of nucleotides, each type of nucleotide having a different number of magnetic particles attached to it than the other types of nucleotides.

In one embodiment, the magnetic particles are single-molecule magnets.

In one embodiment, the nucleotides include multiple types of nucleotides, each nucleotide type having a different type

<p dir="rtl">10 Of a magnetic particle attached to it other than other types of nucleotides.</p>

In one embodiment, the magnetic particles include different magnetic field strengths.

In one embodiment, the magnetic particles include materials exhibiting paramagnetism, diamagnetism, ferromagnetism, or antiferromagnetism.

<p dir="rtl">15 In one embodiment, detected changes in electrical resistance at magnetically responding sensors are caused by the intrinsic spins of electrons in the magnetic particle material.</p>

In one embodiment, executing a plurality of sequential synthesis circuits includes executing a plurality of sequential synthesis circuits, each of the plurality of sequential synthesis circuits comprising delivering multiple types of 20 nucleotides, each nucleotide type being delivered at a separate time.

In one embodiment, executing a plurality of sequential synthesis circuits includes executing a plurality of sequential synthesis circuits, each of the plurality of sequential synthesis circuits including delivering multiple types of nucleotides simultaneously.

In one embodiment, executing a plurality of synthesis cycles by succession includes executing a plurality of synthesis cycles

<p dir="rtl">25 Synthesis by Strength Each of the Duart group of synthesis by sequence involves attaching magnetic particles to the corresponding nucleotides after adding the corresponding nucleotides to the complementary strand.</p>

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In one embodiment, the magnetic particles include a reversible linkage.

In one embodiment, the reversible linkage includes biotin, desthiobiotin, avidin, neutravidin, streptavidin (SA), an aldehyde, a hydrazide, a complementary oligonucleotide, or an acid analogue.

<p dir="rtl">5 nucleic acid analog.</p>

In one embodiment, the magnetic particles include a non-reversible linkage.

In one embodiment, the magnetic particles include photo-cleavable bonds

.linkages

In one embodiment, the magnetic particles include photo-reversible bonds

.linkages 10

In one embodiment, the magnetic particles include photoactivatable ligands

.linkages

In one embodiment, the magnetic particles include cleavable bonds.

In one embodiment, the magnetic particles are configured to bind temporarily to the corresponding nucleotide.

<p dir="rtl">15 In one embodiment, one or more magnetic particles are attached to the gamma phosphate of the nucleotide, the magnetic particle released when the polymerase adds the nucleotide to the complementary strand.</p>

In one embodiment, each particular blank includes a plurality of template strands that are transferred to the surface of a detector substrate.

<p dir="rtl">20 In one embodiment, each particular blank includes an individual template strand transferred to a substrate surface of the detector. In one embodiment, the nucleotides include biotin tags.</p>

In one embodiment, the magnetic particles are streptavidin-coated nanoparticles, nucleotides and magnetic particles forming a biotin/streptavidin magnetic nanoparticle (BSMN) complex.

<p dir="rtl">25 In one embodiment, the detector includes a flow cell that identifies a chamber having designated spaces, nucleotides and magnetic particles delivered to the designated spaces by a flow</p>

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Nucleotides and magnetic particles through the flow cell chamber.

In one embodiment, the detector defines a chamber containing designated voids, the detector has electrodes positioned along the length of the chamber, where nucleotide delivery and magnetic particle delivery involve performing droplet operations using the electrodes.

<p dir="rtl">5 In one embodiment, the set of synthesis events is performed by sequentially through individual vascular reactions</p>

.single pot reactions

In one embodiment, the magnetic particles always change the magnetization processes of the corresponding magnetically responsive sensors such that the magnetization processes of the corresponding magnetically responsive sensors are maintained after the removal of the magnetic particles, wherein the method includes changing the magnetization of at least some of the

<p dir="rtl">10 Magnetically responsive sensors After reading the magnetically responsive sensors.</p>

In one embodiment, the magnetically responsive sensors are read after removing the magnetic particles.

In one embodiment, the method of synthesis is disclosed by respectively. The method includes providing a detector comprising an array of magnetically responsive sensors, each of the magnetically responsive sensors placed in the vicinity of a corresponding blank to detect a magnetic property thereof, the detector also

<p dir="rtl">15 Including a set of DNA template strands arranged in corresponding specific spaces. The method includes providing a plurality of reactants to designated blanks, the reactants including nucleotides and a rice polymer, where at least one of the nucleotides or rice polymers has magnetic particles attached thereto. The method includes detecting changes in electrical resistance at magnetically responsive sensors during a plurality of series synthesis events, where each series synthesis event includes growth</p>

<p dir="rtl">20 Complementary strand By insertion of a single nucleotide into the complementary strand, the changes in electrical resistance that occur when magnetic particles are placed in the corresponding designated spaces during the set of synthesis events by series. The method involves determining genetic properties of complementary strands based on detected changes in electrical resistance.</p>

In one embodiment, the magnetically responsive sensor includes a magnetically resistive sensor.

<p dir="rtl">25 In one embodiment, the magnetically responsive sensors include sensing massive magnetoresistance, changes in electrical resistance caused by changes in current flow through layers of</p>

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Huge magnetic resistance sensor.

In one embodiment, the magnetically responsive sensors include a tunneling magnetoresistance sensor, changes in electrical resistance resulting from changes in tunneling electron current through dielectric layers of the tunneling magnetoresistance sensor.

<p dir="rtl">5 In one embodiment, each of the magnetically responsive sensors includes a first and second ferromagnetic layer and a nonmagnetic layer separating the first and second ferromagnetic layer.</p>

In one embodiment, determining the genetic property of complementary strands includes analysis of detected variations

In electrical resistance to determine whether signals based on detected changes form a pattern

specific.

<p dir="rtl">10 In one embodiment, the determination of genetic properties includes determining sequences of complementary strands, the sequences of the complementary strands being based on the detected changes in electrical resistance that occur at the magnetically responsive sensors for each of the plurality of synthesis events by the sequence.</p>

In one embodiment, the nucleotides include multiple types of nucleotides, each type of nucleotide having a different number of magnetic particles attached to it than the other types of nucleotides.

<p dir="rtl">15 In one embodiment, the magnetic particles are single-molecule magnets.</p>

In one embodiment, the nucleotides include multiple types of nucleotides, each nucleotide type having a different type

Of a magnetic particle attached to it other than other types of nucleotides.

In one embodiment, the magnetic particles include different magnetic field strengths.

In one embodiment, the magnetic properties include at least one magnetic field direction

<p dir="rtl">20 Magnetic direction, or magnetic moment.</p>

In one embodiment, the magnetic particles include materials exhibiting paramagnetism, weak magnetization, ferromagnetism, or antiferromagnetism.

In one embodiment, detected changes in electrical resistance at magnetically responsive sensors are caused by latent spins of electrons in the magnetic particle material.

<p dir="rtl">25 In one embodiment, each particular blank includes a plurality of template strands that are transferred to a substrate surface of the detector.</p>

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In one embodiment, each particular blank includes an individual template strand transferred to a substrate surface of the detector. In one embodiment, each particular blank includes an individual rice polymer molecule transferred to a substrate surface of the detector. In one embodiment, the detector includes a flow cell that identifies a chamber having designated voids, the reactants are delivered to the designated voids by simultaneously flowing the reactants through the cell chamber.

<p dir="rtl">5 the flow.</p>

In one embodiment, the detector defines a chamber containing the specified voids, the detector has electrodes positioned along the length of the chamber, where delivery of reactants involves carrying out distillations using the electrodes.

In one embodiment, each nucleotide includes one or more phosphate-linked magnetic particles

<p dir="rtl">10 Gamma nucleotide, the magnetic particle that is released when the polymerase adds a nucleotide to the complementary strand.</p>

In one embodiment, magnetic particles are attached to the rice polymer, detectable changes resulting from the presence of the magnetic particles at the designated spaces when the rice polymer adds nucleotides.

<p dir="rtl">15 In one embodiment, each nucleotide type includes a corresponding insertion rate that differs from the insertion rate of the other nucleotide types.</p>

In one embodiment, the method of synthesis is disclosed by respectively. The method includes providing a detector comprising an array of magnetically responsive sensors, each of the magnetically responsive sensors placed in the vicinity of a corresponding blank to detect a magnetic property thereof, the detector also

<p dir="rtl">20 Including a set of DNA template strands arranged in corresponding specific spaces. The method includes executing a plurality of synthesis cycles in succession to give a complementary strand along each template strand. Each cycle of synthesis by stranding involves (a) delivering nucleotides to the designated spaces and allowing the addition of nucleotides to complementary strands. Each cycle of synthesis by stranding involves (b) delivering magnetic particles to the designated spaces, the magnetic particles being captured by</p>

<p dir="rtl">25 Nucleotides. Each cycle includes the synthesis by succession (c) detection of changes in electrical resistance at magnetically responsive sensors, changes resulting from the magnetic properties of the particles</p>

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Magnetism. Each cycle of synthesis by sequence (d) involves the removal of magnetic particles from designated spaces. The method involves determining genetic properties of complementary strands based on detected changes in electrical resistance.

In one embodiment, steps (a)-(d) are repeated for multiple nucleotide types, each 5-nucleotide type being delivered separately to designated spaces.

In one embodiment, the simultaneous delivery of nucleotides includes delivering multiple types of nucleotides and the simultaneous delivery of magnetic particles includes delivering multiple types of magnetic particles, each type of magnetic particle having a corresponding magnetic field strength that differs from the magnetic field strengths of the other types of magnetic particles.

<p dir="rtl">10 In one embodiment, each particular blank includes a plurality of template strands that are transferred to a substrate surface of the detector.</p>

In one embodiment, each particular blank includes an individual template strand transferred to a substrate surface of the detector.

In one embodiment, the nucleotides include biotin tags.

In one embodiment, the magnetic particles are coated nano-sized magnetic particles

<p dir="rtl">15 Streptavidin, nucleotides and magnetic particles forming a nano-sized biotin/streptavidin magnetic particle complex. The method also includes removing the nano-sized biotin/streptavidin magnetic particle complex.</p>

In one embodiment, the magnetic particles are activated nano-sized magnetic particles.

In one embodiment, the magnetic particles are nano-sized magnetic particles coated 20 with streptavidin.

In one embodiment, the designated blanks are placed in a flow cell chamber wherein nucleotide delivery and magnetic particle delivery comprise nucleotide flow and magnetic particle flow, respectively, through the chamber.

In one embodiment, the detector identifies a chamber containing the designated voids, the detector having electrodes 25 positioned along the length of the chamber, wherein the delivery of the nucleotides and the delivery of the magnetic particles involve performing distillation processes using the electrodes.

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In one embodiment, each plurality of synthesis circuits by series includes detecting a basic level of electrical resistance after (d).

In one embodiment, the nucleotides include blocking groups, the method further including removing the blocking groups after (c).

<p dir="rtl">5 In one embodiment, the magnetically responsive sensor includes a magnetically resistive sensor.</p>

In one embodiment, the magnetically responsive sensors include a magnetoresistance sensor, changes in electrical resistance caused by changes in current flow through layers of magnetoresistance sensors.

In one embodiment, the magnetically responsive sensors include a tunnel magnetoresistance sensor,

<p dir="rtl">10 Changes in electrical resistance caused by changes in electron current tunneling through insulating layers</p>

From a tunnel magnetic resistance sensor.

In one embodiment, each of the magnetically responsive sensors includes a first and second ferromagnetic layer and a nonmagnetic layer separating the first and second ferromagnetic layer.

In one embodiment, determining the genetic property of complementary strands includes analysis of detected variations

<p dir="rtl">15 In electrical resistance to determine whether signals, based on detected changes, form a specific pattern.</p>

In one embodiment, the determination of the genetic properties includes determining sequences of complementary strands, the sequences of the complementary strands being based on the detected changes in electrical resistance that occur at the magnetically responsive sensors of each of the pluralities of synthesis cycles by the series.

<p dir="rtl">20 In one embodiment, the magnetic properties include at least one of a magnetic field, magnetic direction, or magnetic moment.</p>

In one embodiment, the magnetic particles include materials exhibiting paramagnetism, weak magnetization, ferromagnetism, or antiferromagnetism.

In one embodiment, the detected changes in electrical resistance at the magnetically responding sensors 25 are produced by the latent spins of electrons in the magnetic particle material.

In one embodiment, the magnetic particles always alter the magnetization processes of the responding sensors

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corresponding magnetically so that the magnetization processes of the magnetically responsive sensors are maintained

The corresponding after removal of the magnetic particles, wherein the synthesis cycles by series include changing the magnetization of at least some of the magnetically responsive sensors after reading the magnetically responsive sensors.

In one embodiment, the magnetically responsive sensors are read after removing the magnetic particles.

<p dir="rtl">5 In one embodiment, the method of synthesis is disclosed by respectively. The method includes providing a detector</p>

Includes an array of magnetically responsive sensors, each of which is magnetically responsive

Placed near a given blank corresponding to detecting a magnetic property thereof, the detector also

Including a set of DNA template strands arranged in corresponding specific spaces. The method includes executing a plurality of synthesis cycles in succession to give a complementary strand along each template strand.

<p dir="rtl">10 Each cycle of synthesis by (a) involves attaching nucleotides to the designated spaces and allowing the addition of nucleotides to complementary strands, nucleotides including at least first, second, and third nucleotides. The first, second, and third nucleotides have different bases. Each cycle involves synthesis by</p>

Respectively (b) delivery of magnetic particles to the designated spaces, the magnetic particles captured by the first nucleotide and by the second nucleotide. Each cycle includes synthesis by

<p dir="rtl">15 (c) Detection of changes in electrical resistance at magnetically responsive sensors. Each synthesis cycle by series (d) involves the removal of magnetic particles from the first nucleotides. Each synthesis cycle by series (e) involves delivery of magnetic particles to designated spaces , the magnetic particles captured by the three nucleotides. Each cycle involves synthesis by (and) detecting changes in electrical resistance at the responding sensors.</p>

<p dir="rtl">20 Magnetically. The method involves determining genetic properties of complementary strands based on the detected changes</p>

In electrical resistance.

In one embodiment, the first nucleotide extends the complementary strand at (a) if a change in electrical resistance is detected at (c) but is not detected at (f); the second nucleotide extends the complementary strand at (a) if a change in electrical resistance is detected at (f); In the electrical resistance at (c) and it was detected at (f);

<p dir="rtl">25 The third nucleotide extends the complementary strand at (a) if a change in electrical resistance is not detected at (c) but is detected at (f).</p>

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In one embodiment, (a) includes connecting four nucleotides wherein the four nucleotide extends the complementary strand at (a) if no change in electrical resistance is detected at (c) and is not detected at (f).

In one embodiment, each of the plurality of synthesis cycles includes, respectively: (g) particle removal

<p dir="rtl">5 Magnetism of the second and third nucleotides.</p>

In one embodiment, (d) and (e) occur simultaneously.

In one embodiment, determining the genetic property of complementary strands includes analyzing detected changes in electrical resistance to determine whether signals based on the detected changes form a particular pattern.

<p dir="rtl">10 In one embodiment, the determination of the genetic properties includes determining sequences of complementary strands, the sequences of the complementary strands being based on the detected changes in electrical resistance that occur at the magnetically responsive sensors of each of the pluralities of synthesis cycles by the series.</p>

In one embodiment, the magnetic properties include at least one of a magnetic field, magnetic direction, or magnetic moment.

<p dir="rtl">15 In one embodiment, the magnetic particles include materials exhibiting paramagnetism, weak magnetization, ferromagnetism, or antiferromagnetism.</p>

In one embodiment, detected changes in electrical resistance at magnetically responsive sensors are caused by latent spins of electrons in the magnetic particle material.

In one embodiment, the nucleotides include hindering groups, the method further including removing the groups

<p dir="rtl">20 The obstacle after (c).</p>

In one embodiment, the magnetic particles always change the magnetization processes of the corresponding magnetically responsive sensors such that the magnetization processes of the corresponding magnetically responsive sensors are maintained after the removal of the magnetic particles after (f), wherein the synthesis cycles by series include changing the magnetization of at least some of Magnetically responsive sensors after reading the sensor

<p dir="rtl">25 Magnetically responsive.</p>

In one embodiment, the magnetically responsive sensors are read after removing the magnetic particles.

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In one embodiment, the method of synthesis is disclosed by respectively. The method includes providing a detector

Includes an array of magnetically responsive sensors, each of which is magnetically responsive

Placed in the vicinity of a corresponding blank to detect a magnetic property thereof, the detector also including a plurality of nucleic acid template strands placed in corresponding specific blanks. The method includes

<p dir="rtl">5 Perform a set of synthesis loops in succession to give a complementary strand along each template strand. Each cycle of synthesis by sequence (a) includes attaching at least the first and second nucleotides to designated spaces to extend the complementary strands. The first and second nucleotides have different bases, with the first and second nucleotides having magnetic particles attached to them. Each cycle of synthesis by sequence (b) includes detection Reports changes in electrical resistance at magnetically responsive sensors, where particles trigger</p>

<p dir="rtl">10 The magnetism held by the first nucleotide results in a different change in electrical resistance than the magnetic particles held by the second nucleotide. The method involves determining genetic characteristics</p>

of complementary strands based on detected changes in electrical resistance.

In one embodiment, determining the genetic property of complementary strands includes analyzing detected changes in electrical resistance to determine whether signals based on the detected changes form a particular pattern 15 .

In one embodiment, the determination of the genetic properties includes determining sequences of complementary strands, the sequences of the complementary strands being based on the detected changes in electrical resistance that occur at the magnetically responsive sensors of each of the pluralities of synthesis cycles by the series.

In one embodiment, determining complementary strand sequences includes determining whether the changes are detected

<p dir="rtl">20 When the magnetically responding sensor is approximately equal to a first volume or approximately equal to a second volume.</p>

In one embodiment, determining complementary strand sequences includes determining whether the changes detected when magnetically responsive sensors exceed a threshold value.

In one embodiment, determining complementary strand sequences includes determining whether the changes are detected

<p dir="rtl">25 When the magnetically responsive sensors are in a specific range of values.</p>

In one embodiment, determining complementary strand sequences includes comparing the changes detected at each

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A magnetically responsive sensor during several synthesis cycles in series.

In one embodiment, determining complementary strand sequences includes comparing, for each synthesis cycle by sequence, the detected changes associated with a plurality of magnetically responsive sensors.

In one embodiment, the first and second nucleotides capture a different number of magnetic particles,

<p dir="rtl">5 The different number of magnetic particles is configured to make different magnitudes of changes in electrical resistance.</p>

In one embodiment, the magnetic particles are single-molecule magnets.

In one embodiment, the first nucleotide captures a first type of magnetic particle and the second nucleotide captures a second type of magnetic particle, the first and second types of

<p dir="rtl">10 Magnetic particles are configured to make different magnitudes of changes in electrical resistance.</p>

In one embodiment, the first and second types of magnetic particles include different paramagnetic materials.

In one embodiment, delivering the first and second nucleotides at (a) includes connecting the first and second nucleotides to designated spaces to extend the complementary strands and thereby delivering the magnetic particles to

<p dir="rtl">15 As a result, the magnetic particles attach to the first and second nucleotides.</p>

In one embodiment, the nucleotides include hindering groups, the method further including removing the hindering groups after each synthesis event by succession.

In one embodiment, the first and second nucleotides each have one or more magnetosomes attached to the gamma phosphate of the nucleotide, the magnetosome that is released when the polymer

<p dir="rtl">20 By adding the first or second nucleotide to the complementary strand.</p>

In one embodiment, the method of synthesis is disclosed by respectively. The method includes providing a detector including an array of magnetically responsive sensors, each of the magnetically responsive sensors positioned in proximity to a corresponding designated blank to detect a magnetic property thereof, the detector also including an array of strands of a nucleic acid template placed in corresponding designated blanks. The method includes

<p dir="rtl">25 Perform a set of synthesis loops in succession to give a complementary strand along each template strand. Each cycle of synthesis by sequence (a) includes the delivery of at least the first and second nucleotides to the blanks</p>

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Designated to extend complementary strands, the first and second nucleotides have different bases. The first and second nucleotides have first and second monomolecular magnets, respectively, attached to them. Both the first and second monomolecular magnets have different magnetic states that respond to different frequencies of light. Each synthesis cycle involves successively (b) modifying the magnetic state of the first monomolecular magnets

<p dir="rtl">5 By shining the first light frequency. Each cycle of synthesis by series (c) includes detecting changes in electrical resistance at magnetically responsive sensors, where the changes are produced by the magnetic state of the first monomolecular magnets. Each cycle of synthesis by series (d) includes modifying the magnetic state of the first monomolecular magnets By irradiation of a second light frequency. Each cycle of synthesis involves successively (e) modifying the magnetic state of the second monomolecular magnets by irradiation</p>

<p dir="rtl">10 Third light frequency. Each cycle of synthesis involves detecting changes in electrical resistance at the magnetically responsive sensors, where the changes are produced by the magnetic state of the second monomolecular magnets. The method includes determining genetic properties of the complementary strands based on the detected changes in electrical resistance. .</p>

In one embodiment, each of the synthesis cycles by series also includes modification of the magnetic state

<p dir="rtl">15 For the second monomolecular magnets by shining a light frequency of four.</p>

In one embodiment, the monomolecular magnets include organometallic compounds that exhibit superparamagnetic behavior.

In one embodiment, at least one (b)-(d) or (e)-(f) mart is repeated for at least some of the synthesis cycles by, respectively.

<p dir="rtl">20 In one embodiment, determining the genetic property of complementary strands includes analyzing detected changes in electrical resistance to determine whether signals based on the detected changes form a particular pattern.</p>

In one embodiment, determining genetic properties includes determining complementary strand sequences, the complementary strand sequences being based on the detected changes in electrical resistance that occur at the sensors

<p dir="rtl">25 Magnetically responding to each of the set of synthesis events by respectively.</p>

In one embodiment, determining complementary strand sequences includes determining whether the changes are detected

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When the magnetically responding sensor is approximately equal to a first volume or approximately equal to a second volume.

In one embodiment, determining complementary strand sequences includes determining whether the changes detected when the magnetically responsive sensors exceed a threshold value.

<p dir="rtl">5 In one embodiment, determining complementary strand sequences includes determining whether changes are detected when the magnetically responsive sensors are in a specified range of values.</p>

In one embodiment, determining complementary strand sequences includes comparing the changes detected by each magnetically responsive sensor over plurality of synthesis cycles by the sequence.

In one embodiment, the identification of complementary strand sequences includes comparing, for each synthesis cycle by sequence, 10 detected changes associated with a plurality of magnetically responsive sensors.

In one embodiment, the nucleotides include hindering groups, the method further including removing the hindering groups after each synthesis event by succession.

In one embodiment, the first and second nucleotides each have one or more magnetosomes attached to the gamma phosphate of the nucleotide, the magnetosome that is released when the polymer

<p dir="rtl">15 By adding the first or second nucleotide to the complementary strand.</p>

In one embodiment, the method of synthesis is disclosed by respectively. The method includes providing a detector including an array of magnetically responsive sensors, each of the magnetically responsive sensors positioned in proximity to a corresponding designated blank to detect a magnetic property thereof, the detector also including an array of strands of a nucleic acid template placed in corresponding designated blanks. The method includes

<p dir="rtl">20 Perform a set of synthesis loops in succession to give a complementary strand along each template strand. Each cycle of synthesis by (a) includes attaching at least the first and second nucleotides to the designated spaces to extend the complementary strands. The first and second nucleotides have different bases, where the first and second nucleotides have monomolecular magnets attached to them. The first and second nucleotides have a number of different magnets. Attached to them, monomolecular magnets have responsive magnetic states</p>

<p dir="rtl">25 For different light frequencies. Each cycle of series synthesis involves (b) modifying the magnetic state of monomolecular magnets by the application of a first light frequency. Each cycle of series synthesis involves</p>

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(c) Detection of changes in electrical resistance at magnetically responsive sensors. Each cycle includes the synthesis by sequence (d) Modification of the magnetic state of single-molecule magnets by the application of a second frequency of light. The method involves determining genetic properties of complementary strands based on the detected changes In electrical resistance.

<p dir="rtl">5 In one embodiment, the monomolecular magnets include organometallic compounds that exhibit superparamagnetic behavior.</p>

In one embodiment, (b)-(d) are repeated several times at least for some of the cycles of the synthesis by succession.

In one embodiment, the first and second nucleotides include at least a first, a second, and a third nucleotide which

<p dir="rtl">10 Each has monomolecular magnets attached to it, and the first, second, and third nucleotides have a number of different monomolecular magnets attached to them.</p>

In one embodiment, the monomolecular magnets include organometallic compounds that exhibit superparamagnetic behavior.

In one embodiment, determining the genetic specificity of complementary strands includes analyzing detected changes 15 in electrical resistance to determine whether signals based on the detected changes form a pattern

specific.

In one embodiment, the determination of the genetic properties includes determining sequences of complementary strands, the sequences of the complementary strands being based on the detected changes in electrical resistance that occur at the magnetically responsive sensors of each of the pluralities of synthesis cycles by the series.

<p dir="rtl">20 In one embodiment, determining complementary strand sequences includes determining whether the sizes of the detected changes are approximately equal to a first size or approximately equal to a second size.</p>

In one embodiment, determining the complementary strand sequences includes determining whether the magnitudes of the changes

Detected when magnetically responsive sensors exceed a threshold value.

In one embodiment, determining the complementary strand sequences includes determining whether the magnitudes of the changes

<p dir="rtl">25 Detected when the magnetically responsive sensors are within a specified value range.</p>

In one embodiment, determining complementary strand sequences includes comparing the magnitudes of the detected changes

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Each sensor responds magnetically during several synthesis cycles in series.

In one embodiment, determining complementary strand sequences includes comparing, for each synthesis cycle by sequence, the magnitudes of the detected changes associated with a plurality of magnetically responsive sensors.

In one embodiment, the nucleotides include hindering groups, the method further including removing the hindering groups 5 at the end of each cycle.

In one embodiment, the first and second nucleotides each have one or more magnetosomes attached to the gamma phosphate of the nucleotide, a magnetosome that is released when the polymerase adds the first nucleotide or the second nucleotide to the complementary strand.

In one embodiment, the method of synthesis is disclosed by respectively. The method includes providing a detector

<p dir="rtl">10 Comprising an array of magnetically responsive sensors, each of the magnetically responsive sensors positioned adjacent to a corresponding blank to detect a magnetic property thereof, the detector also including an array of strands of a nucleic acid template positioned in corresponding specified blanks. The method includes performing a set of synthesis events by sequentially giving a complementary strand by adding nucleotides along each template strand using a rice polymer, the rice polymer having corresponding magnetic particles attached thereto.</p>

<p dir="rtl">15 Which shows views of magnetic properties, where each synthesis event includes successively detecting changes in electrical resistance at magnetically responsive sensors, detected changes resulting from the presence of magnetic particles at the specific spaces when the rice polymer adds nucleotides. The method involves determining genetic properties of complementary strands based on detected changes in electrical resistance.</p>

<p dir="rtl">20 In one embodiment, the magnetic particles are single-molecule magnets, the method further including modifying the magnetic state of the single-molecule magnets using one or more frequencies of light.</p>

In one embodiment, performing a set of synthesis events by sequentially comprising: (a) delivering a first type of nucleotide to the designated spaces and detecting changes in electrical resistance associated with the first type of nucleotides and (b) delivering a second type of nucleotides to the designated spaces and detecting About the changes

<p dir="rtl">25 In electrical resistance, it is linked to type II nucleotides.</p>

In one embodiment, executing a set of synthesis events by sequentially including simultaneously connecting multiple types of

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Nucleotides into specific spaces and detect changes in electrical resistance, where each nucleotide type includes a corresponding rate of insertion that differs from the rate of insertion of other types of nucleotides, where the sequences of complementary strands are based on the durations of the changes detected.

In one embodiment, determining sequences of complementary strands includes determining whether the durations of the changes are equal

<p dir="rtl">5 It is detected approximately with one of a number of values, the number of values being equal to the number of nucleotide types.</p>

In one embodiment, determining complementary strand sequences includes determining whether the durations of the detected variations are in a number of possible ranges of values, the number of possible range values being equal to the number of types

Nucleotides.

In one embodiment, determining sequences of complementary strands includes comparing the durations of the changes detected at

<p dir="rtl">10 Each sensor is magnetically responsive during several synthesis events in succession.</p>

In one embodiment, determining the complementary strand sequences includes comparing, for each synthesis event by sequence,

The durations of the detected changes are linked to an array of magnetically responsive sensors.

In one embodiment, determining the genetic property of complementary strands includes analysis of detected variations

In electrical resistance to determine whether the signals, based on the detected changes, form a specific pattern 15.

In one embodiment, the determination of genetic properties includes determining sequences of complementary strands, the sequences of the complementary strands being based on the detected changes in electrical resistance that occur at the magnetically responsive sensors for each of the plurality of synthesis events by the sequence.

In one embodiment, executing a set of synthesis events by sequentially including simultaneously supplying a set of 20 reactants to designated blanks, the reactants including nucleotides and rice polymers, wherein the events are executed

Synthesis by cascade through individual vascular reactions.

In one embodiment, the method of synthesis is disclosed by respectively. The method includes providing a detector

Includes an array of magnetically responsive sensors, each of which is magnetically responsive

Placed near a given blank corresponding to detecting a magnetic property thereof, the detector also

<p dir="rtl">25 Including a set of DNA template strands arranged in corresponding specific spaces. The method includes executing a plurality of synthesis cycles in succession to give a complementary strand along each template strand.</p>

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Each set of series synthesis circuits includes (a) delivering the first nucleotide and a rice polymer to the designated spaces. The rice polymer has magnetic particles attached to it. Each set of series synthesis circuits includes (b) detecting changes in electrical resistance at Magnetically responsive sensors, changes in electrical resistance caused by the presence of magnetic particles in spaces

<p dir="rtl">5 Designated when the polymerase adds the first nucleotide to the complementary strand. Each of the series synthesis circuits includes (c) delivering a second nucleotide and a rice polymer to the designated spaces. The rice polymer has magnetic particles attached to it. Each of the series synthesis circuits includes (d) detecting changes in electrical resistance at the sensor. Magnetically responsive devices, the changes in electrical resistance resulting from the presence of magnetic particles at the specified gaps when the corresponding rice polymer</p>

<p dir="rtl">10 By adding the second nucleotide to the complementary strand. The method involves determining genetic properties of complementary strands based on detected changes in electrical resistance.</p>

In one embodiment, the magnetic particles are single-molecule magnets, the method further including modifying the magnetic state of the single-molecule magnets using one or more frequencies of light.

In one embodiment, each plurality of synthesis cycles by sequence also includes (e) nucleotide delivery

<p dir="rtl">15 Third to the designated blanks and rice polymer, the rice polymer has magnetic particles attached to it; (f) Detecting changes in electrical resistance at magnetically responsive sensors, changes in electrical resistance resulting from the presence of magnetic particles at specific spaces when the rice polymer adds the third nucleotide to the complementary strand.</p>

In one embodiment, each of the DART synthesis by series also includes the delivery of a four-nucleotide

<p dir="rtl">20 To a thousand designated arghats and cedar bulim.</p>

In one embodiment, determining the genetic property of complementary strands includes analyzing detected changes in electrical resistance to determine whether signals based on the detected changes form a particular pattern.

In one embodiment, determining genetic properties includes determining sequences of complementary strands, strand sequences

<p dir="rtl">25 The complement is based on the detected changes in electrical resistance that occur at the magnetically responsive sensors.</p>

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In one embodiment, the nucleotides include hindering groups, the method further including removing the hindering groups at the end of each cycle.

In one embodiment, the method of synthesis is disclosed by respectively. The method includes providing a detector including an array of magnetically responsive sensors, each of the magnetically responsive sensors

<p dir="rtl">5 Placed in the vicinity of a corresponding blank to detect a magnetic property thereof, the detector also including a plurality of nucleic acid template strands placed in corresponding specific blanks. The method includes performing a plurality of synthesis events by successively to give a complementary strand along each template strand. Each of the series of synthesis events by sequence includes (a) delivering at least the first and second nucleotides and a rice polymer to the designated spaces, the first and second nucleotides having different bases, the rice polyme having</p>

<p dir="rtl">10 Magnetic particles attached to it. Each of the set of synthesis events by series includes (b) detecting changes in electrical resistance at magnetically responsive sensors, changes in electrical resistance resulting from the presence of magnetic particles at the designated spaces when the rice polymer adds the first nucleotide or the second nucleotide to the strand; Complementary strands, where the first and second nucleotides have different insertion rates. The method involves determining the genetic properties of the complementary strands</p>

<p dir="rtl">15 On detected changes in electrical resistance.</p>

In one embodiment, the magnetic particles are single-molecule magnets.

In one embodiment, connecting at least a first and second nucleotide includes connecting a first, second, and third nucleotide that each includes a different base and a different insertion rate.

In one embodiment, connecting at least a first and a second nucleotide includes connecting a first, a second nucleotide,

<p dir="rtl">20 Three and four each involve a different base and a different input rate.</p>

In one embodiment, determining the genetic property of complementary strands includes analyzing detected changes in electrical resistance to determine whether signals based on the detected changes form a particular pattern.

In one embodiment, determining genetic properties includes determining sequences of complementary strands, strand sequences

<p dir="rtl">25 The complement is based on the detected changes in electrical resistance that occur at the magnetically responsive sensors.</p>

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In one embodiment, the nucleotides include hindering groups, the method further including removing the hindering groups at the end of each cycle.

In one embodiment, executing a set of synthesis events by sequentially including simultaneously supplying a set of reactants to the designated spaces, the reactants including the first and second nucleotides and the rice polymer, wherein

<p dir="rtl">5 Synthetic events are carried out successively during individual vascular reactions.</p>

In one embodiment, the synthesis system is disclosed by a sequence. The system includes a detector including an array of magnetically responsive sensors, each of the magnetically responsive sensors comprising at least two ferromagnetic layers and a non-magnetic layer separating the two ferromagnetic layers, each of the magnetically responsive sensors comprising at least one

<p dir="rtl">10 Massive magnetoresistance or tunnel magnetoresistance sensor Magnetically responsive sensors are placed adjacent to corresponding designated spaces in a room and configured to detect magnetic particles from the corresponding designated spaces. The system includes a reading circuit connected to the magnetically responsive sensors, where the reading circuit is configured to broadcast signals that respond to the electrical resistances of the magnetically responsive sensors. The system includes a fluid control system configured to flow reagents through the chamber for implementation</p>

<p dir="rtl">15 A synthesis protocol using sequential reagents including a set of nucleotide types, where the readout circuit is configured to emit signals after each input event.</p>

In one embodiment, the magnetically responsive sensors include massive magnetoresistance sensors configured to switch between the first and second states, where the two magnetic iron layers are coupled antimagnetically to the first state such that the nonmagnetic layer includes an electrical resistor.

<p dir="rtl">20 First, where an external magnetic field impedes the anti-iron magnetic coupling in the second case, so that the non-magnetic layer includes a second electrical resistance.</p>

In one embodiment, the magnetically responsive sensors include tunneled magnetoresistance sensors configured to switch between the first and second states, wherein the two layers of magnetic iron include opposite directions of magnetization in the first state such that the nonmagnetic layer includes electrical resistance.

<p dir="rtl">25 First, where the two layers of magnetic iron contain the same direction of magnetization in the second case, so that the non-magnetic layer includes a first electrical resistance.</p>

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In one embodiment, the fluid control system is configured to (a) flow nucleotides into designated spaces to add nucleotides to complementary strands; and (b) flow magnetic particles into designated spaces, magnetic particles attached to nucleotides, magnetic particles exhibiting a magnetic property detectable counterpart; and (d) the removal of magnetic particles from designated spaces; and where they are prepared

<p dir="rtl">5 Reading circuit to detect electrical resistance at magnetically responsive sensors after (b).</p>

In one embodiment, the fluid control system is configured to: (a) deliver nucleotides to designated spaces to add nucleotides to complementary strands, the nucleotides including at least first, second, and third nucleotides, the first, second, and third nucleotides having different bases; b) Delivering magnetic particles to the designated spaces. The magnetic particles are attached to the first nucleotides and by the nucleotides.

<p dir="rtl">10 the second; (c) Removing magnetic particles from the first nucleotides; (d) Delivering magnetic particles to the designated spaces. The magnetic particles are attached to the third nucleotides, where the reading circuit is configured to detect electrical resistance at the magnetically responsive sensors after (b) and after (d). (.</p>

In one embodiment, the fluid control system is configured to deliver at least the first and second nucleotides to designated spaces to extend the complementary strands, the first and second nucleotides having different bases, wherein

<p dir="rtl">15 The first and second nucleotides have magnetic particles attached to them, where the reading circuit is configured to detect changes in electrical resistance at the magnetically responding sensors, the magnetic particles of the first nucleotide leading to a different change in electrical resistance than the magnetic particles of the second nucleotide.</p>

In one embodiment, the synthesis system is disclosed by a sequence. The system includes comprehensive reading information

<p dir="rtl">20 The arm and a magnetically responsive sensor attached to the arm, the comprehensive magnetically responsive sensor is one on</p>

Less than a massive magnetoresistance sensor or a tunnel magnetoresistance sensor, a magnetically responsive sensor is configured to detect magnetic particles. The system includes a sample substrate having a substrate surface, the substrate surface configured to include a plurality of nucleic acid template strands disposed in specified spaces along the surface of the substrate, where at least one of the reading beds and the sample substrate are configured to move

<p dir="rtl">25 Relative to the other to position the magnetically responsive sensor near the designated spaces in an operational relationship. The system includes a readout circuit that is contact-coupled to the magnetically responsive sensor, where initialization takes place</p>

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A reading circuit for transmitting signals that respond to the electrical resistance of the magnetically responsive sensor when positioned at one of the specified spaces.

In one embodiment, the sample substrate is rotatable about an axis.

In one embodiment, the sample substrate has a disc shape.

<p dir="rtl">5 In one embodiment, the readout includes a plurality of magnetically responsive sensors attached to the arm, wherein the readout circuitry is configured to emit signals from at least the plurality of magnetically responsive sensors for at least some operational relationship.</p>

In one embodiment, the method of synthesis is disclosed by respectively. The method includes providing a comprehensive reading signal of an arm and a magnetically responsive sensor attached to the arm, the comprehensive magnetically responsive sensor

<p dir="rtl">10 At least one of a massive magnetoresistance sensor or a tunneling magnetoresistance sensor, a magnetically responsive sensor configured to detect magnetic particles. The method involves providing a substrate</p>

A sample having a set of die strands placed at specific intervals along the surface of a substrate. The method includes performing a plurality of synthesis cycles in succession to give complementary strands by inserting nucleotides along each of the template strands, at least some of which are marked with particles.

<p dir="rtl">15 Magnetism analogy showing corresponding magnetic properties; Wherein, for each of the synthesis cycles by series, the method includes placing the magnetically responsive sensor adjacent to designated spaces along the surface of the substrate and detecting the electrical resistance at the magnetically responsive sensors. The method includes</p>

Determining genetic properties of complementary strands based on revealed changes in electrical resistance.

In one embodiment, the sample substrate is rotatable about an axis and where positioned includes the transponder sensor

<p dir="rtl">20 Magnetically rotate the sample substrate around the axis.</p>

In one embodiment, the sample substrate has a disc shape.

In one embodiment, the reading device includes a plurality of magnetically responsive sensors attached to the arm.

In one embodiment, the method of synthesis is disclosed by respectively. The method includes providing a detector

Includes an array of magnetically responsive sensors, each of which is magnetically responsive

25 Placed near a designated area corresponding to the detection of a magnetic property thereof, the detector also includes a rice polymer transported to the designated areas, the rice polymer configured to hold a corresponding template strand. Includes

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Method: Executing a set of synthesis events by series to give a complementary strand by inserting nucleotides along a corresponding template strand, nucleotides attached to corresponding magnetic particles having corresponding magnetic properties, wherein each set of synthesis events includes detecting changes in electrical resistance at the responding sensors. Magnetically generated by isotropy

<p dir="rtl">5 Magnetism corresponding to magnetosomes where nucleotides are added to the complementary strand. The method involves determining genetic properties of complementary strands based on detected changes in electrical resistance.</p>

In one embodiment, the magnetically responsive sensor includes a magnetically resistive sensor.

In one embodiment, the magnetically responsive sensors include a massive magnetoresistance sensor,

<p dir="rtl">10 Changes in electrical resistance resulting from changes in current flow during the implementation of layers of</p>

Huge magnetic resistance sensor.

In one embodiment, the magnetically responsive sensors include a tunneling magnetoresistance sensor, changes in electrical resistance resulting from changes in tunneling electron current through dielectric layers of the tunneling magnetoresistance sensor.

<p dir="rtl">15 In one embodiment, each of the magnetically responsive sensors includes a first and second ferromagnetic layer and a nonmagnetic layer separating the first and second ferromagnetic layer.</p>

In one embodiment, determining the genetic property of complementary strands includes analyzing detected changes in electrical resistance to determine whether signals based on the detected changes form a particular pattern.

<p dir="rtl">20 In one embodiment, the determination of genetic properties includes determining sequences of complementary strands, the sequences of the complementary strands being based on the detected changes in electrical resistance that occur at the magnetically responsive sensors for each of the plurality of synthesis events by the sequence.</p>

In one embodiment, determining complementary strand sequences includes determining whether changes in electrical resistance have occurred at the magnetically responsive sensors.

<p dir="rtl">25 In one embodiment, determining complementary strand sequences includes determining the magnitudes of changes in electrical resistance at magnetic response sensors.</p>

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In one embodiment, the nucleotides include multiple types of nucleotides, each type of nucleotide having a different number of magnetic particles attached to it than the other types of nucleotides.

In one embodiment, the magnetic particles are single-molecule magnets.

In one embodiment, the nucleotides include multiple types of nucleotides, each nucleotide type having a different type

<p dir="rtl">5 Of a magnetic particle attached to it other than other types of nucleotides.</p>

In one embodiment, the magnetic particles include different magnetic field strengths.

In one embodiment, the magnetic properties include at least one of a magnetic field, magnetic direction, or magnetic moment.

In one embodiment, the magnetic particles include materials exhibiting paramagnetism, weak magnetization, 10 ferromagnetism, or antiferromagnetism.

In one embodiment, detected changes in electrical resistance at magnetically responsive sensors are caused by latent spins of electrons in the magnetic particle material.

In one embodiment, each of the plurality of synthesis events by sequentially includes delivery of multiple types of nucleotides, each nucleotide type being delivered at a discrete time.

<p dir="rtl">15 In one embodiment, each of the plurality of synthesis events by sequentially includes delivering multiple types of nucleotides simultaneously.</p>

In one embodiment, each of the plurality of synthesis events by the sequence includes delivering the magnetic particles to the corresponding nucleotides after adding the corresponding nucleotides to the complementary strand.

In one embodiment, the magnetic particles include a reversible coupling.

<p dir="rtl">20 In one embodiment, each designated area includes an individual die strand that is gripped by the polymer rice.</p>

In one embodiment, the detector includes a flow cell that identifies a chamber having the designated areas, nucleotides and magnetic particles delivered to the designated areas by flowing the nucleotides and magnetic particles through the flow cell chamber.

In one embodiment, the detector defines a chamber containing the designated areas, the detector having electrodes 25 positioned along the length of the chamber, wherein nucleotide delivery and magnetic particle delivery involve performing distillation processes using the electrodes.

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In one embodiment, the method of synthesis is disclosed by respectively. The method includes providing a detector

Includes an array of magnetically responsive sensors, each of which is magnetically responsive

Placed near a designated area corresponding to the detection of a magnetic property thereof, the detector also includes a rice polymer transferred to the designated areas, the rice polymer prepared to attach to the corresponding die strands. Includes

<p dir="rtl">5 The method is to perform a set of synthesis events by succession to give complementary strands along the template strands. Each synthesis event involves (a) delivering nucleotides to designated regions and permitting the addition of nucleotides to complementary strands. Each synthesis event involves (b) delivering magnetic particles to designated regions, magnetic particles held by the nucleotides, magnetic particles providing a magnetic field External views include every event</p>

<p dir="rtl">10 Synthesis by sequencing (c) Detection of changes in electrical resistance at magnetically responsive sensors. Each synthesis event involves (d) removal of magnetic particles from designated regions. The method involves determining genetic properties of complementary strands based on the detected changes</p>

In electrical resistance.

In one embodiment, the repeats (a)-(d) are of multiple nucleotide types, each nucleotide type being delivered 15 separately to designated regions.

In one embodiment, the nucleotide delivery involves simultaneously delivering multiple types of nucleotides and the magnetic particle delivery includes simultaneously delivering multiple types of magnetic particles, each type of magnetic particle having a corresponding magnetic field property that differs from the magnetic field properties of the other types of magnetic particles.

<p dir="rtl">20 In one embodiment, each designated region includes an individual template strand transferred to a substrate surface of the detector. In one embodiment, the designated areas are placed in a flow cell chamber wherein nucleotide delivery and magnetic particle delivery comprise nucleotide flow and magnetic particle flow, respectively, through the chamber.</p>

In one embodiment, the detector identifies a chamber containing the designated areas, the detector having electrodes 25 positioned along the length of the chamber, wherein it includes delivering nucleotides and delivering magnetic particles

Carrying out distillation operations using electrodes.

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In one embodiment, the plurality of synthesis events by series also includes detection of the base level of electrical resistance after (d).

In one embodiment, the nucleotides include hindering groups, the method further including removing the hindering groups after each of the synthesis events by sequentially.

<p dir="rtl">5 In one embodiment, the method of synthesis is disclosed by respectively. The method includes providing a detector</p>

Includes an array of magnetically responsive sensors, each of which is magnetically responsive

Placed near a certain area corresponding to the detection of a magnetic property thereof, the detector also

Including rice polymer transferred to designated areas, rice polymer prepared for attachment to corresponding mold strands. The method includes performing a plurality of synthesis events by succession to give complementary strands along two strands

<p dir="rtl">10 Template. Each event includes synthesis by (a) attaching nucleotides to designated regions and permitting the addition of nucleotides to complementary strands, nucleotides including at least first, second, and third nucleotides; the first, second, and third nucleotides having different bases. Each event includes synthesis by</p>

Respectively (b) delivery of magnetic particles to designated areas, magnetic particles captured by the first nucleotide and by the second nucleotide. Each event involves synthesis by

<p dir="rtl">15 (c) Detection of changes in electrical resistance at magnetically responsive sensors. Each synthesis event by sequence (d) involves the removal of magnetic particles from the first nucleotide. Each synthesis event by sequence (e) involves the delivery of magnetic particles to designated areas, The magnetosomes are specific to the three nucleotides. Each event involves the synthesis by, respectively, (and) the detection of changes in electrical resistance at magnetically responsive sensors. The method includes</p>

<p dir="rtl">20 Determining genetic properties of complementary strands based on revealed changes in electrical resistance.</p>

In one embodiment, the first nucleotide extends the complementary strand at (a) if a change in electrical resistance is detected at (c) but is not detected at (f); the second nucleotide extends the complementary strand at (a) if a change in electrical resistance is detected at (f); In the electrical resistance at (c) and it is detected at (f); the third nucleotide extends the complementary strand at (a) if no change in electrical resistance is detected at

<p dir="rtl">25 (c) But it was revealed at (f).</p>

In one embodiment, (a) comprising connecting four nucleotides wherein the four nucleotides extend the strand

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The complement at (a) if no change in electrical resistance is detected at (c) and it is not detected at (f).

In one embodiment, each of the plurality of synthesis events includes, respectively: (g) removal of magnetic particles from the second and third nucleotides.

<p dir="rtl">5 In one embodiment, (d) and (e) occur simultaneously.</p>

In one embodiment, determining the genetic property of complementary strands includes analyzing detected changes in electrical resistance to determine whether signals based on the detected changes form a particular pattern.

In one embodiment, determining genetic properties includes determining sequences of complementary strands, strand sequences

<p dir="rtl">10 The complement is based on the detected changes in electrical resistance that occur at sensors responding magnetically to each set of synthesis events by series.</p>

In one embodiment, the magnetic properties include at least one of a magnetic field, magnetic direction, or magnetic moment.

In one embodiment, the magnetic particles include materials exhibiting paramagnetism, weak magnetization, ferromagnetism, or antiferromagnetism.

In one embodiment, detected changes in electrical resistance at magnetically responsive sensors are caused by latent spins of electrons in the magnetic particle material.

In one embodiment, the nucleotides include hindering groups, the method further including removing the hindering groups after each synthesis event by succession.

<p dir="rtl">20 In one embodiment, the method of synthesis is disclosed by respectively. The method includes providing a detector including an array of magnetically responsive sensors, each of the magnetically responsive sensors positioned near a corresponding specified area to detect a magnetic property thereof, the detector also including a rice polymer transferred to the specified areas, the rice polymer configured to attach to the corresponding die strands. The method includes performing a plurality of synthesis events by succession to give complementary strands along two strands</p>

<p dir="rtl">25 Template. Each synthesis event by sequence (a) involves the delivery of at least the first and second nucleotides to designated regions extending complementary strands, the first and second nucleotides having different bases, where</p>

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The first and second nucleotides have magnetosomes attached to them. Each synthesis event involves (b) detecting changes in electrical resistance at magnetically responsive sensors, where the magnetic particles of the first nucleotide cause a different change in electrical resistance than the magnetic particles of the second nucleotide. The method includes determining genetic properties

<p dir="rtl">5 of complementary strands based on detected changes in electrical resistance.</p>

In one embodiment, determining the genetic property of complementary strands includes analyzing detected changes in electrical resistance to determine whether signals based on the detected changes form a particular pattern.

In one embodiment, the determination of genetic properties includes determining sequences of the complementary strands, the sequences of the 10 complementary strands being based on the detected changes in electrical resistance that occur at the magnetically responsive sensors for each of the sets of synthesis events by the sequence.

In one embodiment, determining complementary strand sequences includes determining whether the changes detected when the magnetically responsive sensors are approximately equal to a first size or approximately equal to a second size.

<p dir="rtl">15 In one embodiment, determining complementary strand sequences includes determining whether the changes detected when the magnetically responsive sensors exceed a threshold value.</p>

In one embodiment, determining complementary strand sequences includes determining whether changes are detected when the magnetically responsive sensors are in a specified range of values.

In one embodiment, determining complementary strand sequences includes comparing the changes detected at each

<p dir="rtl">20 Magnetically responsive sensor during several synthesis events by succession.</p>

In one embodiment, identifying complementary strand sequences includes comparing, for each synthesis event by sequence, the detected changes associated with a plurality of magnetically responsive sensors.

In one embodiment, the first and second nucleotides capture a different number of magnetic particles, the different number of magnetic particles being configured to make different magnitudes of changes in resistance

<p dir="rtl">25 Electrophysiology.</p>

In one embodiment, the magnetic particles are single-molecule magnets.

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In one embodiment, the first nucleotide captures a first type of magnetic particle and the second nucleotide captures a second type of magnetic particle, the first and second types of magnetic particles being configured to make different magnitudes of changes in electrical resistance.

In one embodiment, the first and second types of magnetic particles include different paramagnetic materials 5 .

In one embodiment, delivering the first and second nucleotides at (a) includes delivering the first and second nucleotides to designated regions to extend the complementary strands and thereby delivering the magnetic particles to the designated regions, whereby the magnetic particles attach to the first and second nucleotides.

In one embodiment, the nucleotides include hindering groups, the method further including removing the groups

<p dir="rtl">10 Obstructing after each synthesis event by succession.</p>

In one embodiment, the method of synthesis is disclosed by respectively. The method includes providing a detector comprising an array of magnetically responsive sensors, each of the magnetically responsive sensors positioned near a corresponding designated area to detect a magnetic property thereof, the detector also including a rice polymer transferred to the designated areas, the rice polymer configured to attach to the corresponding die strands. Includes

<p dir="rtl">15 The method is to perform a set of synthesis events by succession to give complementary strands along the template strands. Each synthesis event involves (a) delivering at least the first and second nucleotides to designated complementary strand extension regions, the first and second nucleotides having different bases, wherein the first and second nucleotides have first and second monomolecular magnets, respectively, attached to them, each of the monomolecular magnets The first and second molecules have different magnetic states that respond to frequencies</p>

<p dir="rtl">20 different light. Each synthesis event by series (b) involves modifying the magnetic state of the first monomolecular magnets by the application of a first light frequency. Each synthesis event by series (c) involves detecting changes in electrical resistance at magnetically responsive sensors, where the changes are produced by the state Magnetism of the first monomolecular magnets. Each synthesis event involves (d) modifying the magnetic state of the first monomolecular magnets by applying a frequency</p>

<p dir="rtl">25 Second light. Each synthesis event by sequence (e) involves modifying the magnetic state of the second monomolecular magnets by the application of a third light frequency. Each synthesis event by sequence (f) involves</p>

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Detection of changes in electrical resistance in magnetically responsive sensors, where the changes are produced by the magnetic state of the second monomolecular magnets. The method involves determining genetic properties of complementary strands based on detected changes in electrical resistance.

In one embodiment, each of the synthesis events by series also includes modification of the magnetic state

<p dir="rtl">5 For the second monomolecular magnets by shining a light frequency of four.</p>

In one embodiment, the monomolecular magnets include organometallic compounds that exhibit superparamagnetic behavior.

In one embodiment, at least one of the (b)-(d) or (e)-(f) multiples is repeated for at least some of the synthesis events by, respectively.

<p dir="rtl">10 In one embodiment, determining the genetic property of complementary strands includes analyzing detected changes in electrical resistance to determine whether signals based on the detected changes form a particular pattern.</p>

In one embodiment, determining genetic properties includes determining complementary strand sequences, the complementary strand sequences being based on the detected changes in electrical resistance that occur at the sensors

<p dir="rtl">15 Magnetically responding to each of the set of synthesis events by respectively.</p>

In one embodiment, determining complementary strand sequences includes determining whether the changes detected when the magnetically responsive sensors are approximately equal to a first size or approximately equal to a second size.

In one embodiment, determining complementary strand sequences includes determining whether the changes detected 20 when the magnetically responsive sensors exceed a threshold value.

In one embodiment, determining complementary strand sequences includes determining whether changes are detected when the magnetically responsive sensors are in a specified range of values.

In one embodiment, determining complementary strand sequences includes comparing the changes detected at each magnetically responsive sensor during plurality of synthesis events by the sequence.

<p dir="rtl">25 In one embodiment, identifying complementary strand sequences includes comparing, for each synthesis event by sequence, the detected changes associated with a plurality of magnetically responsive sensors.</p>

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In one embodiment, the nucleotides include hindering groups, the method further including removing the hindering groups after each synthesis event by succession.

In one embodiment, the method of synthesis is disclosed by respectively. The method includes providing a detector including an array of magnetically responsive sensors, each of the magnetically responsive sensors

<p dir="rtl">5 Placed near a designated area corresponding to the detection of a magnetic property thereof, the detector also includes a rice polymer transferred to the designated areas, the rice polymer prepared to attach to the corresponding die strands. The method includes performing a plurality of synthesis events by sequentially giving complementary strands along the template strands. Each synthesis event involves, respectively (a) the delivery of at least the first and second nucleotides to designated regions extending the complementary strands. The first and second nucleotides have different bases, including</p>

<p dir="rtl">10 The first and second nucleotides have single-molecular magnets attached to them. The first and second nucleotides have a number of different single-molecular magnets attached to them. Single-molecule magnets have magnetic states that respond to different frequencies of light. Each cascade synthesis event involves (b) modifying the magnetic state of single-molecular magnets by illuminating a first light frequency. Each cascade synthesis event involves (c) detecting changes in electrical resistance at the responding sensors</p>

<p dir="rtl">15 Magnetically. Each strand synthesis event involves modifying the magnetic state of single-molecule magnets by applying a second frequency of light. The method involves determining genetic properties of complementary strands based on detected changes in electrical resistance.</p>

In one embodiment, the monomolecular magnets include organometallic compounds that exhibit superparamagnetic behavior.

<p dir="rtl">20 In one embodiment, (b)-(d) are repeated several times for at least some of the synthesis events by succession.</p>

In one embodiment, the first and second nucleotides include at least first, second, and third nucleotides each of which have monomolecular magnets attached thereto, the first, second, and third nucleotides having a different number of monomolecular magnets attached thereto.

<p dir="rtl">25 In one embodiment, the monomolecular magnets include organometallic compounds that exhibit superparamagnetic behavior.</p>

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In one embodiment, determining the genetic property of complementary strands includes analyzing detected changes in electrical resistance to determine whether signals based on the detected changes form a particular pattern.

In one embodiment, determining genetic properties includes determining sequences of complementary strands, strand sequences

<p dir="rtl">5 The complement is based on the detected changes in electrical resistance that occur at sensors responding magnetically to each set of synthesis events by series.</p>

In one embodiment, determining complementary strand sequences includes determining whether the sizes of the detected changes are approximately equal to a first size or approximately equal to a second size.

In one embodiment, determining the complementary strand sequences includes determining whether the magnitudes of the changes

<p dir="rtl">10 Detected when magnetically responsive sensors exceed a threshold value.</p>

In one embodiment, determining the complementary strand sequences includes determining whether the magnitudes of the changes

Detected when the magnetically responsive sensors are within a specified value range.

In one embodiment, determining complementary strand sequences includes comparing the magnitudes of changes detected by each magnetically responsive sensor during several synthesis events by the sequence.

<p dir="rtl">15 In one embodiment, identifying complementary strand sequences includes comparing, for each synthesis event by sequence, the magnitudes of the detected changes associated with a plurality of magnetically responsive sensors.</p>

In one embodiment, the nucleotides include hindering groups, the method further including removing the hindering groups at the end of each event.

In one embodiment, the method of synthesis is disclosed by respectively. The method includes providing a detector 20 that includes an array of magnetically responsive sensors, each of the magnetically responsive sensors

Placed in the vicinity of a corresponding blank to detect a magnetic property thereof, the detector also including a plurality of nucleic acid template strands placed in corresponding specific blanks. The method includes executing a plurality of synthesis cycles in succession to give a complementary strand along each template strand. Each cycle of synthesis includes, respectively (a) attaching nucleotides to the designated spaces and permitting the addition of nucleotides to complementary strands, 25 nucleotides including at least the first and second nucleotides,

And third, the first, second, and third nucleotides have different bases, where the first and second nucleotides

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The third nucleotide includes the magnetosomes and does not include the magnetosomes. Each synthesis cycle includes (b) the detection of changes in electrical resistance at magnetically responsive sensors produced by the magnetic particles of the first and second nucleotides. Each synthesis cycle includes (c) the removal of the magnetic particles from the first nucleotide.

<p dir="rtl">5 Each synthesis cycle involves (d) delivering magnetic particles to the designated spaces, the magnetic particles captured by the three nucleotides. Each synthesis cycle involves (e) detecting changes in electrical resistance at the magnetically responsive sensors produced by the magnetic particles. For the second and third nucleotides, the method involves determining genetic properties of the complementary strands based on detected changes in electrical resistance.</p>

<p dir="rtl">10 In one embodiment, the first nucleotide extends the complementary strand at (a) if a change in electrical resistance is detected at (b) but is not detected at (e); the second nucleotide extends the complementary strand at (a) if a change in electrical resistance is detected In the electrical resistance at (b) and is detected at (e); the third nucleotide extends the complementary strand at (a) if a change in electrical resistance is not detected at (b) but is detected at (e).</p>

<p dir="rtl">15 In one embodiment, (a) includes connecting four nucleotides wherein the four nucleotide extends the complementary strand at (a) if no change in electrical resistance is detected at (b) and is not detected at (e).</p>

Brief explanation of the drawings

Figure 1a shows a top view of a system including a magnetic sensor array 20 to support, for example, a scheme for the series synthesis of a magnetic biosensing sensor;

Figure 1b shows a cross-sectional view of the system according to Figure 1a;

Figure 2a shows an example of a massive magnetoresistance device;

Figure 2b shows an example of a tunneling magnetoresistance device;

Figure 3 shows an example of a biochip susceptibility diagram using supermagnetic resistance

<p dir="rtl">25 An individual nano-sized magnetic particle;</p>

Figure 4 illustrates and shows a cross-sectional view of part of the detector shown in Figures 1a and 1b

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More details about the magnetic sensor array;

Figure 5 shows a portion of the detector shown in Figures 1A, 1B, and 4 and depicts an example of a synthesis scheme by series for a magnetic biosensor, where an introduced biotinylated nucleotide is used to capture a nano-sized magnetic particle coated with streptavidin and generate

<p dir="rtl">5 detectable signal;</p>

Figure 6a shows a partial structural formula of the biotin-treated oligonucleotide according to Figure 5;

Figure 6b shows a partial structural formula for a nucleotide that has a magnetic particle coupled to the gamma phosphate of the nucleotide;

Figure 7 shows a flow chart for an example of a method for determining a base in a synthesis scheme by sequence for a magnetic biosensor using, for example, the flow cell shown in Figures 1a, 1b, and 4;

<p dir="rtl">10 Figure 8 shows a flow chart of an example method for tagging a base in a synthesis scheme by succession for a “dual-tag” magnetic biosensor using, for example, the flow cell shown in Figures 1a, 1b, and 4;</p>

Figure 9 explains a schematic diagram that pictorially shows the steps of the method according to Figure 8;

Figure 10 shows a flow chart of an example of how a base is distinguished in a synthesis chart by sequence

<p dir="rtl">15 For a “quad-tag” magnetic biosensor using, for example, the flow cell shown in Figures 1a,</p>

<p dir="rtl">1b and 4;</p>

Figure 11 shows a flow chart of an example method for tagging a base in a synthesis scheme by sequence for a “quad-tag” magnetic biosensor using oligonucleotides tagged with a single-molecule magnet.

;)single-molecule magnet (SMM

<p dir="rtl">20 Figure 12 shows a flow chart of an example method for tagging a base in a synthesis scheme by succession of a “quad-tag” magnetic biosensor using single-molecule magnet-tagged oligonucleotides having different magnetic sizes to tag the base; And</p>

Figure 13 shows a flow chart of an example of a base recognition method in the sequence synthesis scheme for a magnetic biosensor using rice doxyribose DNA polymerase.

<p dir="rtl">25 deoxyribonucleic acid (DNA) tagged with single-molecule magnets and nucleotides with insertion rates</p>

Different.

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Figure 14a shows a planar view of the magnetic sensor array in combination with an example of a semi-hydrophobic region in a flow cell or droplet actuator; Figure 14b shows a cross-sectional view of the magnetic sensor array from Figure 14a; Figure 15a shows a planar view of the magnetic sensor array in combination with another example of

<p dir="rtl">5 The semi-hydrophobic region in a flow cell or train engine;</p>

Figure 15b shows a cross-sectional view of the magnetic sensor array from Figure 15a;

Figure 16a shows a plane view of a portion of a train engine that includes the magnetic sensor array to support, for example, a flow-through synthesis scheme for a magnetic biosensor;

Figure 16b explains a cross-sectional view of the cat engine according to Figure 16b;

<p dir="rtl">10 Figure 17 illustrates a planar view of a rotating disc-based device wherein a single movable magnetic sensor is provided to support, for example, a sequential synthesis scheme for a magnetic biosensor;</p>

Figure 18a shows a planar view of the magnetic sensor array in combination with an embodiment where a rice polymer is transported to certain areas;

<p dir="rtl">15 Figure 18b shows a cross-sectional view showing a plane view and a cross-sectional view, respectively, of the magnetic sensor array of Figure 18a; And</p>

Figure 19 illustrates a magnetically responsive sensor according to one embodiment.

Detailed description:

The methods described here can be described in connection with a variety of biological or chemical analytical techniques,

<p dir="rtl">20 Including DNA sequencing techniques. Models can be used to determine a genetic property of a sample based on the presence of changes in electrical resistance that occur as a DNA strand. Specifically applicable techniques are those where biological or chemical samples are placed at designated positions such that the corresponding positions do not change during analysis. For example, nucleic acids can be attached at fixed positions along the surface of a substrate during a given protocol as the array is scanned repeatedly. Forms are used where</p>

<p dir="rtl">25 Features are obtained by different channels, for example, corresponding to different markers to distinguish one nucleotide base type from another, namely. In some embodiments, the process can be to specify a sequence</p>

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Nucleotification of a target nucleic acid is an automated process. Preferred embodiments include sequential synthesis techniques.

As noted here, models can be used to determine a genetic characteristic of a sample. The genetic characteristic can be determined by analyzing changes in electrical resistance that occur at magnetically responsive sensors. for example,

<p dir="rtl">5 Magnetic particles bound to nucleotides or rice polymers can cause changes in electrical resistance at magnetically responsive sensors as nucleotides are added to nucleic acid. Signals from magnetically responsive sensors based on electrical resistance provide data that can be analyzed and used to determine a genetic trait. As used herein, the term “genetic characteristic” includes a DNA sequence or any characteristic based on the DNA sequence, which</p>

<p dir="rtl">10 Whether or not the specified sequence is selected. For example, models can show a strand complementary to a nucleic acid where each nucleotide added to the strand binds to one or more magnetic particles. In some embodiments, the nucleotide can be determined at each insertion event (e.g., in real time). In other embodiments, the nucleotide can be determined only after several insertion events or after the cascade cycle is terminated with a secondary analysis.</p>

<p dir="rtl">15 Still in other embodiments, the genetic feature can be determined without identifying individual nucleotides such that the sequence is known. For example, data provided by signals after one or more input events may be analyzed to distinguish one sequence from one or more other sequences. As a specific example, data derived from two (or more) nucleic acids containing a single nucleotide polymorphism (SNP) can be compared. Without knowledge of the nucleic acid sequences, it is possible to compare</p>

<p dir="rtl">20 The models analyze the patterns of signals received from magnetically responsive sensors. For example, each nucleotide may include a magnetic particle with a different magnetic property. Detected changes in electrical resistance from a sequence of nucleotides can form a pattern. Signals that constitute a first type may include a genotype, and signals that constitute a second type may include a second genotype. Therefore, it is possible to alert about nucleic acids that present type I</p>

<p dir="rtl">25 That it has a specific genetic characteristic, while the nucleic acids that give the second type can be said to have a different genetic characteristic. Again, these determinations can be made without knowledge of the acid sequences</p>

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Nuclear.

It should be understood that “identifying a genetic characteristic” does not necessarily include specifying, in particular, which genetic characteristic a sample might contain. For example, during screening for a particular genotype based on a suspected single nucleotide polymorphism, models may determine that one or more samples contain a specific non-specific genotype.

<p dir="rtl">5 While there are other samples that do not include this pattern. However, the genetic characteristic of the sample was determined. Likewise, “identification of a genetic characteristic” can include determining that a sample does not contain a suspected pathogen or determining that there is a genetic variant that does not include a single nucleotide polymorphism or short tandem repeat (STR).</p>

As another example, a sample from an individual suspected of having a particular condition could be tested. can cause

<p dir="rtl">10 The condition is caused by, for example, a genetic disorder, cancer, or a pathogen (e.g., Ebola). Testing may involve detecting changes in electrical resistance as nucleic acids grow. Again, without knowing the exact sequence of nucleic acids, Models can determine whether an individual has the condition by analyzing signals to identify one or more patterns. “Sequencing techniques” generally involve enzymatic extension of a strand</p>

<p dir="rtl">15 Nucleic acid generated through the repetitive addition of nucleotides against a template strand. In conventional straight-line synthesis methods, a single nucleotide monomer can be delivered to a target nucleotide in the presence of a rice polymer in each delivery. However, in the methods described here, more than one type of nucleotide monomer can be delivered to a target nucleic acid in the presence of a rice polymer in a delivery process.</p>

The synthesis can be performed by running a mononucleotide containing a terminator cleft

<p dir="rtl">20 moiety or those that need no finishing incisions. Methods using oligonucleotide monomers include termination methods including, for example, pyrosequencing and nucleotides tagged with γ-phosphate, as described in more detail below. In methods using mononucleotides that require termination means, the number of nucleotides added in each cycle is generally variable and depends on the template sequence and the mode of nucleotide delivery. For synthesis techniques</p>

<p dir="rtl">25 By using a mononucleotide monomer that has a termination moiety, the termination method can be as effectively irreversible under the conditions of the sequence used as is the case with the conventional Sanger technique, which</p>

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Dideoxynucleotides are used, or the termination method can be reversible as is the case for sequencing methods developed by Solexa (now Illumina, Inc.). Synthesis-by-sequencing techniques can use a mononucleotide containing a nick tag or one that requires Thus, insertion events can be detected based on a property of the tag, such as the fluorescence of the tag; a property of the monomer nucleotide such as molar weight or charge;

A byproduct of nucleotide insertion, such as the release of pyrophosphate; or something like that. In embodiments, where there are two or more different nucleotides in a sequence detector, the different nucleotides can be distinguishable from each other, or alternatively, the two or more different tags can be distinguishable under the detection technique being used. For example, 10 different nucleotides are present in a sequence detector which can include different tags

They can be distinguished using appropriate visual means as exemplified by sequencing methods developed by Solexa (now Illumina Inc.).

The thermal sequence detects the release of inorganic pyrophosphate (PPi) where nucleotides are specifically inserted into the nascent strand (Karamohamed, M., Ronaghi,

<p>P. (1996) “Real-time DNA sequencing using Uhlen, M. and Nyren, B., Pettersson, S. 15</p>

M., 84-9; Ronaghi, detection of pyrophosphate release.” Analytical Biochemistry 242(1)

3-11; (2001) “Pyrosequencing sheds light on DNA sequencing.” GenomeRes. 11(1)

P. (1998) “A sequencing method based on real-time, M. and Nyren, Uhlen, M., Ronaghi

(5375)281 363, pyrophosphate.” Science ; American Patent No. 6210891; With an innocence

<p dir="rtl">20 U.S. Patent No. 6,258,568 and U.S. Patent No. 6,274,320, the disclosures thereof are incorporated herein (reference). In the thermal process, inorganic pyrophosphate released by effervescent conversion to adenosine triphosphate (ATP) by sulfurylase can be detected Adenosine phosphate sulfurylase, and the level of adenosine phosphate is detected via photons generated by rice luciferase</p>

<p dir="rtl">25 Nuclear nuclei are arranged in a matrix, and the matrix can be photographed to detect chemiluminescent signals, which are produced due to the insertion of nucleotides into the matrix.</p>

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An image may be obtained after treating the matrix with a specific nucleotide type (for example, C, T, A, or G). The type of images obtained after adding each nucleotide type will differ relative to the properties detected in the matrix. These differences in the image Unlike the content of the different sequences of properties on the matrix, however, the relative positions of each property will remain uncharged in the images

<p dir="rtl">5 Store, process and analyze images using the methods described here. For example, images obtained after matrix treatment with each different oligonucleotide species may be treated in the same manner as represented here for images obtained from different detection channels for successive methods based on a reversible termination method.</p>

In another ideal type of series synthesis, the series cycle is achieved by the addition of nucleotides

<p dir="rtl">10 A reversible finish containing, for example, a dye mark capable of being cleaved or photobleached as described, for example, in publications under International Patent No. 018497/04 and in US Patent No. 7057026, the disclosures of which are incorporated by reference. This method is commercialized by Solexa (now Illumina Inc.), and is also described in International Patent Publication No. 91/06678 and International Patent Publication No. 123744/07, each of which is incorporated herein by reference.</p>

<p dir="rtl">15 Providing fluorescently-labeled terminators where the termination can be reversed, the cleaved fluorescent tag facilitates efficient cyclic reversible termination (CRT) sequences. Polymerases can also be co-engineered to efficiently introduce and extend these modified nucleotides.</p>

Preferably in succession models based on reversible termination means, tags do not

<p dir="rtl">20 Mainly by inhibiting expansion under synthesis reaction conditions by series. However, detection marks may be removable, for example, by incision or dissolution. The images can be combined after inserting the markers into the properties of the DNA from which the matrix was made. In certain embodiments, each cycle includes simultaneous delivery of four different nucleotide species to the array and each nucleotide species includes a spectrally distinct tag. Four images can then be acquired, each using a detection channel which is</p>

<p dir="rtl">25 Selective to one of the four different tags. Alternatively, different oligonucleotides can be added</p>

Successively the matrix image can be obtained between each addition step. In these models each picture is shown

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Properties of nucleic acid, which include inserted nucleotides of a certain type. There will be different noticeable properties present or absent in different images due to the different sequence content of each property. However, the relative position of the features will remain unchanged in the images. Images obtained from these reversible termination-synthesis methods may be stored, processed and analyzed as described herein. After the image capture step, labels can be removed and reversible termination moieties can be removed for subsequent cycles of nucleotide addition and detection. Removing marks after they are detected in a specific cycle and before the next cycle provides the advantage of reducing background signal and interference between cycles. Examples of useful signs and removal methods are listed below.

In certain embodiments some or all of the nucleotide monomer may include reversible termination means. In 10 such embodiments, the reversible/cleavable fluors may include fluor attached to a ribose cleavage via a 3' ester linkage (Genome Res). (Metzker 2005) 15:1767-1776 (which is incorporated herein by reference). There are other methods that have chemistry

fluorescence label (Ruparel) separate from the slit fluorescence label terminator chemistry termination medium

Proc Natl Acad Sci USA 102: 5932-7 (et al., 2005), which are incorporated herein by reference15. Ruparel et al described the development of reversible terminators that used a small 3' allyl group to impede expansion, However, it can be unblocked by a brief association with a palladium catalyst. A fluorophore is attached to the base via a photocleavable linkage that can be cleaved by a 30-second exposure to long-wavelength ultraviolet light. Either disulfide reductase (SS) or photocleavage 20 can be used to cleave bonds, for example. Another method for reversible termination is to use natural termination, which comes after applying a block dye to deoxynucleotide (dNTP). Charged block dye on dioxynucleotide as an effective termination method during steric and/or electrostatic hindrance. The presence of a single insertion event prevents further insertions unless the dye is removed. The dye cleavage removes the fluorine and effectively reverses the termination. 25 Examples of modified oligonucleotides are also described in US Patent 7,427,673 and US Patent 7,057,026, the disclosures of which are incorporated herein by reference.

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Systems and methods of synthesis may be used by additional exemplary sequences which may be used with methods and systems described herein in US Patent 7,541,444, US Patent 7,566,537, US Patent 7,057,026, US Patent 8,460,910, US Patent 8,623,628, Patent Publication. International Patent No. 065814/05, US Patent No. 5, 7985565, published under International Patent No. 064199/06, published under International Patent Patent No. 010251/07, published under US Patent No. 064199/06. 20120270305 US Patent Publication No. 20130260372, the disclosures thereof have been incorporated here for further reference.

Some embodiments can use detection of four different nucleotides using fewer than four different tags. For example, the synthesis may be carried out by succession using the methods and systems 10 described in the material entered for US Patent Publication No. 20130079232. As an example

First, a pair of nucleotide species can be detected at the same wavelength, but are distinguished based on the difference in intensity of one number of the pair compared to the other, or based on a change towards one member of the pair (e.g., via chemical modification, photochemical modification). modification (physical modification) which results in an apparent signal that appears or disappears compared to the signal detected by the other member of the pair. As a second example, three out of

Four different nucleotide types under the given conditions while the four nucleotide types require a tag that is detected under these conditions, or is less detected under these conditions (e.g., less detected due to background fluorescence, etc.). The entry of the first three types can be selected of nucleotides in DNA based on the presence of corresponding signals, and the introduction of a four-nucleotide type into DNA can be determined based on the absence or less of any signal detected. As a third example, a single nucleotide type can include a marker

It is detected in two different channels, with different nucleotide species being detected in no more than one of the channels. The third ideal configurations mentioned will not be considered mutually exclusive and can be used in different combinations. An exemplary model that combines all three examples is a fluorescence-based sequence synthesis method that uses the first 25 nucleotide species detected in a first channel (eg, deoxyadenosine triphosphate

Deoxyadenosine triphosphate (dATP) has a marker that is detected in the first channel upon arousal

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By the first excitation wavelength), a second nucleotide species is detected in a second channel (e.g., deoxycytidine triphosphate (dCTP) has a label that is detected in the second channel. When excited by the second excitation wavelength), a second nucleotide species is detected. The third nucleotide in both the first and second channels (for example, deoxythymidine triphosphate)

<p dir="rtl">5 triphosphate (dTTP) has a single marker that is detected in all channels when excited by the first and/or second excitation wavelength) and a four-nucleotide type that requires a marker that is not detected, or is detected less frequently, in any channel (e.g., D Deoxyguanosine triphosphate (dGTP) has no label.</p>

Also, as described in the material entered for U.S. Patent No

<p dir="rtl">10 20130079232, consecutive data can be obtained using a single channel. In single row methods</p>

With the mentioned dye, the type of the first nucleotide is marked, but the mark is removed after generating the first image, and the type of the second nucleotide is marked only after generating the first image. The third nucleotide type gets its mark in both the first and second images, and the fourth nucleotide type remains unmarked in both images. Some models can be used in series by linking techniques. These techniques use ligase

<p dir="rtl">15 A DNA ligase to insert oligonucleotides and determine the insertion of these oligonucleotides. These oligonucleotides ideally include various tags that correlate with the identity of a particular nucleotide in the sequence to which the oligonucleotides hybridize. For other sequence synthesis methods, images can be obtained after treating a matrix of nucleic acid properties with the reagents of the labeled sequence. Each image will show properties of nucleic acid, including...</p>

<p dir="rtl">20 Inserted tags of a specific type. There will be different properties present or absent in different images due to the different sequence content of each image, but the relative position of the properties will remain unpaired in the images. Images obtained from ligation-based sequencing methods can be stored, processed and analyzed as described here. Synthesis systems and methods are described by exemplary sequences that can be used with the methods and systems described herein</p>

<p dir="rtl">25 US Patent No. 6969488, US Patent No. 6172218, and US Patent No. 6172218.</p>

6306597, the statements thereof are incorporated herein by reference.

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Some embodiments may use nanopore sequencing

M. “Nanopores and nucleic acids: prospects for ultrarapid,” D. W. &amp; Akeson, (Deamer

, D. and D. Branton, 147-151 (2000); Deamer,sequencing.” Trends Biotechnol. 18 “Characterization of nucleic acids by nanopore analysis”. Acc. Chem. Res. 35:817-825

“DNA, and J.A. Golovchenko, E. Brandin, D. Stein, M. Gershow, J., (2002); “Li 5 molecules and configurations in a solid-state nanopore microscope” Nat. Mater. 2:611

2003 (615), the disclosures of which are incorporated herein (reference). In these models, the target DNA passes through nano-sized pores, although some nano-pore models can be performed using methods that include real-time monitoring. To introduce the rice nucleic acid polynucleotide

<p dir="rtl">10 Doxyribose. The nano-sized pores can be synthetic pores or a biological membrane protein, such as α-hemolysin. In one exemplary embodiment, as the target DNA passes through the nano-sized pore, each base can be identified by measuring oscillations in the electrical conductivity of the pore. b) US Patent 7001792; A. Progress, G.V. &amp; Meller, Sony”</p>

1996- “Toward ultrafast DNA sequencing using solid-state nanopores.” Clin. Chem. 53

, K. “Nanopore-based single-molecule DNA analysis.” Nanomed. 2,2001 (2007); Healy 15

MR “A single-, M. &amp; Ghadiri, Amorin, J., Chu, S.L., 459-481 (2007); Cockroft molecule nanopore device detects DNA polymerase activity with single-nucleotide

130 818-820 (2008, resolution.” J. Am. Chem. Soc), the disclosures of which are incorporated herein (reference). Data obtained from a sequence with pore-sized pores can be stored, processed, and analyzed.

<p dir="rtl">20 Nano as mentioned here. Specifically, the data may be treated as an image in accordance with the ideal treatment of optical and other images described herein.</p>

Some embodiments may employ methods that include real-time monitoring of rice doxyribose DNA polymerase activity. Nucleotide insertions can be detected during fluorescence resonance energy transfer (FRET) reactions between a fluorophore-bearing rice polymer.

<p dir="rtl">25 fluorophore-bearing polymerase and γ-phosphate-tagged nucleotides as described, for example, in US Patent 7,329,492 and US Patent 7,211,414 (each of which is incorporated herein by reference) or cases of insertion of a nucleotide with a zero-position guiding wave As is</p>

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described, for example, in US Patent 7,315,019 (which is incorporated herein by reference) and using fluorescent nucleotide analogues and polymerases designed as described, for example, in US Patent 7,405,281 and US Patent 8,343,746 (which has been Each is incorporated here by reference. The zeptoliter-sized illumination can be restricted around a 5-surface tethered rice polymerase such that the insertion of fluorescently labeled nucleotides can be observed with a background

MJ et al. “Zero-mode waveguides for single-molecule analysis at Low, Levene

<p>PM et al. “Parallel, 682-686 (2003); Lundquist, high concentrations.” Science 299</p>

1026-1028 (2008); “confocal detection of single molecules in real time.” Opt. Lett. 33

<p>J. et al. “Selective aluminum passivation for targeted immobilization of single Korlach DNA polymerase molecules in zero-mode waveguide nano structures.” Proc. Natl. Acad. 10</p>

105 1176-1181 (2008, Sci. USA), the lists of which are incorporated herein. Images obtained from these methods can be stored, processed, and analyzed as stated here.

In certain embodiments, the polymer is moved or attached to a specified area along a surface near a magnetically responsive sensor. These embodiments can increase the probability that 15 different magnetic particles will be detected by the magnetically responsive sensor, which may include a cue.

The developing complement is relatively equal distances away from the magnetically responsive sensor.

Embodiments described herein may also include oligonucleotides tagged with γ-phosphate where the tag is coupled to a magnetosome containing γ-phosphate to alter the electrical resistance of the magnetically responsive sensors.

<p dir="rtl">20 Some models of straight synthesis involve detecting a proton that is released when the nucleotide is introduced into the D product. For example, cascade may be based on the detection of emitted protons using an electrical detection device and related techniques commercially available from a CT, Ion Torrent (Guilford Life Technologies subsidiary) or cascade methods and systems described in US Patent 8262900; 7948015; US Patent Publication No. 25 20100137143; or US Patent Publication No. 8349167, each of which is incorporated herein by reference</p>

for reference. The methods described here can be applied to amplify target nucleic acids

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Acids using kinetic exclusion on substrates are already used to detect protons. More specifically, the methods described here can be used to produce clonal populations of amplicons that are used to detect protons.

The above-mentioned series synthesis methods can be implemented in many multiplex modes

<p dir="rtl">5 formats so that many different target nucleic acids are modified simultaneously. In certain embodiments, different target nucleic acids may be treated in a common reaction vessel or on the surface of a particular substrate. This allows for convenient delivery of reagents in series, removing unreacted reagents and detecting input events in a multiplexed manner. In embodiments using surface-linked target nucleic acids, the target nucleic acids may be in a matrix form.</p>

<p dir="rtl">10 In a matrix format, the target nucleic acids can be ideally bound to a surface in an ergically recognizable manner. Target nucleic acids can be attached by direct covalent attachment, attachment to a molecule or other particle, or attachment to a rice polymer or other surface-attached molecule. The array can include a single copy of a target DNA at each site (also referred to as a feature) or many copies with the same sequence located at each site or feature. Many copies can be produced by</p>

<p dir="rtl">15 Amplification methods such as bridge amplification or rice polymerase chain reaction (PCR) for an emulsion are described in more detail.</p>

The methods described here can use matrices with properties at any of a variety of intensity values including, for example, at least about 10 properties/cm2, 100 properties/cm2, 500 properties/cm2, 1,000 properties/cm2, 5,000 properties/cm2, 10,000 properties. properties/cm2, 50,000 properties/cm2, 100,000

<p dir="rtl">20 properties/cm2, 1,000,000 properties/cm2, 5,000,000 properties/cm2, or more.</p>

An advantage of the methods described here is that they provide rapid and efficient detection of a range of target nucleic acids in parallel. The present disclosure therefore provides integrated systems capable of preparing and detecting nucleic acids using techniques known in the art such as those represented above. Thus, an integrated system for the present detection could include fluidized components capable of delivering reagent agents for amplification

<p dir="rtl">25 and/or reagents to sequence one or more transcribed DNA fragments. The system includes components such as pumps, valves, reservoirs, fluid lines, and the like.</p>

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The flow cell can be adapted and/or used in an integrated system for detection of target nucleic acids. Exemplary flow cells are described, for example, in US Patent No. 8,241,573 and Publication No. 20120270305, each of which is incorporated herein by reference. As an example of flow cells, one or more fluidic components of an integrated system may be used

<p dir="rtl">5 For magnification method and detection method. Taking the DNA cascade model as an example, one or more of the fluidized components of an integrated system of an amplification method described herein may be used for the delivery of cascade reagents in a cascade method such as that described above. Alternatively, an integrated system may include separate fluidization systems to implement amplification methods and to implement detection methods. Examples of integrated sequence systems capable of generating amplified nucleic acids and also determining nucleic acid sequences with, without</p>

<p dir="rtl">10 In reference to, CA, San Diego, Inc., the MiSeqTM (Illumina) platform and devices described in U.S. Patent Publication No. 20120270305, which is incorporated herein by reference.</p>

As used herein, the following terms have the meanings indicated. “Drop” means the volume of fluid on the engine of the Qatar Airways. Ideally, a droplet is at least partially bound by filler fluid. For example, the droplet may be entirely surrounded by a filling fluid or may be bound by a single filling fluid

<p dir="rtl">15 Or more Cat Art engine surfaces. As another example, a droplet may be bound by a filling fluid, one or more surfaces of the droplet motor, and/or the atmosphere. As another example, a drop can be linked by a filling fluid and the atmosphere. Drops can be, for example, aqueous or non-aqueous, or they can be mixtures or emulsions containing both aqueous and non-aqueous components. Cats can be in a wide variety of shapes; Non-restricted examples generally include disk-shaped, slug-shaped, truncated spheroid, ellipsoidal, spherical,</p>

<p dir="rtl">20 Partially compressed sphere, semi-spherical, oval, cylindrical, combinations of these shapes, and various shapes formed during distillation processes, such as merging, cleaving, or formed as a result of these shapes with one or more surfaces of a distillation engine. For examples of fluid droplets that can be subjected to distillations using the present disclosure approach, see Eckhardt et al., publication under International Patent No. 120241/2007, entitled, “Droplet-Based Biochemistry,” published on October 25, 2007, and</p>

<p dir="rtl">25 The full disclosure is hereby incorporated by reference.</p>

In many embodiments, the droplet can include a biological sample, such as whole blood, a fluid

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lymphatic fluid, serum, plasma, sweat, tear, saliva, sputum, cerebrospinal fluid, amniotic fluid, seminal fluid, vaginal excretion, serous fluid, synovial fluid synovial fluid, pericardial fluid, peritoneal fluid

<p dir="rtl">5 peritoneal fluid, pleural fluid, transudates, bodily secretions</p>

exudates, cystic fluid, bile fluid, urine, gastric fluid, intestinal fluid, fecal samples, fluids containing one or many cells, fluids containing organelles, tissues fluidized tissues, fluidized organisms, fluids containing multiple organisms

<p dir="rtl">10 Cells, biological swabs and biological washes. Furthermore, the drop may include a reagent, such as water, deionized water, saline solutions, acidic solutions, basic solutions, detergent solutions. solutions and/or buffers. The droplet may include nucleic acids, such as doxyribonucleic acid, deoxyribonucleic acid</p>

<p dir="rtl">15 genomic ribonucleic acid (RNA), messenger ribonucleic acid (mRNA) or analogues of the above; nucleotides such as deoxyribonucleotides, ribonucleotides or analogues of the above such as analogues having termination clefts such as those shown In Nature 456:53-59, Bentley et al 2008)(Gormley et al., publication application, International Patent No. 131962/2013, entitled,</p>

<p dir="rtl">20 “Improved Methods of Nucleic Acid Sequencing,” published September 12, 2013; Barnes</p>

et al., publication application for US Patent No. 7,057,026, titled “Labelled Nucleotides,” issued July 6, 2006; Kozlov et al., application for publication under International Patent No

042067/2008, titled, “Compositions and Methods for Nucleotide Sequencing,” published April 10, 2008; Rigatti et al., Application for Publication under International Patent No

<p dir="rtl">25 117595/2013, entitled, “Targeted Enrichment and Amplification of Nucleic Acids on a</p>

Support,” published August 15, 2013; Hardin et al., US patent application for publication

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No. 7,329,492, entitled, “Methods for Real-Time Single Molecule Sequence Fetermination,” issued on February 12, 2008; Hardin et al., US Patent Application No. 7,211,414, titled, “Enzymatic Nucleic Acid Synthesis: Compositions and Methods for Altering Monomer Incorporation Fidelity,” issued May 1, 2007;

<p dir="rtl">5 Turner et al., U.S. Patent Application No. 7,315,019, titled, “Arrays of Optical Confinements and Uses Thereof,” issued January 1, 2008; Xu et al., U.S. Patent Application No. 7,405,281, titled, “Fluorescent Nucleotide Analogs and Uses Therefor,” issued July 29, 2008; and Ranket al., US Patent No. 20080108082, entitled “Polymerase Enzymes and Reagents for Enhanced Nucleic Acid</p>

<p dir="rtl">10 Sequencing,” published on May 8, 2008, the disclosures of which are incorporated herein by reference; Enzymes such as polymerases, ligases, recombinases, or transposases; Common binding partners such as antibodies, epitopes, streptavidin, avidin, biotin, lectins or carbohydrates; Or other biochemically active molecules. Other examples of content include:</p>

<p dir="rtl">15 A drop containing reagent agents, such as a biochemical protocol reagent, such as a nucleic acid amplification protocol, affinity-based assay protocol, enzymatic assay protocol, sequencing protocol, and/or analysis protocol biological fluids. The drop may include one or more pellets.</p>

<p dir="rtl">20 The term “catart engine” means a device for modifying catart. Examples of locomotive motors include, see Pamula et al., US Patent Application No. 6,911,132, titled “Apparatus for Manipulating Droplets by Electrowetting-Based Techniques,” issued June 28, 2005; Pamula et al., US Patent Application No. 20060194331, titled</p>

“Apparatuses and Methods for Manipulating Droplets on a Printed Circuit Board.”

<p dir="rtl">25 Published August 31, 2006; Pollack et al., International Patent Application No. 120241/2007, titled “Droplet-Based Biochemistry,” published October 25, 2007;</p>

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Shenderov, US Patent Application No. 6,773,566, titled “Electrostatic Actuators for Microfluidics and Methods for Using Same,” issued August 10, 2004; Shenderov, US Patent Application No. 6,565,727, titled “Actuators for Microfluidics Without Moving Parts,” issued May 20, 2003; Kim et al., Patent Application No. 5, US Patent No. 20030205632, titled “Electrowetting-driven Micropumping.”

Published November 6, 2003; Kim et al., US Patent Application No. 20060164490, titled “Method and Apparatus for Promoting the Complete Transfer of Liquid Drops from a Nozzle,” published July 27, 2006; Kim et al., US Patent Application No. 20070023292, titled “Small Object Moving on Printed Circuit Board 10,” published February 1, 2007; Shah et al., US Patent Application No. 20090283407,

“Method for Using Magnetic Particles in Droplet Microfluidics,” published November 19, 2009; Kim et al., publication application under US Patent No. 20100096266, titled

Method and Apparatus for Real-time Feedback Control of Electrical Manipulation of “

Droplets on Chip,” published April 22, 2010; Velev, application for publication in US Patent No. 15, No. 7,547,380, entitled “Droplet Transportation Devices and Methods Having a Fluid

Surface,” released June 16, 2009; Sterling et al., US Patent Application No. 7,163,612, “Apparatus and Article for Microfluidic Control via Biochemical and Biological Assays and the Like Method for Chemical,Electroetting,” issued January 16, 2007; Becker et al., Publication Application for US Patent No. 7,641,779, titled 20 “Method and Apparatus for Programmable Fluidic Processing,” issued January 5,

2010; Becker et al., US Patent Application No. 6,977,033, entitled “Method and Apparatus for Programmable Fluidic Processing,” issued December 20, 2005; Decre et al., US Patent Application No. 7,328,979, entitled “System for Manipulation of a Body of Fluid,” issued February 12, 2008; Yamakawa et al., Application 25, published under US Patent No. 20060039823, entitled “Chemical Analysis Apparatus.”

Published on February 23, 2006; Wu, US Patent Application No. 20110048951,

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“Digital Microfluidics Based Apparatus for Heat-exchanging Chemical Processes,” titled

Published March 3, 2011; Fouillet et al., U.S. Patent Application No. 20090192044, titled “Electrode Addressing Method,” published July 30, 2009; Fouillet et al., publication application under US Patent No. 7,052,244, entitled “Device for

Displacement of Small Liquid Volumes Along a Micro-catenary Line by Electrostatic 5

Forces,” issued May 30, 2006; Marchand et al., U.S. Patent Application No. 20080124252, titled “Droplet Microreactor,” issued May 29, 2008; Adachi et al., US Patent Application No. 20090321262, titled “Liquid Transfer Device,” published December 31, 2009; Roux et al., Application for Publication under US Patent No

<p dir="rtl">10 20050179746, titled “Device for Controlling the Displacement of a Drop Between.”</p>

Two or Several Solid Substrates,” published August 18, 2005; Dhindsa et al.,

“Virtual Electrowetting Channels: Electronic Liquid Transport with Continuous Channel.”

10 : 832-836 (2010, “Lab Chip, Functionality”), the disclosures of which are incorporated herein by reference. Certain drip engines will include one or more substrates equipped with a drip gap

<p dir="rtl">15 between them and electrodes attached to (e.g., layered with, attached to, and/or embedded in) the one or more substrates and equipped to carry out one or more distillation processes. For example, certain locomotive engines will include a base (or bottom) of a substrate, Distillation electrodes are attached to the substrate, one or more dielectric layers above the substrate and/or electrodes, and optionally one or more hydrophobic layers above the substrate, dielectric layers and/or electrodes forming a distillation surface may be provided</p>

<p dir="rtl">20 Also upper, separated from the distillation surface by a gap, generally referred to as a distillation gap. Various electrode placements on the top and/or bottom of substrates are discussed in the above-referenced patents and applications and specific electrode placements are described in the description of the present disclosure. During distillation operations, it is preferable for the droplets to remain in continuous or frequent contact with a ground or reference electrode. A ground or reference electrode can be connected to the upper substrate facing the gap, the lower substrate facing the gap, in</p>

<p dir="rtl">25 Gap. Where electrodes are provided on each of the substrates, electrical contacts may be attached to couple the electrodes to a train drive device to control or monitor the electrodes on one or both of the panels. In some cases, the electrodes on one substrate are electrically coupled to the other such that the substrate touches</p>

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Only one with Cat Art engine. In one embodiment, the conductive material (e.g., an epoxy, such as MASTER BOND™ Polymer System EP79, available from Master Bond, NJ, Hackensack, Inc.) provides electrical contact between electrodes on one substrate and electrical paths on the other substrates, For example, a ground electrode on an upper substrate coupled to an electrode on a 5 lower substrate may be coupled by this conductive material. Where multiple substrates are used, a spacer may be provided

Between the pillars to determine the height of the gap between them and determine the dispensing reservoirs on the engine. The spacer height can be, for example, at least about 5 µm, 100 µm, 200 µm, 250 µm, 275 µm or more. Alternatively or additionally the spacer height can be at most about 600 µm, 400 µm, 350 µm, 10 300 µm, or less. The spacer can be created, for example, from a layer of a Pro-Azt image that forms the top pillars

or bottom, and/or material inserted between the top and bottom piles. One or more openings may be provided in the one or more substrates to form a fluid path through which the fluid may be delivered to the distillation cavity. The one or more orifices may be aligned in some cases to interact with one or more electrodes, e.g., aligned such that the flow of liquid through the orifice is close enough to the one or more 15 distillation electrodes to allow the distillation process to be influenced by the distillation electrodes using

Questioner. The base (or bottom) or top substrates may in some cases be configured as an integrated component. One or more reference electrodes may be provided on the base (or bottom) and/or top substrates and/or in the gap. Examples of reference electrode setups are provided in B The above reference patents and patent applications In many embodiments, the modulation of the electrode by a 20 electrode drive can be, for example, mediated by electrowetting or electrophoresis.

dielectrophoresis or Coulombic force. Examples of other techniques include distillation processes that may be used in locomotive engines according to the present disclosure, including the use of devices that induce hydrodynamic fluidic pressure, such as those operating on the basis of mechanical principles (e.g., external syringe 25 pumps, diaphragm pumps Pneumatic membrane pumps, diaphragm pumps

vibrating membrane pumps, vacuum devices, centrifugal force

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forces, piezoelectric/ultrasonic pumps, acoustic forces (e.g. electrical or magnetic principles), electroosmotic flow, electrokinetic pumps, ferrofluidic plugs, electrodynamic pumps

<p dir="rtl">5 electrohydrodynamic pumps, attraction or repulsion using magnetic forces and magnetohydrodynamic pumps; thermodynamic principles (e.g. volume expansion induced by a change in gas bubble generation/phase); there are other types of surface-wetting principles) For example, electrowetting, optoelectrowetting, in addition to chemical gradations,</p>

<p dir="rtl">10 Thermal, structurally induced and radiatively active surface; gravity; surface moment</p>

tension (e.g., capillary action); electrostatic forces (e.g., electroosmotic flow); centrifugal flow (a substrate placed on a compact disc and rotated); magnetic forces (e.g., oscillating ions Which causes the flow (; magneto-hydrodynamic forces

<p dir="rtl">15 magnetohydrodynamic forces; Vacuum or differential pressure. In certain embodiments, combinations of two or more of the foregoing techniques may be used to implement the distillation process in a QART engine according to the present disclosure. Likewise, one or more of the above may be used to deliver liquid into a distillation cavity, for example, from a reservoir in another device or from a reservoir external to the locomotive engine (e.g., a reservoir linked to a substrate locomotive motor and a flow path from the reservoir in the distillation cavity). Surface distillation processes engines</p>

<p dir="rtl">20 Certain diameters in accordance with the present disclosure are made of hydrophobic materials or may be coated or treated to render them hydrophobic</p>

Waterproof. For example, in some cases some or all of the surface distillation processes may be derived from materials with surface energy or chemical structures, for example, by precipitation or by in situ synthesis using compounds such as poly- or per-fluorinated compounds in solution Or polymerizable monomers. Examples include TEFLON® AF

<p dir="rtl">25 (available from DE, Wilmington, DuPont), members of the cytop family of materials, coatings in the FLUOROPEL® family of hydrophobic and hydrophobic coatings</p>

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and superhydrophobic coatings (available from Cytonix Corporation, MD, Beltsville), silane coatings, fluorosilane coatings, hydrophobic phosphonate derivatives (e.g., those sold by Aculon, Inc.), and electronic coatings NOVEC™ (available from MN,St. Paul,M Company3(, other Monom Art

<p dir="rtl">5 Fluorine treatment for plasma-enhanced chemical vapor deposition (PECVD), and organosiloxane (e.g., SiOC) for plasma-enhanced chemical vapor deposition. In some cases, the distillation surface can include a hydrophobic coating having a thickness in the range of about 10 nm to about 1000 nm. Furthermore, in some embodiments, the top substrate of the catart stirrer includes an organic polymer that is electrophoresed, which is then coated with a hydrophobic 10 coating or treated to make the distillation surface hydrophobic. For example, an organic polymer applied to a plastic substrate can be electroactive (poly(3,4-ethylenedioxythiophene), poly(styrenesulfonate) (PEDOT). Other examples of electrochromic organic polymers and alternative conductive layers are described in Pollack et al., International Patent Application No.</p>

<p dir="rtl">15 002957/2011, titled “Droplet Actuator Devices and Methods,” published January 6,</p>

2011 The full disclosure is hereby incorporated by reference. One or both of the substrates may be fabricated using a printed circuit board (PCB), glass, indium tin oxide (ITO) coated glass, and/or semiconductor materials as the substrate. When the substrate is coated glass With indium tin oxide, the indium tin oxide 20 coating preferably has a thickness of at least about 20 nm, 50 nm, 75 nm, 100 nm or more. Alternatively or additionally the thickness can be at most about 200 nm, 150 nm, 125 nm or less. In some cases, the top and/or bottom substrate includes a printed circuit board substrate which is coated with an insulating material, such as a dielectric polyimide, which in some cases may also be coated or treated to make a distillation surface

<p dir="rtl">25 Hydrophobic. When the substrate includes a printed circuit board, the following materials are examples of suitable materials: 300-MITSUI™ BN (available from MITSUI Chemicals America, San Jose, Inc.)</p>

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6-NELCO® N4000 and 30/32-N5000 (from Melville, Park Electrochemical Corp., NY); ISOLA FR406™ (from AZ). (Isola Group, Chandler, especially IS620); fluoropolymer family (suitable for fluorescence detection as it has a low background fluorescence); polyimide family; polyester; polyethylene naphthalate; polycarbonate; polyether polyetheretherketone; liquid crystalline polymer crystal polymer; cyclo-olefin copolymer (COC); cyclo-olefin polymer (COP); aramid; nonwoven THERMOUNT® aramid backing (available from DE, Wilmington, DuPont); NOMEX® fiber Available from DuPont, 10 DE, Wilmington (and paper). There are several materials also suitable for use as an insulating component of the substrate.

Examples include: Vapor deposition sealant, such as PARYLENE™ C (especially on glass), PARYLENE™ N, and PARYLENE™ HT (for high temperature, ~300°C) (available from Parylene Coating Services, TX, Katy, Inc.). (available at

N.V., Inc. Carson City, Taiyo America (Good thermal properties for applications involving thermal control), and 8165 PROBIMER™ (Good thermal properties for applications involving thermal control) Los Angeles, Huntsman Advanced Materials Americas Inc CA. ; a dry film welding cap, such as those found in the VACREL® 20 Dry Film Welding Cap line (available from DE, Wilmington, DuPont); film dielectrics, film dielectrics

Such as polyimide film (e.g., KAPTON® polyimide film, available from Wilmington, DuPont, DE), polyethylene, fluoropolymers (e.g., FEP), polytetrafluoroethylene; polyester; polyethylene naphthalate; cyclopolymer -co-olefin; cyclo-olefin polymer; any other printed circuit board substrate material listed above; black matrix polypropylene; black flexible circuit materials, such as DuPont™ Pyralux

HXC and DuPont™ Kapton® MBC (available from DuPont, Wilmington, DE). Can be selected.

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Droplet transport voltage and frequency for performance with reagents used in specific screening protocols. Design variables can vary, for example, the number and placement of reservoirs on a motor, the number of independent electrode connections, the size of the various reservoirs, the logic of placing the magnets/ball wash, the electrode size, the inter-electrode pitch, and the height of the gap (between Top and bottom 5 substrates) for use with specific reagents, protocols, drop sizes, etc. In some cases, a substrate according to the present disclosure may be derived with materials having low surface energy or chemical properties, for example, using precipitation or in situ synthesis using poly- or per-fluoro-cured compounds in solution or polymerizable monomers. Examples include TEFLON® AF and FLUOROPEL® coatings for dip or spray coating, or other fluorine monomers for enhanced chemical vapor deposition

<p dir="rtl">10 Plasma-enhanced chemical vapor deposition. Additionally, in some cases, some part or all of the distillation surface may be coated with a material to reduce background noise, such as background fluorescence from a printed circuit board substrate. For example, it may include Black matrix resin noise reduction coating, such as black matrix resin available from Toray Japan, Inc., industries. The electrodes of a train engine are therefore ideally controlled by a 15 controller or processor, which is itself provided as part of the system, which can include processing functions as well as data storage capabilities, software, inputs and outputs. Reagents may be supplied on a dropper motor in the distillation cavity or in a reservoir fluidly coupled to the distillation cavity. The reagents may be in liquid form, for example, drop-art, or may be provided in reconstituted form in the distillation cavity or in a reservoir fluidly coupled to the distillation cavity. maybe</p>

<p dir="rtl">20 Ideally combine reconstituted reagents with liquids for reconstitution. An example of reconfigurable reagent agents suitable for use with the methods and device described herein includes those described in Meathrel et al., US Patent No. 7,727,466, titled “Disintegratable Films for Diagnostic Devices,” issued June 1, 2010, The full disclosure is hereby incorporated by reference.</p>

<p dir="rtl">25 “Distillation Process” means any modification of a droplet on a droplet engine. The distillation process may include, for example: loading a drop into the droplet motor; Distributing one or more droplets from a source droplet; incision,</p>

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Separating or dividing a droplet into two or more droplets; Moving a drop from one position to another in any direction; combining or combining two or more drops into a single drop; drop dilution; drop mixing; drop stirring; drop distortion; Get a drop in place; drop nursery; drop heating; drop evaporation; drop cooling; drop disposal; Move the drop out of the CatArt engine; Other distillation processes described here;

<p dir="rtl">5 And/or any combination of the above. The terms "collect," "merge," "aggregate," "mix" and the like are used here to describe the formation of a drop from two or more droplets. It should be understood that when this term is used in reference to two or more stills, any combination of distillations sufficient to result in a combination of two or more stills in one drop may be used. For example, "merging droplet A with droplet B," can be achieved by moving droplet A in contact with stationary droplet B, moving droplet B in contact with stationary droplet</p>

<p dir="rtl">10 A, or move the cat A and B touching each other. The terms “splitting,” “separating,” and “splitting” are not intended to imply that a given yield is relative to the size of the resulting droplets (i.e., the size of the resulting droplets could be the same or different) or the number of resulting droplets (the number of droplets generated could be The resulting drops are 2, 3, 4, 5 or more). The term “mixing” refers to distillation processes that result in a more homogeneous distribution of one or more components in the drop. Examples of “loading” distillation processes include microdialysis loading</p>

<p dir="rtl">15 microdialysis loading, pressure assisted loading, robotic loading, passive loading, and pipette loading. Distillation processes can be electrode-based. In some cases, distillation processes are also facilitated by the use of hydrophilic and/or hydrophobic regions on surfaces and/or by physical obstacles. As examples of distillation processes, see the patents and patent applications listed above under the heading</p>

<p dir="rtl">20 For "Cat Art Engine." Impedance or capacitance sensing or imaging techniques can sometimes be used to determine or confirm the distillation yield. Examples of these techniques are described in Sturmer et al., U.S. Patent Application No. 20100194408, entitled “Capacitance Detection in a Droplet Actuator,” published on August 5, 2010, the full disclosure of which is incorporated by reference. Generally speaking, sensing or imaging techniques can be used to confirm the presence</p>

<p dir="rtl">25 Or the absence of a drop at a specific electrode. For example, the presence of a droplet distributed at the desired electrode after the droplet dispensing process confirms that the droplet dispensing process was effective. Likewise, the presence of a drop can</p>

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A detection zone at an appropriate step in an assay protocol confirms that a previous set of distillations has successfully produced the detection drop. Droplet transfer time can be very fast. For example, in many embodiments, the transfer of a droplet from one electrode to the next can exceed about 1 s, about 0.1 s, about 0.01 s, or about 0.001 s. In one embodiment, the electrode is operated in alternative current (AC) mode but switched to direct current (DC) mode for imaging. It is useful to perform drop zone trace distillations similar to the electrowetting zone; Or in other words, 1-2x-3x, If the droplet trace is greater than the number of electrodes available to carry out the distillation process at a given time, the difference between the droplet size and the number of electrodes should ideally not be greater than 1; Or 10 In other words, x2 drops are advantageously controlled with 1 electrode and x3 drops with 2 electrodes.

When drops include spheres, it is useful for the droplet size to be equal to the number of electrodes controlling the droplet, for example, transporting the droplet.

The term “filling fluid” means a fluid associated with a drop-phase distillation process, and such fluid is miscible with a drop phase to obtain a drop-phase material into 15-electrode based distillation processes. For example, the drip hole of a train engine is ideally filled with filling fluid. The filling fluid can be, for example, or include a low-viscosity oil, such as silicone oil or hexadecane. The filling fluid may be or include a halogenated oil, such as fluorinated or perfluorinated oil. Filling fluid may be filled throughout the entire catart engine cavity or one or more surfaces of the catart engine may be coated. Filling fluids can be conductive or non-conductive. 20 Filling fluids can be selected to optimize distillation processes and/or reduce loss of reagent or target materials from droplets, improve formation of microdroplets, reduce cross-contamination between drops, reduce contamination of droplet drive surfaces, reduce degradation of droplet drive materials etc. For example, filling fluids can be selected to be compatible with the Catart engine materials. As an example, fluorinated filling fluids can be used with the surface of fluorinated coatings. Fluorinated filling fluids are useful in reducing the loss of lipophilic compounds, such as umbelliferone substrates such as 6-hexadecanoylamido-4-methylumbelliferone (for example,

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For use in Niemann-Pick, Krabbe, or other kits); other umbelliferone substrates are described in Winger et al., US Patent Application No. 20110118132, titled “Enzymatic Assays Using Umbelliferone Substrates with Cyclodextrins in Droplets of Oil,” published in May 19, 2011, and the full disclosure is hereby incorporated by reference and includes examples

<p dir="rtl">5 Suitable fluorinated oils include those in the Galden line, such as Galden HT170 (boiling point = 170 mM, viscosity = 1.8 centistokes, density = 1.77), Galden HT200 (boiling point = 200 mM, viscosity = 2.4 centistokes, density = 1.79), Galden HT230 (boiling point = 230C, viscosity = 4.4 centistokes, density = 1.82) (both Solvay Solexis); those in the Novec line, such as Novec 7500 (boiling point = 128C, viscosity = 0.8 centistokes, density = 1.61), Fluorinert</p>

<p dir="rtl">10 40-FC (boiling point = 155 mM, viscosity = 1.8 centistokes, density = 1.85), 43-Fluorinert FC</p>

(boiling point = 174 mM, viscosity = 2.5 centistokes, density = 1.86) (both M3). In general, selection of perfluorinated filling fluids is based on kinematic viscosity (preferred > 7 centistokes, but not required), and on boiling point (< 150 pM is preferred, but not required, for use in doxyRNA/DNA-based applications

<p dir="rtl">15 Ribose (rice polymer chain reaction, etc.). Filling fluids may, for example, be impregnated with surfactants or other additives. For example, additives may be selected to optimize distillation processes and/or reduce loss of reagent or material. Targeted droplets, microdroplet composition, cross-contamination between droplets, contamination of drivetrain surfaces, degradation of drivetrain materials, etc. Filling fluid compositions, including surfactant and doping agent, can be selected for performance with</p>

<p dir="rtl">20 Reagents used in specific screening protocols and actively interacting or not interacting with catart engine materials. Examples of filling fluids and filling fluid formulas suitable for use with the methods and apparatus described herein are provided in Srinivasan et al, International Patent Application No. 027894/2010, titled “Modified Fluids and Methods, Droplet Actuators,” published June 3, 2010; Srinivasan et al, International Patent Application No. 021173/2009, titled</p>

<p dir="rtl">25 “Use of Additives for Enhancing Droplet Operations,” published February 12, 2009; Sista</p>

et al., International Patent Application No. 098236/2008, entitled “Droplet Actuator Devices

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and Methods Employing Magnetic Beads,” published January 15, 2009; and Monroe et al., U.S. Patent Application No. 20080283414, titled “Electroetting Devices,” published on November 20, 2008, the disclosures of which are incorporated herein by reference, as well as other patents and patent applications. Sponsor the others mentioned here. Fluorinated oils may be tainted

<p dir="rtl">5 In some cases with fluorinated surfactants, e.g., Zonyl FSO-100 (Sigma Aldrich) and/or others. The filling fluid is ideally a liquid. In some embodiments, a filling gas may be used instead of the liquid.</p>

“Container” means a container or partial container adapted to hold, store or supply a liquid. A locomotive engine system according to the present disclosure can include reservoirs on the cartridge and/or reservoirs separate from

<p dir="rtl">10 cartridge. Reservoirs on a cartridge can be (1) on-actuator reservoirs, which are reservoirs in the distillation chamber or on the distillation surface; (2) off-actuator reservoirs, which are Reservoirs on the dropper cartridge, but outside the drip cavity, and not in contact with the drip surface; or (3) hybrid reservoirs that include areas above the drive and areas separate from the drive. An example of a separate reservoir is</p>

<p dir="rtl">15 The motor is a storage unit located in the upper bracket. An armature reservoir is ideally connected across the fluid to an orifice or flow path provided for fluid to flow from the armature reservoir into a distillation cavity, such as in a motor mounted reservoir. A reservoir separate from the cartridge can be a reservoir that is not part of the cat-art drive cartridge at all, but serves to flow fluid into some part of the cat-art drive cartridge. For example, a magazine separate from the cartridge could be:</p>

<p dir="rtl">20 The part of the system or installation station to which the catart drive cartridge is coupled while it is in operation. Likewise, a reservoir separate from the cartridge can be a reagent storage container or a syringe used to direct a fluid into a reservoir on the cartridge or into a distillation chamber. A system using a separate cartridge reservoir will ideally include a fluid passage means so that the liquid can be transferred from the separate reservoir into the reservoir on the cartridge or into a drip chamber.</p>

<p dir="rtl">25 The terms "top," "bottom," "top," "under," and "over" are used throughout the description in reference to the relative positions of the flow cell and/or drop-art motor components, such as the relative positions of the overhead pedestals</p>

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and the bottom of the flow cell and/or train engine. It will be understood that the flow cell and/or motor drive is flown regardless of its orientation in empty space.

A fluid in any form (e.g., a droplet or continuous object, whether moving or stationary) is described as being “on,” “at,” or “on” an electrode, matrix, tissue, or surface. This fluid can be in contact

<p dir="rtl">5 Directly with an electrode/matrix/tissue/surface, or may be in contact with one or more layers or membranes placed between the liquid and the electrode/matrix/tissue/surface. In one example, the filling fluid can be thought of as a membrane between that fluid and the electrode/matrix/tissue/surface.</p>

When a droplet is described as being “atop” or “mounted on top” of a dropper motor, it should be understood that the droplet is equipped on the dropper motor in such a way as to facilitate the use of the dropper motor to perform one or more distillation operations.

<p dir="rtl">10 On the droplet, the droplet on the droplet motor is equipped in such a way as to facilitate the sensing of a property or signal from the droplet, and/or the droplet undergoing a distillation process on the droplet motor.</p>

Embodiments described herein may include methods, systems, apparatus, and equipment for biological or chemical analysis using a magnetic sensing scheme. For example, embodiments may use magnetic sensing detection to base the detection and discrimination during synthesis by a series protocol. You can play many

<p dir="rtl">15 The models provide methods for the synthesis of serially based magnetic biosensing on a flow cell and/or integrated CMOS engine. In some embodiments, the flow cell may include one or more channels defined by surfaces that may include die strands transferred thereto. Different solutions can be directed through the channels, according to a predetermined scheme, to deliver reagents for the synthesis sequence by series. In other embodiments, the reagents may be delivered by cat</p>

<p dir="rtl">20 Which is controlled on a catart engine.</p>

In some embodiments, the synthesis sequence may be carried out by cascade through a single vessel reaction (also referred to as one-vessel synthesis). For example, the primers may be simultaneously supplied with a rice polymer, reversibly inhibited nucleotide analogs, and deblocking agents. Nucleic acids, rice polymers, reversible nucleotide analogues and deblocking agents are present.

<p dir="rtl">25 In real-time interaction. Polymerases are able to catalyze the addition of a reversibly reversible single nucleotide analogue to the primer to form an extended primer that has a reversible 3' end. Disablement removal agents are able to dismantle</p>

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Immobilizing the 3' end of the extended primer so that the resulting nucleotide analogues can be added to the extended primer. In yet another embodiment, the nucleotides may not include a 3'-hinder and no de-hindering factors are added. Changes in resistance can be monitored in real time as the rice polymer contains successive nucleotides. These models can apply specifically to the analysis of single molecules. Because the 5 reagents are simultaneously present, the starting material can be extended sequentially to introduce multiple nucleotide analogues into a single angiogenic reaction. At least one advantage of a single vessel reaction is that reagent agents need to be added to the reaction rather than removed from the reaction, thus reducing reagent residue generated by repeated fluid transfers and increasing the time change of the reaction by reducing time-consuming fluid transfer steps. The sequence of synthesis by the sequence through individual angiogenic reactions 10 is described in US Patent Application Publication No. 2013/0085073, which is incorporated herein by reference.

During single-strand interactions, magnetically responsive sensors actively monitor the complementary strand and detect the addition of a nucleotide to the strand. In these embodiments, either the nucleotide or the polymer may include a magnetic particle attached thereto. For example, each nucleotide type may include a 15-magnetic particle (or particles) that give a unique magnetic property such that the nucleotide is recognizable

Other types of nucleotides. In other embodiments, the polymer may include magnetic particles attached thereto. As shown here, different nucleotide types can have different insertion rates so that models can determine which type of nucleotide is added.

As shown herein, the template strands can be transferred in some embodiments to, for example, the surface of a flow cell.

<p dir="rtl">20 In other embodiments, however, the polymerase may be transferred to the surface of the flow cell. The polymer can be transported to a small reaction room or chamber. For example, the polymer rice can be placed at a small size (e.g., on the zeptoliter scale) such that freely dispersed magnetic particles can be effectively distinguished from those stably bound to the polymer rice, based on the time the signal is present. Each size can be assigned to one or more magnetically responsive sensors. .</p>

<p dir="rtl">25 Polymers can be transferred to a surface using known binders. Examples of these ligands include: N-hydroxysuccinimide esters (NHS-esters), iso compounds</p>

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Isocyanates, and isothicyanate linker to amines, maleimides to cysteines, click-chemistry with azides to alkynes, use of fusion tags such as Spycatcher-Spytag, Halotag, etc. Another method of bioconjugation similar to protein-protein 5. For more information about the ideal links that can

For its use, see the following references, the entire contents of which are incorporated herein by reference: Hermanson,

“Peptide tag forming a, 2008; Zakeri et al., Elsevier, 2nd Ed., Bioconjugate Techniques

“PNAS, through engineering a bacterial adhesin, rapid covalent bond to a protein” Specific Enzyme Immobilization, 109(12): E691-E697 (2012); and Liu et al.

Topics in Catalysis 55(16-18): Approaches and Their Application with Nanomaterials 10, 1146-1156 (2012).

In one illustrative embodiment, the reduced thiol group (SH) (also called the sulfhydryl group) of a cysteine residue can be reacted with a phase having a reactive thiol group. Examples of such groups include maleimide and iodoacetamide.

<p dir="rtl">15 Basic thiol-reactive reagents, including iodoacetamide, maleimide compounds, benzylic halides, and bromomethylketones, which can be reacted by S-alkylation of thiol compounds to generate stable thioether products; And the treatment of arylating reagents such as 7-2-3-oxadiazole (NBD,1,nitrobenz) compounds, which can react with thiol compounds or 20 amine compounds via a substituent. Similar to aromatic halide halide by nucleophile; Because the thiolate anion is a better nucleophile than the neutral thiol, cysteine is more reactive above its pKa. Additionally, the group reactive with sulfhydryls includes haloacetyls, maleimides, aziridines, acryloyls, aryl curing agents, and vinylsulfones.</p>

<p dir="rtl">25 vinylsulfones, pyridyl disulfides, TNB thiol compounds (2-nitro-5-thiobenzoic acid), and disulfide reduction agents;</p>

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These groups can be attached to sulfhydryl compounds via alkyl treatment (e.g., by forming a thioether bond) or disulfide exchange (e.g., by forming a disulfide bond). Sulfhydryl exchange reactions may also be used appropriately.

Alternatively, amine compounds (NH2-) can be targeted. For example, basic amine compounds of a lysine unit

<p dir="rtl">5 The lysine structural and the polpypeptide N-terminus are relatively reactive. Amine residues can be targeted by N-hydroxysuccinimide ester compounds, which can form a stable amide bond, or covalent imidoester crosslinkers, which can react with basic amine compounds to form amide bonds. There are many compounds reactive with amine. For example, it includes synthetic chemical groups that can form chemical bonds with basic amine compounds</p>

<p dir="rtl">10 Isothiocyanate compounds, isocyanate compounds, acyl azide compounds, N-hydroxysuccinimide ester compounds, sulfonyl chlorides, aldehydes, glyoxals, epoxides, oxiranes, carbonates, aryl halide compounds halides, imidoesters, carbodiimides, anhydrides, and fluorophenyl esters</p>

<p dir="rtl">15 fluorophenyl esters; These groups can be conjugated to amine compounds, for example, via acylation or alkyl treatment. In still other embodiments, an amino acid modified residue can be used to introduce a new functional such as an azide or an alkene to be used in a click reaction. For example, a thiol or amine reaction such as the one described above can be used with ligands that allow for the functional addition of an azide or alkene to also be used in a click chemistry reaction.</p>

<p dir="rtl">20 In some embodiments, the sequence can be carried out by causing a particular reaction which binds to two moieties or separates (e.g., cleaves) two moieties. In many cases, a particular reaction can be induced chemically or enzymatically. In some embodiments, however, the The specific reaction is produced by changing the temperature or electrical property that is experienced by the reactants.</p>

In some embodiments, the magnetic particles have stable or homogeneous magnetic properties or states.

<p dir="rtl">25 For example, magnetic properties can provide a constant or uniform magnetic field. In other embodiments, however, the magnetic property or state may be induced or tunable. For example, maybe</p>

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Modifying magnetic properties from one state to another by applying electromagnetic energy of a specific frequency. Many models also include a detection system and/or device. As used herein, the “detector” includes an array of magnetically responsive sensors and a chamber that allows a fluid to flow through it in close proximity to the magnetically responsive sensors. In many embodiments, the detector includes a solid-state device.

<p dir="rtl">5 The fluid flow may be, for example, a continuous flow of liquid, such as those described in US Patent Application Publication No. 2015/0079596, US Patent No. 8951781, and 2015/089092, each of which are incorporated by reference. How much do I come back? Alternatively, fluid flow can also be directed through distillation processes, such as electrowetting processes, which are described in more detail here.</p>

<p dir="rtl">10 Embodiments may include a scheme for the series synthesis of a magnetic biosensor based on magnetoresistance and/or vortex electronics. For example, a flow cell or high-density train motor could include a magnetic sensor array based on massive magnetoresistance devices and/or tunneling magnetoresistance devices. Massive magnetoresistance devices and tunneling magnetoresistance devices can also be referred to as massive magnetoresistance sensors or tunneling magnetoresistance sensors.</p>

<p dir="rtl">15 respectively. In certain embodiments, the magnetic sensor array can be used to detect an amplified clonal population of doxyribonucleic acid or individual strands of doxyribonucleic acid tagged with magnetic particles. Magnetic particles can be, for example, nano-sized magnetic particles and/or single-molecular magnets.</p>

As used herein, an array of magnetically responsive ARTS sensors includes an array of ARTS sensors 20 having a specific arrangement. The array may include sensors placed side by side in a mesh or fabric array (e.g., 10 rows and 10 columns) or the sensor array may include a more dispersed, heterogeneous array. In some embodiments, the magnetically responsive sensors of the array may be located next to each other Some directly without any intervening element. In other embodiments, however, the magnetically responsive sensors can be unloaded from the matrix to each other. Optionally, 25 other elements (e.g., electrodes) can be placed between adjacent magnetically responsive sensors.

In some embodiments, biological or chemical samples may be selectively placed adjacent to one or more of...

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The sensor responds magnetically to the array before detecting signals. For example, each magnetically responsive sensor can be assigned to a corresponding area or volume (commonly referred to as a mapped space) so that

The magnetically responsive sensor detects an external magnetic field from the designated vacuum. As a specific example, template strands may be transferred to a surface or texture placed at a designated blank. As another example, it could

<p dir="rtl">5 Place the biological or chemical sample in a cavity (for example, an eye) placed over one or more of the objects</p>

Magnetically responsive ART sensor.

Alternatively, biological or chemical samples can include positions of unknown length

Magnetic sensor array before detection. In these embodiments, it can only be determined after detecting whether magnetic particles are present in the designated spaces of the magnetically responsive sensors.

<p dir="rtl">10 In these embodiments, one or more of the magnetically responsive sensors may be unable to detect a biological or chemical sample. In other embodiments, there can be a plurality of magnetically responsive sensors in the vicinity of an individual sample such that each plurality of sensors can detect the same magnetic particle or can detect different magnetic particles associated with the same sample.</p>

<p dir="rtl">15 As used herein, phrases such as “array of [elements]” or “array of [elements]” and the like, when used in detailed descriptions and safeguards do not include every element that a component may contain. A component can include other elements similar to an element set. For example, the phrase “a group of magnetically responsive sensors [having a stated property]” does not necessarily mean that each magnetically responsive sensor of a detector has the stated property. May not include magnetically responsive sensors</p>

<p dir="rtl">20 Other mentioned property. Therefore, unless explicitly stated otherwise (e.g., “each magnetically responsive sensor [has a stated property]”), embodiments can include similar elements that do not include properties</p>

mentioned.

Both magnetically responsive sensors can be used to detect a change in electrical resistance. For example, each magnetically responsive sensor may have an electrical resistance associated with it.

<p dir="rtl">25 A magnetically responsive sensor can detect changes in electrical resistance that are caused by, for example, a magnetic property of a material placed near the responsive sensor.</p>

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Magnetically. As used herein, a “magnetic property” can include a magnetic field, magnetic direction, or magnetic moment. The magnetic property can be produced by materials exhibiting paramagnetism, weak magnetization, ferromagnetism, and antiferromagnetism. The magnetic property can also be caused, at least in part, by the spin of electrons in the material. In some models,

<p dir="rtl">5 The magnetic property can be unchangeable. In other cases, however, the magnetic property can be modified or induced.</p>

For example, a magnetoresistance sensor could include the implementation of a layer that includes electrical resistance capable of changing when in the presence of a material with a particular magnetic property. For example, magnetic particles can include magnetic fields or corresponding magnetic moment values that cause a change in...

<p dir="rtl">10 Resistance. A magnetoresistance sensor may include a first electrical resistance when an external magnetic field is not present and a second electrical resistance when an external magnetic field is not present. Likewise, a tunneling magnetoresistance sensor may include an insulating layer that detects a tunneling current. The flow of tunneling current is impeded by the electrical resistance of a tunneling magnetoresistance sensor. A tunnel magnetoresistance sensor may include a first electrical resistance where it does not</p>

<p dir="rtl">15 Magnetic material is present and electrical resistance is second when magnetic material is present. The models here are able to determine the difference in electrical resistance to determine if magnetic material is present. In some cases, a magnetic material can have different magnetic properties. Therefore, models may be able to distinguish different magnetic fields and/or magnetic moment values.</p>

<p dir="rtl">20 For each magnetically responsive sensor, a detector circuit, such as the circuit in a readout circuit, can emit signals associated with electrical resistance at the magnetically responsive sensor. For example, the circuit may be electrically coupled to one or more layers of a magnetically responsive sensor, such as one of the ferromagnetic layers and/or one of the non-magnetic layers. Signals resulting from the presence and absence of external magnetic fields can be compared to detect a change in electrical resistance. maybe</p>

<p dir="rtl">25 Determining the change in electrical resistance determines whether magnetic particles are present when signals are transmitted. For example, a fundamental change in electrical resistance could indicate that magnetic particles...</p>

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present. Furthermore, in some embodiments, the magnitude of the change can be analyzed to determine the type of magnetic particle present or the number of magnetic particles present. In other words, models can be configured to (a) detect whether any magnetic field is present at a given void or (b) determine the strength of the magnetic field present at a given void. With this data, models may be able to determine

<p dir="rtl">5 Useful information related to the biological or chemical sample. Useful information could be, for example, the identity of a nucleotide or a DNA sequence.</p>

As described above, models can receive signals, which represent electrical resistance, both when magnetism is present and when magnetism is absent. This data can be analyzed to determine the change in electrical resistance. Understand that models also receive signals when they include the property

<p dir="rtl">10 Magnetism is a first state or quality and when the magnetic property includes a different second state or quality.</p>

Again, this data can be analyzed to determine the change in electrical resistance. For example, a magnetic material may include a magnetic property that is modified or induced. As one example, a single-molecular magnet particle could be sensitive to a different set of light-on/on frequencies. The magnetic state of a single-molecular magnet particle can be modified by providing a light on/off switch. Therefore, it can

<p dir="rtl">15 The models compare the signals received after repeatedly turning the light on to the signals received after repeatedly turning the light off.</p>

The examples shown below involve determining changes in electrical resistance produced by magnetic fields alone. It will be understood, however, that these variations can be caused by other magnetic properties (e.g., magnetic direction and/or torque) which are implementation dependent.

<p dir="rtl">20 In certain embodiments, devices and methods can be used to sequence amplified clonal clusters of doxyribonucleic acid or single strands of doxyribonucleic acid.</p>

In certain embodiments, nucleotides are tagged with a hapten activator and nano-sized magnetic particles are used to detect and recognize a nucleotide insertion event into the synthesis scheme by succession to a magnetic biosensor.

<p dir="rtl">25 In certain embodiments, nucleotides tagged with single-molecule magnets are used to detect and tag the base in the synthesis scheme by succession to a magnetic biosensor.</p>

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In certain embodiments, unlabeled oligonucleotides and an activated doxyribonucleic acid polymer are used to detect and tag the base in the synthesis scheme by succession to a magnetic biosensor. In one example, the rice doxyribose DNA polymer is functionalized (tagged) with a magnetic particle, such as a single-molecule magnet.

<p dir="rtl">5 1.1 Magnetoresistance ART sensor for doxyribose DNA sequences</p>

Embodiments described herein include methods, systems, apparatus, and equipment for biological or chemical analysis using a magnetic sensing scheme. For example, embodiments may include devices and methods for using magnetic biosensing of a DNA sequence, such as to support a sequence-mediated synthesis scheme for a magnetic biosensor. Specifically, one or more embodiments provide a flow cell and/or

<p dir="rtl">10 Engine QART includes a scheme for the sequential synthesis of a magnetic biosensor based on magnetoresistance and/or spintronics. Magnetic resistance is the property of a material to change its electrical resistance value when an external magnetic field is applied to it. Certain materials (and multilayer devices) exhibit colossal magnetoresistance (CMR), tunneling magnetoresistance, and extraordinary magnetoresistance.</p>

<p dir="rtl">15 magnetoresistance (EMR). Generally, resistance can be based on either magnetization (controlled by an applied magnetic field) or a direct magnetic field. Spiral electronics, also known as spinelectronics or fluxtronic, is a fusion technology that exploits the inherent spin of an electron And the associated magnetic moment, in addition to its fundamental electronic charge, in solid-state devices</p>

<p dir="rtl">20 Vortex Electronics Vortexes are modified not only by magnetic fields, but also by electric fields.</p>

One or more embodiments may use, for example, a massive magnetoresistance-based and/or tunneling magnetoresistance-based array of sensors. Whereas the detection mechanisms of traditional series synthesis devices require large and expensive optical systems, they can be implemented

<p dir="rtl">25 Sensors based on massive magnetoresistance and/or magnetoresistance</p>

Tunneling affects well-known semiconductor manufacturing processes for making memory arrays, which can

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Use them to cheaply manufacture magnetic sensor arrays. Also, using these well-known semiconductor fabrication processes, high-density magnetic sensor arrays can be implemented in a synthesis scheme by cascading a magnetic biosensor, e.g., in a flow cell and/or a train motor.

<p dir="rtl">5 In doing so, the models could provide an inexpensive and portable non-optical sequencer where (1) even complex biological samples require a detectable magnetic background signal, (2) biological samples do not interfere with the magnetic transduction mechanism, and) 3) Contamination from salt, pH, background fluorescence is not a problem relative to magnetic biosensing. Also, one or more models can lead to diagnostic processes (blood, metabolites</p>

<p dir="rtl">10 cell analysis, saliva, urine, etc.). Relative to succession, these properties are subject to single molecule detection (in some embodiments the kits still include an advantage in terms of accuracy) and minimal sample preparation applications. Figures 1a and 1b illustrate a top view and a cross-sectional view, respectively, for an example of a system 100. In the embodiment shown, the system 100 includes a detector (or detection device) 102, a fluid control system 104 (Figure 1a) that is flow-connected to the detector 102, a reader circuit 106 (Figure 1a),</p>

<p dir="rtl">15 and an analysis circuit 105 (Figure 1a). The detector 102 includes a magnetic sensor array 110 to support, for example, a series synthesis scheme for a magnetic biosensor. For example, a detector 102 includes a substrate 108 that includes a printed circuit board 112 and a magnetic sensor array 110 mounted on a board. Printed circuit 112. The detector 102 also includes an upper substrate (or flow cell) 114 provided relative to the magnetic sensor array 110. The sensor array is positioned</p>

<p dir="rtl">20 The magnet 110 is located along the surface of a substrate 109 (Figure 1b) of the lower substrate 108. A chamber or cabinet 118 is defined between the surface of the substrate 109 and the upper substrate 114. The magnetic sensor array 110 can include an array of sensors positioned near certain voids in the chamber 118. For example, the sensor may include exposed surfaces defining the chamber 118. Alternatively, one or more layers (e.g., a passivation layer) may be placed between the chamber 118 and the</p>

<p dir="rtl">25 Magnetic sensor 110. For example, the surface of the substrate 109 may be defined by a passivation layer. In the illustrated embodiment, the upper substrate 114 and the lower substrate 108 are separated by spacers</p>

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<p dir="rtl">116. In other embodiments, the upper substrate 114 can be configured to form a chamber 118 when the upper pillar 114 is mounted on the lower pillar 108.</p>

The top substrate 114 can be, for example, a glass substrate or a plastic substrate. In one example, the top substrate 114 includes a thickness of approximately 400 micrometers. In one example, the spacers are 116 phrases

<p dir="rtl">5 About adhesive spacings of approximately 100 micrometers in height. In another example, the spacers 116 are lifting means integrated with either the top or bottom substrate and are approximately 100 micrometers in height. The sequential chamber 118 is a flow channel provided with an inlet 120 and an outlet 122 in the upper bracket 114. Specifically, liquid can flow to/from the sequential chamber 118 using the inlet 120 and outlet 122.</p>

<p dir="rtl">10 In one example, the magnetic sensor array 110 is a 10 x 10 matrix where the pitch of the magnetically responsive sensor can vary, for example, from about 10 µm to about 100 µm. In another example, the magnetic sensor array 110 includes a high-density, CMOS-based magnetic sensor array, such as an 8000 x 8000 array where the magnetically responsive sensor pitch is about 200 nm (for all 64 Mbit devices), or</p>

<p dir="rtl">15 100,000 x 100,000 array wherein the magnetically responsive sensors are about 100 nm (for 10 Gbit current devices). In one example, the magnetic sensor array 110 is a 100 nm x 400 nm device.</p>

The magnetically responsive sensors forming the magnetic sensor array 110 can be, for example, massive magnetoresistance-based devices or electromagnetic sensors or devices based on

<p dir="rtl">20 Tunnel magnetoresistance or sensor. Massive magnetoresistance-based or tunneling magnetoresistance-based devices can be used, for example, to detect amplified clonal groups of DNA or single strands of DNA labeled with, for example, nano-sized magnetic particles and/ Or single-molecule magnets. The system 100 can be used for other applications, such as diagnostic applications, where probes or others</p>

<p dir="rtl">25 Of moieties that have magnetic particles that selectively attach to specific biological or chemical targets. As shown in Figure 1a, the reader circuit 106 is separated from the detector 102. In other embodiments,</p>

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However, the readout circuitry 106 can be fully integrated with the detector 102. For example, the detector 102 can include a solid-state device, such as a CMOS, including circuitry that configures at least part of the readout circuitry 106. In some embodiments, the readout circuitry 106 can be fully integrated with the detector 102. The lower substrate includes 108 CMOS devices.

The readout circuit 106 is communicatively coupled to the magnetically responsive sensors forming the array 110. 5 The readout circuit 106 is configured to transmit signals, which may be based on (pilot or analog) resistors

Electrical conductivity of magnetically responsive sensors, analysis circuit 105. Reading circuit 106 includes conductive paths. In some embodiments, the readout circuit 106 includes circuitry configured to modulate the signals before transmitting the signals to the analysis circuitry 105. For example, the readout circuit 106 can amplify signals, digitize signals, shift signals based on a look-up table, etc. Alternatively, the readout circuit 106 10 does not modify the signals before transmitting the signals to the analysis circuit.

In some embodiments, the read circuit 106 determines the electrical resistance at the magnetically responsive sensors and transmits this data to the analysis circuit 105. In other embodiments, the read circuit 106 transmits raw data to the analysis circuit 105 and the analysis circuit determines the electrical resistance at Each sensor is magnetically responsive. Electrical resistance can be calculated using Ohm's law or another 15-log algorithm based, at least in part, on Ohm's law. Electrical resistance can be calculated, for example, by supplying information (for example, a detected current or voltage) to a lookup table that converts the information into a signal or value representing the electrical resistance.

The analysis circuit 105 is configured to receive (directly or indirectly) signals from the readout circuit 106 and analyze the signals according to one or more predetermined formulas/algorithms to provide useful information. 20 Optionally, the analysis circuit 105 may be integrated with the detector 102. E.g. The analysis circuit may be installed on the bottom bracket 108.

The reading circuit 106 and/or analysis circuit 105 may analyze a detected change in electrical resistance at each of the magnetically responsive sensors. As used here, the phrases “determine a detected change in electrical resistance” (etc.) are not intended to be restricted to a simple mathematical calculation.

<p dir="rtl">25 In some cases, the only information necessary is whether electrical resistance (or another property that indicates electrical resistance, such as current or voltage) meets the given conditions. For example, if</p>

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The electrical resistance is less than a certain value, then the reading can be designated as a positive reading (i.e., the magnetic particle is present in the designated void). If the electrical resistance is above a certain value, then the reading can be designated as a negative reading (i.e., (with no magnetic particles present). In the above example, the amount by which the electrical resistance differs from a given value is irrelevant. The question is only whether

<p dir="rtl">5 The electrical resistance is above or below the specified value.</p>

In other embodiments, however, the amount of variation in electrical resistance (or other electrical properties) from a given value can be useful. For example, the amount of change in electrical resistance can indicate the strength of the magnetic field. The strength of the magnetic field can, in turn, correspond to With the number of magnetic particles and/or the type of magnetic particles in a given blank.

<p dir="rtl">10 Therefore, the step of determining a detected change in electrical resistance may include (a) determining whether a change exists and/or (b) determining the amount of change. Furthermore, the step of determining a detected change in electrical resistance using values that Refers to other electrical properties (e.g., current, voltage).</p>

According to one example, the result of a detected change can be determined by finding the difference between the first 15 detected values (for example, the limit electrical resistance value, the limit current value, or the limit voltage value)

that is obtained at a first time period, such as after a slit operation, and a second detected value obtained at a subsequent second time period, such as after an insertion event.

As another example, a disclosed change can only be determined after receiving an individual disclosed value. For example, each magnetically responsive sensor in the array can be assigned a certain threshold or baseline value. maybe

<p dir="rtl">20 Identify a reading as positive or negative by comparing this particular value to the disclosed value. In other embodiments, the disclosed value is applied to a lookup table, which can be output. The output can indicate the strength of the magnetic field, which can, in turn, correspond to the number of magnetic particles and/or the type of magnetic particles in the given spaces.</p>

In other embodiments, the disclosed value may be compared to a range of different values. can correspond

<p dir="rtl">25 Each of these values has a different type of magnetic particle. For example, if the detected value is approximately equal to the first magnitude, then it could be the first type of magnetic particle in the given vacuum.</p>

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If the detected value is approximately equal to the second volume, then there could be a second type of magnetic particle in the given void. Likewise, the disclosed value can be compared to a range of different value ranges. If the detected value is in the first range, then it can be the first type of magnetic particle in the given vacuum. If the detected value is in the second range, then 5 could be the second type of magnetic particle in the given space.

The disclosed value can represent a single value obtained at one time. In some cases, however, the disclosed value may be obtained over a predetermined time period or over multiple predetermined time periods. For example, the disclosed value can be the maximum or minimum value detected during the time period or it can be the average value 10 detected during the time period. In other embodiments, the duration of the change in electrical resistance also provides useful information.

The analysis circuit 105 is configured to analyze detected changes to provide useful information related to the biological or chemical sample. For example, the analysis circuit 105 may identify or alert that a nucleotide has been added for each synthesis event by successively identifying a nucleic acid sequence. 15 The sequence-by-sequence synthesis event can include one or more steps to cause the addition of a nucleotide to a sequence.

complement and one or more steps to detect the addition. The synthesis event by sequence can involve the addition of a single nucleotide to a set of assemblies (e.g., hundreds, thousands of assemblies) or it can involve the addition of a single nucleotide to a complementary single strand. Several methods for identifying a nucleotide are described here. The methods can include the processes described above To detect changes in electrical resistance 20, for example, in some embodiments, only a single detected change is suitable for determining the nucleotide

In other models, two or more detected changes can be compared to identify a nucleotide.

In some embodiments, the nucleotide and/or sequence may be identified by comparing, for each synthesis event by sequence, the detected changes associated with a plurality of magnetically responsive sensors. For example, if a first magnetic effector sensor has a first electrical resistance, and a second magnetic effector 25 sensor has a different second electrical resistance, then it can be determined that the magnetic particles

Which are detected by the first and second sensors are different. If there is a third sensor

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The magnetically responsive sensor has an electrical resistance that is essentially equal to the electrical resistance of the four magnetically responsive sensors, so it can be determined that the magnetic particles detected by the three and four sensors are the same.

In some embodiments, the nucleotide can be named and/or a sequence can be identified by comparing the detected changes

<p dir="rtl">5 It is linked to each magnetically responsive sensor. For example, following a series synthesis protocol, a magnetically responsive sensor could have hundreds of different readouts associated with it. Each read can correspond to one of the four bases integrated within the complementary strand. Based on the assumption that magnetic particles of the same type (or number) will give the same changes in electrical resistance, nucleotides can be labeled for each read.</p>

<p dir="rtl">10 The reading circuit 106 and/or analysis circuit 105 may include a program and/or software system that performs one or more functions. For example, read circuit 106 and/or analysis circuit 105 is a computer processor, control device, or other logic-based device that performs operations based on instructions stored on a tangible, non-transitional, computer-readable storage medium, such as computer memory. Alternatively, the reading circuit 106 and/or analysis circuit 105 may include a</p>

<p dir="rtl">15 Hard-wired device performs operations based on logic that is wired to the device.</p>

The reading circuit 106 and/or analysis circuit 105 may include or provide a program and related instructions (e.g., a program stored on a tangible, non-transitory storage medium readable by a computer, such as a computer hard drive). 20 random access memory (RAM), read-only memory (ROM), or similar, which performs one or more of the operations described here. The software may include electronic circuits that include and/or are connected to one or more logic-based devices, such as microprocessors, processors, controls, or the like. These devices may be off-the-shelf devices that are suitably programmed or that issue instructions to perform operations described herein from the instructions described above. Additionally or alternatively, one or more than 25 of these devices may be wirelessly connected to a logic device to perform these operations.

As used herein, a structure, restriction, or element that is "configured to" perform a task or operation configured with a specific structure

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Specifically, constructed, or configured in a way that corresponds to a task or process. For clarity and avoidance of doubt, an intent that can be modified to perform a task or operation is not “configured to” perform a task or operation as used herein. Instead, the use of “configured to” as used here refers to structural configurations or properties, and refers to a structural requirement for any structure, restriction, or element that is marked as “configured to” to carry out a task or process. For example, it can be understood

<p dir="rtl">5 A read circuit or analysis circuit “configured to” perform a task or process as being configured to carry out the task or process (e.g., having one or more programs or instructions stored on it or used in connection with or intended to carry out the task or process, and/or (Has processing equipment (a circuit designed or required to perform a task or operation).) For clarity and avoidance of doubt, a general purpose computer (which can be “configured to” perform a task or operation if appropriately programmed) is not “configured to” perform a task or operation unless It is programmed</p>

<p dir="rtl">10 Or modify it structurally to implement the task or process. Furthermore, it will be noted that the operations implemented by the reading circuit 106 and/or analysis circuit 105 (e.g., operations corresponding to the operations or methods described herein, or aspects thereof) can be sufficiently complex that the operations can be performed by a human In a reasonable period of time.</p>

The system and/or detection device may also include a fluid control system configured to flow reagent agents,

<p dir="rtl">15 According to a certain scheme, during the room to carry out a predetermined protocol. A fluid control system includes a network of channels, which may be configured by pipes, flow cells, or other fluid devices. The flow may be controlled by one or more valves and pumps that are selectively activated to deliver the desired reagent. The protocol may be a series synthesis protocol where reagents are provided, including a combination of oligonucleotides, enzymes (e.g., rice polymerase), or other</p>

<p dir="rtl">20 Reaction components, into the designated spaces to extend template strands. The fluid control system may be similar to or operate in a manner similar to the systems described in U.S. Patent Application Publication No. 2015/0079596 and 2015/0045234; b American Patent Nos. 8,951,781 and 8,173,080; and International Application Nos. 143010/2014 and 089092/2015, which are incorporated herein by reference. After or during each input event, the readout circuit can broadcast signals to the analysis circuit.</p>

<p dir="rtl">25 In some embodiments, the fluid control system provides a continuous flow of reagents. In other embodiments, however, the detector 102 includes a train motor. For example, one could include:</p>

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Less than the upper and lower pillars 114, 108 electrodes to carry out distillation operations. The electrodes may be positioned or distributed interfacially in the magnetic sensor array 110. Alternatively, the magnetic sensor array 110 may be positioned versus the electrodes within the chamber 118 in relation to each other in other embodiments. Figures 2a and 2b show an example of a massive magnetoresistance device 200 and a magnetoresistance device

<p dir="rtl">5 tunnel 205, respectively. Both the massive magnetometer 200 and the tunnel magnetometer 205 include a pair of ferromagnetic layers separated by a nonmagnetic layer.</p>

Referring to Figure 2a, the mega-resistance device 200 includes a first ferromagnetic layer 210, a non-magnetic layer 212, and a second ferromagnetic layer 214.

<p dir="rtl">10 The non-magnetic layer 212 is between the ferromagnetic layer 210 and the ferromagnetic layer 214. The ferromagnetic layer 210 and the ferromagnetic layer 214 are ferromagnetic alloys. The nonmagnetic layer 212 is an ultra-thin, nonmagnetic, electrically conductive layer (e.g., a copper layer).</p>

Figure 2a shows a massive anti-magnetic device 200 in two cases, where the direction of the magnetization in 15 the ferromagnetic layer 214 is fixed using a stabilizing layer (not shown) above the ferromagnetic layer 214. First, the magnetic moments in the ferromagnetic layer 210 and the ferromagnetic layer 214 are opposite directions. Opposite due to ferromagnetic coupling in this case, the resistance to current (I) is high. The non-magnetic copper layer 212 is naturally an excellent conductor, but only a few atoms thick. The scattered electron increases the resistance of the copper.

<p dir="rtl">20 Significantly. These changes in resistance dependent on the relative orientation of the electron rotate the surrounding implementing layer (i.e., the non-magnetic layer 212).</p>

Subsequently, the state of the antiferromagnetic device 200 can be changed by applying an external magnetic field (H) which overcomes the antiferromagnetic coupling and aligns the magnetic moment values in the ferromagnetic layer 210 and the ferromagnetic layer 214.

<p dir="rtl">25 Use exposure to external magnetic field (H) variations (i.e., dips) in the resistive structure of the device so as to sense an external field. Practical devices are often made of many layers</p>

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Interchangeable magnetic and non-magnetic layers for improved sensitivity. The change in resistance in a Mega-Resistance 200 device is subjected to a magnetic field ideally from 10% to about 20%, which is greater compared to the lower maximum sensitivity of other types of magnetic sensors.

<p dir="rtl">5 Referring to Figure 2B, the tunneling magnetoresistance device 205 includes the ferromagnetic layer 210, the nonmagnetic layer 212, and the ferromagnetic layer 214. However, where the nonmagnetic layer 212 in the massive magnetoresistance device 200 is electrically connected, in the tunneling magnetoresistance device 205 The non-magnetic layer 212 is a thin insulating layer.</p>

When two ferromagnetic layers separate (for example, ferromagnetic layer 210

<p dir="rtl">10 and the ferromagnetic layer 214) via a thin dielectric layer (e.g., non-magnetic layer 212), the electrical resistance of the multilayer in the direction perpendicular to the film changes depending on the directions of the magnetization processes of the ferromagnetic layers due to the spin-dependent electron tunneling between the two ferromagnetic layers. .</p>

Figure 2b shows a tunnel magnetoresistance device 205 in two cases, where the direction of the magnetization is fixed in

<p dir="rtl">15 Ferromagnetic layer 214 using a pinning layer (not shown) above the ferromagnetic layer 214. First, when the directions of the magnetization processes of the two ferromagnetic layers are opposite, electron transfer with the opposite spin orientation relative to the magnetization of the ferromagnetic layer cannot be achieved. Therefore, the tunneling electron current is smaller (i.e., has higher resistance) compared to the case with the same directions of magnetization processes. Then, when the directions of the two magnetization processes are</p>

<p dir="rtl">20 The ferromagnetic layers are the same, the probability of electron tunneling between the two ferromagnetic layers through the insulating layer becomes greater, resulting in a larger tunneling current (i.e., lower resistance).</p>

The design of a massive magnetoresistance device 200 according to Figure 2a and a tunnel magnetoresistance device 205 according to Figure 2b is based on parallel anisotropy, meaning parallel layer of magnetization processes.

<p dir="rtl">25 Free and installed with substrate level. However, the magnetic sensor array 110 can be based on a known geometry of a massive magnetoresistance/tunneling magnetoresistance device. In example</p>

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Else, the magnetic sensor array 110 can be based on massive magnetoresistance/tunneling magnetoresistance engineering designs that use perpendicular anisotropy rather than parallel anisotropy, meaning that the free and pinned magnetoprocess layer are perpendicular to the plane of the substrate.

Relative to the use of a magnetoresistive-based magnetic sensor array 110

<p dir="rtl">5 Massive/Magnetic Resistance Tunneling Flow Cell 100 To detect amplified clonal assemblies of DNA or single strands of DNA labeled with, for example, nano-sized magnetic particles and/or single-molecular magnets, Figure 3 shows an example of a scheme. 300 Sensitivity of a biochip has tremendous magnetic resistance using a single nano-sized magnetic particle. Referring to the 300 plot, the measured homogeneous field dependence on the pre-amplified signal shows that</p>

<p dir="rtl">10 The lowest detected change in the field is 0.1 Oe. A single nano-sized particle generates a homogeneous field of 0.12 Oe against the sensor area (by induction), which indicates that the biochip has enormous magnetic resistance that can perform detection of a single nano-sized particle (molecule). It can be expected that the use of assemblies including One or more doxyribonucleic acid template molecules increase the intensity of the readout signal.</p>

<p dir="rtl">15 Figure 4 is a cross-section view of a portion of the detector 102 shown in Figures 1a and 1b, and shows more detail of the magnetically responsive sensors of the magnetic sensor array 110. Again, the detector 100 includes the magnetic sensor array 110 mounted on a printed circuit board. 112. Figure 4 shows that the magnetic sensor array 110 includes an array of magnetically responsive art sensors 130. In some embodiments, a</p>

<p dir="rtl">20 Magnetic response sensors 130 in rows and columns. However, other ranges can be chosen</p>

Depending on the desired application. Each of the magnetically responsive sensors 130 may be, for example, a massive magnetoresistance-based device (e.g., a massive magnetoresistance device 200 according to Figure 2a) or a tunneling magnetoresistance-based device (e.g., a tunneling magnetoresistance device 205 According to Figure 2b). Both sensors can include magnetically responsive sensors

<p dir="rtl">25 130 The non-magnetic layer 212 is contained between the first ferromagnetic layer 210</p>

and the second ferromagnetic layer 214. In this example, the ferromagnetic layer is oriented

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The first 210 of each magnetically responsive sensor 130 towards the room 118. Also, the direction of magnetization in the second ferromagnetic layer 214 is fixed using a mounting layer 216 located adjacent to the second ferromagnetic layer 214. Although Figure 4 only illustrates the first and second ferromagnetic layers 210, 214 and the non-magnetic layer 212, it must be understood that other embodiments

<p dir="rtl">5 It may include more than two ferromagnetic layers and more than one non-ferromagnetic layer grouped relative to each other.</p>

As shown, each of the magnetically responsive sensors 130 is configured to detect an external magnetic field placed or generated in a designated void 131 or corresponding room 118. As used herein, the term “specific void” means a nearby void in which the particle can be detected Magnetic

<p dir="rtl">10 or particles by a corresponding magnetically responsive sensor. It should be understood that the specific size and shape of the void can be based on a variety of factors, such as the size and strength of the magnetic particles, the configuration of the magnetically responsive sensors (e.g., size, shape, and number of layers), or the sensitivity of the magnetically responsive sensors. The specified blank varies depending on the application although it is configured so that the magnetically responsive sensor can detect a field</p>

<p dir="rtl">15 External magnetic field located next to the designated blank of the sensor, this external magnetic field can be relatively weak and any signals can be identified as noise.</p>

In the illustrated embodiment, each of the mapped voids is only a portion or volume of room 118, which extends continuously along the side of the magnetic sensor array 110 such that adjacent mapped voids are not physically separated by something else, such as a wall. In other models, however, it can

<p dir="rtl">20 The designated spaces are physically separate from each other. For example, every given blank can exist in</p>

An eye or cavity defined by one or more walls. Grandparents can separate specific blanks. For embodiments that include drop engines, the designated void may be occupied by a drop when delivering reagents to the designated void. In these embodiments, the designated voids may be separated from each other by a filling fluid. However, it is also configured so that a single droplet can occupy many

<p dir="rtl">25 Of the thousand argat designated fo r.</p>

Additionally, Figure 4 shows that the detector 102 may include a layer 140 disposed between

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The magnetically responsive sensor 130 and the chamber 118. Figure 4 also shows that the detector 102 may include a conductive layer 150 placed along the upper substrate 114. The conductive layer 150 on the upper substrate 114 may, for example, be a layer of gold or tin oxide. Indium. In one example, the conductive layer 150 may be used as a reference Vdd level 5 that is not shared with all magnetically responsive sensors 130 for the magnetic sensor array.

<p dir="rtl">110 .</p>

Layer 140 may be composed of any hydrophilic material, hydrophobic material, or combination of a hydrophilic material and a hydrophobic material suitable for performing surface chemistry in chamber 118. Layer 140 can be, for example, from about 300 nanometers to about 400 nanometers thick. In one example, layer 140 is a 10 polyacrylamide gel polish, such as a mixture of norbornene, norbornylene, or

Norcampphene and Poly(5)-N-azidoacetamidylpentyl(acrylamide-co-acrylamide) Poly(N-(5-azidoacetamidylpentyl) acrylamide-co-acrylamide) (PAZAM). Find out more details about Poly(5) N-Pentyl azidoacetamidyl(acrylamide-CO-acrylamide) Referring to George et al., US Patent Application No. 784,368/13, titled “Polymer 15 Coatings,” filed on March 4, 2013, the full disclosure of which is incorporated by reference For reference.

In Figure 4, an array of oligonucleotide primers 142 is transferred onto a layer 140 in a chamber 118 and positioned relative to a magnetically responsive sensor 130 to a magnetic sensor array 110. In one example, the oligonucleotide primers 142 are primers upon which fragments are hybridized and amplified. Single-stranded doxyribose DNA to create assemblies of 20 clonal doxyribose DNA templates for synthesis by series.

As described herein, in some embodiments, a signal introduced during the synthesis reaction may be provided by, e.g., successively introducing a nucleotide tagged directly or indirectly with a magnetic particle and detected using a magnetically responsive arterial sensor 130 as described in more detail below. The magnetic particle could be, for example, a nano-sized magnetic particle or a monomolecular magnet25.

<p dir="rtl">1.2 Series synthesis based on nano-sized magnetic particle</p>

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In one embodiment, functionalized nano-sized magnetic particles and hapten-tagged nucleotides are used to detect a nucleotide insertion event into the synthesis scheme by successively a magnetic biosensor. In one example, nucleotides (C, G, A, and T) are treated with biotin and nano-sized magnetic particles are coated with streptavidin. For example, a single nano-sized magnetic particle type and four (4) 5 fluid cycles/detector are used for sequential addition of nucleotides In the synthesis cycle by succession.

Figures 5-12 illustrate several methods that can be implemented by the detection systems and devices mentioned here. For example, the method may include providing a detector including an array of magnetically responsive sensors. Each of the magnetically responsive sensors can be placed near a corresponding blank to detect an external magnetic field from it. The detector also includes a set of 10-strand nucleic acid templates placed in corresponding designated spaces. The method also includes performing a plurality of synthesis events by sequentially giving a complementary strand by inserting nucleotides along each template strand. At least some of the nucleotides are attached to corresponding magnetic particles which give off corresponding magnetic fields. Each set of synthesis events includes the detection of changes in electrical resistance at the magnetically responsive sensors generated by magnetic fields 15 corresponding to the magnetic particles. The method may also include determining sequences of complementary strands.

Complementary strand sequences are based on the detected changes in electrical resistance that occur at sensors responding magnetically to each set of synthesis events by series.

Figure 5 shows a portion of the flow cell 100 shown in Figures 1A, 1B, and 4 and depicts an example of the synthesis scheme by series for a magnetic biosensor 500. In the synthesis scheme by series 20 of a magnetic biosensor 500 an introduced biotin-treated oligonucleotide is used to capture a nano-sized magnetic particle. Coated with streptavidin and generated a detectable signal. In this example, DNA template strands 510 (i.e., DNA template strands 510a and 510b) formed in an assembly amplification process are transferred onto layer 140. The 510a DNA template strand is one template strand of a first clonal population and the 25doxyribose DNA template strand 510b is one template strand of a second clonal population.

Primers for sequences 515a and 515b are hybridized to the strands of the DNA template

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510a and 510b, respectively. In a base addition reaction, the biotin-treated nucleotide 520 is introduced to extend the starting material sequence 515. The biotin-treated nucleotide 520 is described in more detail by referring to Figure 6. In one example, the biotin-treated nucleotide 520 is deoxyadenosine triphosphate. The biotin-treated oligonucleotide 520 is incorporated into the complementary growth strand only on the acid template

<p dir="rtl">5 Nucleic acid deoxyribose 510b (i.e., deoxyadenosine triphosphate is not complementary to adding a base to the DNA template doxyribose 510a). A solution (not shown) containing an array of streptavidin-coated nano-sized magnetic particles 525 is followed in the sequencing chamber 118 of a cell Flux 100. The nano-sized magnetic particle 525 can be, for example, a nano-sized superparamagnetic particle with a diameter from about 10 nm to about 50 nm bound</p>

<p dir="rtl">10 The nano-sized magnetic particle 525 oligonucleotide treated with biotin 520 was introduced during the formation of the biotin-streptavidin binding complex. Unbound 525 nano-sized magnetic particles are removed by washing. The inserted nucleotide-tethered magnetic particle 520 modifies the resistance of the magnetic sensor 130b and the corresponding electrical signals are modified and measured. Since there is no nano-sized magnetic particle 525 attached to the DNA template strand 510a/</p>

<p dir="rtl">15 The starting material sequence 515a at a magnetic sensor 130a, the signal generated by the magnetic sensor 130a is different from the signal generated by the magnetic sensor 130b.</p>

Figure 6a shows a partial structural formula of the biotin-treated nucleotide 520 according to Figure 5. The biotin-treated oligonucleotide 520 includes a biotin tag 610. The biotin tag 610 is linked to base 615 of the nucleotide 520 via the cleavable linker 620. The 3′ hydroxyl (OH) group is protected. nucleotide

<p dir="rtl">20 520 by the blocking group 625. After inserting the nucleotide 520 into the DNA growth strand D</p>

Oxyribose Complementation and Detection (Magnetic Biosensing) Insertion event, the nano-sized biotin/streptavidin magnetic particle complex can be removed from the oligonucleotide 520 by the cleavable ligand 620. After removal of the nano-sized biotin/streptavidin magnetic particle complex, the detection signal is restored To background levels the blocking group 625 can be removed by the next entry unblocking interaction

<p dir="rtl">25 For the following biotin-treated nucleotide supplement.</p>

Figure 6b shows the partial structural formula of magnetically labeled nucleotide 650, which can be used

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In some models. The nucleotide 650 includes a base 655 and a magnetic particle 660 attached to a gamma phosphate 665 through a linker 670. A variety of linkers and a variety of magnetic particles may be used. Figure 7 illustrates a flow chart of an example method 700 for determining a base in a synthesis scheme by succession for a magnetic biosensor using, for example, the flow cell 100 shown in Figures 1A, 1B,

<p dir="rtl">5 And 4. Method 700 uses sequential addition of the biotinylated nucleotide (i.e., one nucleotide per</p>

one time) and one type of nano-sized magnetic particle coated with streptavidin for base identification. In one example, method 700 utilizes a synthesis scheme by successively a magnetic biosensor 500 according to Figure 5 and a biotin-treated oligonucleotide 520 according to Figure 6. Referring to Figure 7, method 700 includes , but not limited to, the following steps.

<p dir="rtl">10 At step 710, the biotinylated oligonucleotide 520 is first combined to give complementary deoxyribonucleic acid strands in a first base addition reaction of the synthesis cycle by straightening. The first oligonucleotide treated with biotin 520 can be delivered to the specific template strands. For example, a solution containing the first biotin-treated nucleotide 520 (e.g., biotin-treated nucleotide 520a) flows into the flow chamber 118 of the flow cell 100 and through designated spaces to allow the first biotin-treated nucleotide</p>

<p dir="rtl">15 520 to extend the growth of complementary strands. As another example, a drop of a solution containing a nucleotide can be delivered</p>

The first is biotinylated 520 to each specific blank using the distillation processes described here. The droplet can occupy the designated space for a predetermined period of time to allow the first nucleotide treated with biotinylate 520 to extend the growth of complementary strands. In one example, the first nucleotide is biotin-treated deoxyadenosine triphosphate.

<p dir="rtl">20 At step 715, nano-sized magnetic streptavidin particles are introduced into the flow cell. Nano-sized magnetic streptavidin particles can be delivered to specific gaps that have template strands and the first signal can be detected. For example, a solution containing nano-sized streptavidin magnetic particles 525 may be followed into the chamber 118 of the flow cell 100. The nano-sized streptavidin magnetic particles 525 are allowed to be captured by the biotinylated first nucleotide 520. E.g.</p>

<p dir="rtl">25 Nano-sized magnetic particles 525 can be captured via a biotin/streptavidin binding complex at the sites (aggregates). As another example, a drop of solution can be delivered to each specific blank using</p>

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Distillation processes described here. The droplet can occupy the designated space for a predetermined amount of time to allow nano-sized magnetic streptavidin particles to attach to the labeled nucleotides. After magnetic particles attach to the tagged nucleotides, a first signal can be detected. The signal could be a change in electrical resistance at the magnetically responsive sensors. It could be change

<p dir="rtl">5 In electrical resistance, it is produced by magnetic particles placed in the designated spaces.</p>

At step 720, the magnetic particles can be removed from the labeled nucleotides. For example, the nano-sized biotin/streptavidin magnetic particle complex can be removed from the introduced nucleotides 520 by the cleavable ligand 620. After removal of the nano-sized biotin/streptavidin magnetic particle complex, the signal is restored to background levels. The disability group 625 of nucleotides 520 is removed

<p dir="rtl">10 By a deamidation reaction for the subsequent insertion of the next complementary nucleotide.</p>

The sequence of synthesis continues by successive base addition reactions. In certain embodiments, second, third, and quadruple base addition reactions may be performed. For example, a solution containing the second biotin-treated nucleotide 520 (e.g., biotin-treated oligonucleotide 520b) is flowed into the flow chamber 118 of the flow cell 100. In one example, the second nucleotide is deoxyguanosine triphosphate treated

<p dir="rtl">15 With biotin.</p>

At step 725, nano-sized magnetic streptavidin particles are introduced into the flow cell and the second signal is detected. For example, nano-sized magnetic particles 525 are captured by a biotin/streptavidin binding complex at sites (aggregates) with a G insertion and a second signal is detected at the corresponding magnetic sensors 130.

<p dir="rtl">20 At step 730, the biotin/streptavidin nano-sized magnetic particle complex is removed from the introduced nucleotides 520 by the cleavable ligase moiety 620. The binding group 625 of the nucleotides 520 is removed by a debinding reaction for subsequent insertion of the next complementary nucleotide. The synthesis cycle is continued by a third addition reaction. For example, a solution containing the third oligonucleotide treated with biotin 520 (e.g., oligonucleotide treated with biotin 520c) is flowed followed by a</p>

<p dir="rtl">25 Series 118 of flow cell 100. In one example, the third nucleotide is treated with biotin deoxycytidine triphosphate.</p>

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At step 735, nano-sized magnetic streptavidin particles are introduced into the flow cell and a third signal is detected. For example, nano-sized magnetic particles 525 are captured by a biotin/streptavidin binding complex at all sites (assemblies) with a C insertion and the third signal is detected at the corresponding magnetic sensors 130.

<p dir="rtl">5 At step 740, the biotin/streptavidin nano-sized magnetic particle complex is eluted from the introduced nucleotides 520 by the cleavable ligation moiety 620. The binding group 625 of the nucleotides 520 is removed by a debinding reaction for subsequent insertion of the next complementary nucleotide. The synthesis cycle continues with a four-base addition reaction. For example, a solution containing the four biotin-treated nucleotides 520 (e.g., the four-biotin-treated oligonucleotides 520D) is flowed into the sequential chamber 118</p>

<p dir="rtl">10 For flow cell 100. In one example, the third nucleotide is biotinylated deoxythymidine triphosphate.</p>

At step 745, nano-sized magnetic streptavidin particles are introduced into the flow cell and signal four is detected. For example, 525 nano-sized magnetic particles are captured by a biotin/streptavidin binding complex at all sites (aggregates) with a T insertion and a signal of four is detected at

<p dir="rtl">15 Corresponding magnetic sensor 130.</p>

At decision step 750, it is determined whether a synthesis cycle rule needs to be added by another quaternary sequence. If another synthesis cycle is needed, then method 700 proceeds to step 755. If no further synthesis cycle is needed, then method 700 terminates.

<p dir="rtl">20 At step 755, the biotin/streptavidin nano-sized magnetic particle complex is eluted from the introduced nucleotides 520 by the cleavable ligation moiety 620. The hindrance group 625 of the nucleotides 520 is eluted by a debinding reaction for subsequent insertion of the next complementary nucleotide. Method 700 goes back to step 710.</p>

In another example, the synthesis scheme is based on the two-tag sequence of a magnetic biosensor

<p dir="rtl">25 Using hapten-tagged oligonucleotides and two different types of nano-sized magnetic particles are activated.</p>

In this example, two fluid/detection cycles are used to distinguish the base in the synthesis cycle by

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straight.

Figure 8 illustrates a flow diagram of an example method 800 of base tagging in a synthesis scheme by succession for a “dual-tag” magnetic biosensor using, for example, the flow cell 100 shown in Figures 1A, 1B, and 4. Figure 9 explains a schematic diagram that pictorially shows the steps of the method 800 according

<p dir="rtl">5 of Figure 8. In one example, Method 800 uses a biotinylated oligonucleotide with a cleavable disulfide linkage (A-LN3-SS-biotin), a biotinylated C oligonucleotide (C-LN3-biotin),</p>

Nano-sized streptavidin-coated magnetic particles for detection of A and C insertion, digoxigenin (DIG)-tagged T oligonucleotides (T-LN3-DIG), and nano-sized magnetic particles coated with an antibody or antibody fragment) selective for digoxigenin-tagged T oligonucleotides.

<p dir="rtl">10 G is a non-detector parameter. Referring to Figure 8, method 800 includes, but is not limited to, the following steps.</p>

At step 810, nucleotides are introduced into complementary growing strands into the synthesis cycle by stranding. The nucleotide can be A-LN3-SS-biotin, C-LN3-biotin, T-LN3-digoxigenin, or unaccented G. This step is also illustrated pictorially in schematic diagram 15 according to Figure 9.

At step 815, a first signal of the introduction of nucleotides A or C is detected. For example, using the magnetic sensor 130 of the flow cell 100, a first signal of the introduction of nucleotides A or C is detected. A solution of nano-sized streptavidin-coated magnetic particles is flowed through the flow chamber 118 of the flow cell 100 and biotin/streptavidin complexes are formed at the sites (aggregates) with the introduction of

<p dir="rtl">20 A or C. This step is also illustrated pictorially in the schematic diagram according to Figure 9.</p>

At step 820, a solution containing magnetic nanoparticles (NPs) coated with anti-digoxigenin (anti-digoxigenin nanoparticles) and a disulfide cleavage medium is flowed through the flow chamber 118 of the flow cell 100. The formation of the complex occurs between the T-LN3-DIG nucleotides and the NPs. Antidigoxigenin nanoparticles selectively localize (assemblies) with the insertion of T

<p dir="rtl">25 The die-sulfide cleavage method cleaves a die-sulfide ligation into the introduced A-LN3-SS-biotin nucleotides and effectively removes biotin/streptavidin complexes from the nucleotides and thus eliminates signals that may</p>

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generated from these sites. This step is also illustrated pictorially in the schematic diagram according to Figure 9.

At step 825, a second signal is detected for the insertion of T nucleotides. For example, using the magnetic sensor 130 of the flow cell 100, a second signal for the inserted T nucleotides is detected.

<p dir="rtl">5 A signal from the C nucleotide insertion is also detected. This step is also illustrated pictorially in the schematic diagram according to Figure 9.</p>

At step 830, base alerts can be made using bioinformatics software. In this example, input A and C are detected in the first signal detection. The input of T and C is detected in the second signal detection. Because the disulfide cleavage method is followed through the flow cell at step 820, the signal is determined to be

<p dir="rtl">10 of the introduced nucleotides are absent in the second signal detection. The G input is selected based on the signal deficiency at the first and second detectors. This step is also illustrated pictorially in the schematic diagram according to Figure 9.</p>

In decision step 835, it is determined whether another synthesis cycle is needed by successively. If another successive synthesis cycle is required, then method 800 is continued to step 840.

<p dir="rtl">15 If no further synthesis cycle is needed, then method 800 terminates.</p>

At step 840, a denaturation reaction and a cleavage reaction are performed. The debinding reaction is used to remove a hindrance group on the introduced nucleotide to add the next nucleotide in the synthesis cycle by the following sequence. The cleavage reaction is used to remove bound nano-sized magnetic particles from the introduced nucleotides and return the signal to background levels. Method 800 returns to step

<p dir="rtl">20 810. This step is also illustrated pictorially in the schematic diagram according to Figure 9.</p>

In other embodiments, the magnetic particles may actually be attached to one or more nucleotides when the nucleotides are added to the complementary strand. For example, the nucleotides that flow through the sequencing chamber for addition to the complementary strand could be A-LN3-SS-magneparticle, C-LN3-biotin, T-LN3-magneparticle, and unlabeled G. In these forms, it is not necessary to append

<p dir="rtl">25 Magnetic particles with nucleotides A and T after adding nucleotides to the complementary strand. Alternatively, a first signal can be detected from A and T nucleotides. For example, using magnetic sensors</p>

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130 For flow cell 100, a first signal is detected for the introduction of A or T nucleotides.

Therefore, a solution including a disulfide cleavage device may be followed through the flow chamber 118 of the flow cell 100. The die sulfide cleavage device cleaves the disulfide bond at the introduced A-LN3-SS-magnetic particle nucleotides thereby eliminating signals that could be generated from these sites. . maybe

<p dir="rtl">5 Follow the solution containing magnetic particles to attach C-LN3-Biotin through the running chamber</p>

<p dir="rtl">118.</p>

The second signal can thus be detected for the inserted T nucleotides and the inserted C nucleotides. For example, using the magnetic sensor 130 of the flow cell 100, a second signal is detected for the inserted T nucleotides and the inserted C nucleotides.

<p dir="rtl">10 After the first and second signals are detected, it can be carried out using bioinformatics software. In this example, input A and T are detected in the first signal detection. The input of T and C is detected in the second signal detection. Because the disulfide moiety method is followed through the flow cell, the signal from the introduced nucleotides is absent in the second signal detection. The G input is selected based on the lack of signal in the first and second detectors.</p>

<p dir="rtl">15 As described above, if no further cycles are required, a desorting reaction and a cleavage reaction can be carried out. The debinding reaction is used to remove a hindrance group on the introduced nucleotide to add the next nucleotide in the synthesis cycle by the following sequence. The cleavage reaction is used to remove bound nano-sized magnetic particles from the introduced nucleotides and return the signal to background levels.</p>

<p dir="rtl">20 In another example, a sequence-by-synthesis scheme for a “quad-tag” magnetic biosensor uses tagged nucleotides and different magnetic sizes to tag the base. In one example, the different magnetic sizes are provided by grasping one or more nano-sized magnetic particles at sites of an insertion nucleotide. For example, deoxyadenosine triphosphate is modified to hold one nano-sized magnetic particle, deoxythymidine triphosphate is modified to hold two nanoparticles.</p>

<p dir="rtl">25 Nano-sized magnetism, dioxycytidine triphosphate is modified to hold three nano-sized magnetic particles, and dioxyguanosine triphosphate is modified to hold four particles</p>

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Nano-sized magnetism. The magnitude of the detected signal is therefore a function of the base entered.

In one example, a modified nucleotide containing a thiol (SH) group is used to hold a monomolecular magnet that includes only one reactive group (e.g., a maleimide-modified monomolecular magnet). The nucleotide can include one, two, three, or four thiol groups and hold one two three,

or four maleimide-modified monomolecular magnets, respectively. Aldehyde (CHO)-aminooxy or hydrazine is an example of another chemical pair used in the successive synthesis scheme of a “quad-label” magnetic biosensor using tagged nucleotides and single-molecular magnets.

<p dir="rtl">10 In another example, up to four basic chemical properties are used to modify a nucleotide such that a single nucleotide can make up from 1 to 4 magnetically responsive spheres. An example of a series synthesis scheme for a “quad-tag” magnetic biosensor is illustrated in more detail by referring to Figure 10.</p>

In another embodiment, nano-sized particles comprising various paramagnetic materials may be used in 15 synthesis scheme by sequentially a magnetic biosensor. For example, paramagnetic materials are chosen such that each nano-sized particle type has a different response to the frequency of an applied external magnetic field. Some symmetrical magnetic particles can have tunable resonance frequencies and will not become paramagnetic, or follow the applied external field well, at non-absolute frequencies. Because each nano-sized particle type corresponds to a differently applied external field, each 20 nano-sized particle type can be used to characterize the base. Nano-sized particles incorporating different paramagnetic materials can be used, for example, in a synthesis scheme by successively for a “single-tag,” “dual-tag,” or “quad-tag” magnetic biosensor.

In another embodiment, the size/diameter of the nano-sized particles for each marker type can be different. For example, a 10 nm diameter versus a 50 nm diameter results in about a 100-fold volume difference, and about a 25-fold surface area difference (the signal is affected by both size and surface area).

Figure 10 shows a flow chart of an example of a method 1000 for distinguishing a base in a synthesis scheme by

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sequence of a “quad-tag” magnetic biosensor using, for example, flow cell 100 shown in Figures 1A, 1B, and 4. In this example, dioxyadenosine triphosphate is modified to hold one nano-sized magnetic particle or single-molecular magnet(s), dioxythymidine triphosphate is modified to hold two nano-sized magnetic particles or single-molecular magnets(

<p dir="rtl">5 Dioxycytidine triphosphate is modified to hold three nano-sized magnetic particles or monomolecular magnets (and dioxyguanosine triphosphate is modified to trap four nano-sized magnetic particles or monomolecular magnets). Method 1000 includes, but is not limited to, the following steps.</p>

At step 1010, nucleotides are introduced into complementary growing strands into the synthesis cycle by

<p dir="rtl">10 straight. The nucleotide can be C, T, A, or G.</p>

At step 1015, signals are detected for the introduced nucleotides. For example, using the magnetic sensor 130 of the flow cell 100, signals are detected for the introduced nucleotides. A solution of activated nano-sized magnetic particles is flowed through the flow chamber 118 of the flow cell 100 and nucleotide/nanoparticle complexes are formed at all locations (aggregates) with the introduction

<p dir="rtl">15 C, T, A, or G.</p>

At step 1020, base alerts are generated based on magnetic volume using bioinformatics software. In this example, A input is detected by a first magnitude signal, T input is detected by a second magnitude signal, C input is detected by a third magnitude signal, and G input is detected by a fourth magnitude signal.

<p dir="rtl">20 In decision step 1025, it is determined whether another synthesis cycle is needed by successively. If another synthesis cycle is needed, then the method 1000 proceeds to step 1030. If no further synthesis cycle is needed, then method 1000 terminates. At step 1030, a denaturation reaction and a cleavage reaction are performed. The debinding reaction is used to remove a hindrance group on the introduced nucleotide to add the next nucleotide in the synthesis cycle by</p>

<p dir="rtl">25 The following successive. The cleavage reaction is used to remove bound nano-sized magnetic particles from the introduced nucleotides and return the signal to background levels. Method 1000 returns to step</p>

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.1010

In an alternative embodiment of Figure 10, the synthesis method may be implemented by sequentially using individual vessel reactions. In this example, the mold strands can be transferred to the surface or the transferred rice polymer can be transferred to the surface. For a single vascular reaction, reversibly inhibited oligonucleotides are provided that have magnetic particles 5 attached to them simultaneously with deblocking agents. For these models where the template strands are transferred to the surface, the rice polymer can be supplemented with nucleotides and blocking agents.

At step 1010, nucleotides can be inserted into complementary growing strands. At step 1015, signals are detected for the introduced nucleotides. Specifically, with the addition of a nucleotide to the complementary strand by polymerase, magnetically responsive sensors can detect the change in electrical resistance induced by the presence of magnetic particles. Magnetic particles can provide a constant external magnetic field or, alternatively, can be influenced by an external inducer.

At step 1020, base alerts are executed based on detected changes in electrical resistance. For example, A input is detected by a first magnitude signal, T input is detected by a second magnitude signal, C input is detected by a third magnitude signal, and G 15 input is detected by a fourth magnitude signal.

At step 1030, a denaturation reaction and a cleavage reaction are performed. The debinding reaction is used to remove a hindrance group on the introduced nucleotide to add the next nucleotide in the synthesis cycle by the following sequence. The cleavage reaction is used to remove bound nano-sized magnetic particles from the introduced nucleotides and return the signal to background levels.

<p dir="rtl">20 In single-pot models, reactants do not include 3'-blocking agents or de-blocking agents. The electrical resistance of each magnetically responsive sensor can be monitored to identify input events in real time. These models can apply specifically to single-molecule protocols.</p>

Because the above embodiments explain a single vascular reaction, it should be understood that steps 1010, 1015, and 1030 may occur at different times for different template strands. In some embodiments, one or more 25 steps may be controlled. For example, step 1030 may be performed by an external prompt delivered by the system.

Furthermore, the 1030 move can take place in real time. Alternatively, the step can be done

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ten thirty After a set of input events or after the synthesis sequence is completed by the sequence. In other alternative embodiments, such as single-molecule protocols, step 1030 is not performed.

<p dir="rtl">1.3 Monomolecular magnet synthesis by series</p>

In another embodiment, nucleotides tagged with single-molecule magnets are used to mark the base in a scheme

<p dir="rtl">5 Series synthesis of a magnetic biosensor. Monomolecular magnets are a class of organometallic compounds that exhibit superparamagnetic behavior, i.e., they are magnetic only in the presence of an external magnetic field. The magnetic properties or states of some single-molecular magnets can be modified by external induction. In one example, the magnetic state of a single-molecule magnet can be switched using light. For example, one frequency of light can be used to power...</p>

<p dir="rtl">10 Single-Molecular Magnets Another light frequency can be used to close a single-molecule magnet. Because the magnetic state can be switched, the signal-to-noise (S/N) ratio can be improved via repeated sampling. One or more monomolecular magnets can be chosen such that the size of the monomolecular magnet is compatible with the chemistry of the nucleotide. In one example, The size of a single-molecule magnet can be about 1.2 nanometers.</p>

<p dir="rtl">15 Single-molecule magnets that can involve changing their magnetic properties or states by applying an external stimulus are described in “Tristability in a Light-Actuated Single-Feng et al.”</p>

pp. 15880–15884; Mathonière, 135 (42), 2013,” J. Am. Chem. Soc.,Molecule Magnet

“Photoinduced Single-Molecule Magnet Properties in a Four-Coordinate Iron(II), et al.

pp. 19083–19086; , 135 (51), 2013,” J. Am. Chem. Soc.,Spin Crossover Complex

Mrs Bulletin 25.11 (2000): 66-71; “Single-,Christou et al. “Single-molecule magnets 20

“Volume 122 of Structure and bonding, molecular magnets and related phenomena

Editors Richard Winpenny and Single-molecule magnets and related phenomena

“Proc Jpn Acad, “Switchable molecular magnets,” Springer (2006); Sato, Guillem Aromí

Ser B Phys Biol Sci. 2012 Jun 11; 88(6): 213–225; Sato (2003) “Optically switchable

and photoinduced, photochromism, molecular solids: Photoinduced spin-crossover 25

692–700; Sato et al. (2007) “Control of magnetism, magnetization.” Acc. Chem. Res. 36

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2187–2152. “properties through external stimuli have been integrated.” Angew. Chem. Int. Ed. 46

I refer back to all of these matters here.

In one example, a nucleotide tagged with a single-molecule magnet includes essentially the same structure as nucleotide 520

According to Figure 6. In this example, the biotin tag 610 is replaced by one or more monomolecular magnets 5.

In one example, single-molecule magnets are used in a synthesis scheme by succession for a “quad-tag” magnetic biosensor. In this example, each nucleotide (C, G, A, and T) is tagged with a single-molecule magnet that is sensitive to a different set of light-on/on frequencies. For example, A is tagged with a first monomolecular magnet that is sensitive to a first set of light-on/on frequencies, G is taught

<p dir="rtl">10 A second monomolecular magnet is sensitive to a second set of light-on/off tags, C is marked with a third monomolecular magnet that is sensitive to a third light-on/off tags, and T is marked with a fourth monomolecular magnet that is sensitive to a four-light set of light-on/off tags. . Figure 11 illustrates a flow chart of an example method 1100 for tagging a base in a synthesis scheme by succession to a “quad-tag” magnetic biosensor using nucleotides tagged with a single magnet.</p>

<p dir="rtl">15 molecule. In this example, A is tagged with a first monomolecular magnet that is sensitive to a first set of light-on/off karts, G is tagged with a second monomolecular magnet that is sensitive to a second set of light-on/on tachograms, and C is tagged with a third monomolecular magnet that is sensitive to a set of Three light-on/off switches, and the T is marked with four monomolecular magnets that are sensitive to a group of four light-on/off switches.</p>

<p dir="rtl">20 At step 1110, nucleotides tagged with a single-molecule magnet are introduced into the complementary growing strands in the synthesis cycle by respectively. The nucleotide can be C, G, A, or T.</p>

At step 1115, a first set of light on/off repeaters is used to detect the insertion of the first nucleotide, e.g., A. For example, the operating frequency is used to actuate a single-molecule magnet tag of the incorporated nucleotide and the signal is detected. The light-locking frequency is used to lock a single magnet

<p dir="rtl">25 The molecule and return the signal to background levels.</p>

At step 1120, a second set of light on/off repeaters is used to detect an input

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The second nucleotide, eg, G. For example, the operating frequency is used to trigger a single-molecule magnet tag for the introduced nucleotide G and the signal is detected. The light-locking frequency is used to lock a single-molecule magnet and return the signal to background levels.

At step 1125, a third set of light on/off switches is used to detect an input

<p dir="rtl">5 The third nucleotide, say, C. For example, the operating frequency is used to trigger a single-molecule magnet tag for the introduced C nucleotide and the signal is detected. The light-locking frequency is used to lock a single-molecule magnet and return the signal to background levels.</p>

At step 1130, a set of four light on/off switches is used to detect the insertion of the four nucleotide, eg, T. For example, the operating frequency is used to turn on a single-molecule magnet tag.

<p dir="rtl">10 for the T nucleotide that is introduced and the signal is detected. The light-locking frequency is used to lock a single-molecule magnet and return the signal to background levels.</p>

In decision step 1135, it is determined whether another synthesis cycle is needed by successively. If another synthesis cycle is needed, then method 1100 continues to step 1140. If no further synthesis cycle is needed, then method 1100 terminates.

<p dir="rtl">15 At step 1140, a denaturation reaction and a cleavage reaction are performed. The debinding reaction is used to remove a hindrance group on the introduced nucleotide to add the next nucleotide in the synthesis cycle by the following sequence. The cleavage reaction is used to remove a single-molecule magnet tag from the introduced nucleotides. The method 1100 goes back to step 1110.</p>

In another example, nucleotides tagged with a single-molecule magnet may be used in the synthesis scheme

<p dir="rtl">20 By cascading a “quad-marker” magnetic biosensor using different magnetic sizes to mark the base. In one example, dioxyadenosine triphosphate is labeled with one monomolecular magnet, dioxyguanosine triphosphate is labeled with two monomolecular magnets, dioxycytidine triphosphate is labeled with three monomolecular magnets, and dioxythymidine triphosphate is labeled with four magnets. Monomolecular. Therefore, the magnitude of the detected signal is...</p>

<p dir="rtl">25 A function of the entered rule.</p>

Figure 12 illustrates a flow chart of an example of a method 1200 for distinguishing a base in a synthesis chart by

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Succession of a “quad-tag” magnetic biosensor using single-molecule magnet-tagged oligonucleotides having different magnetic sizes to mark the base. In this example, a single type of single-molecular magnet is used, but each nucleotide is labeled with a number of different single-molecular magnets. For example, D-oxyadenosine triphosphate is labeled with a single monomolecular magnet, D-oxyadenosine triphosphate is labeled with one monomolecular magnet

<p dir="rtl">5 Oxyguanosinetaryphosphate is labeled with two monomolecular magnets, dioxycytidinetaryphosphate is labeled with three monomolecular magnets, and dioxythymidinetaryphosphate is labeled with four monomolecular magnets. The method 1200 uses, for example, the flow cell 100 shown in Figures 1a, 1b, and 4. Method 1200 includes, but is not limited to, the following steps. At step 1210, nucleotides tagged with a single-molecule magnet are introduced into the growing strands</p>

<p dir="rtl">10 Complementary in the synthesis cycle by series. The nucleotide can be C, G, A, or T.</p>

At step 1215, signals are detected for the introduced nucleotides using, for example, the magnetic sensors 130 of the flow cell 100. A first light frequency is used to drive the single-molecule magnet tags and the signal is detected at all locations (assemblies) with input C, G , A, or T. A second light frequency is used to close the single-molecular magnets and return the signal to background levels.

<p dir="rtl">15 At step 1220, base alerts are implemented based on magnetic volume using bioinformatic software. In this example, A input is detected by a first magnitude signal, G input is detected by a second magnitude signal, C input is detected by a third magnitude signal, and T input is detected by a fourth magnitude signal.</p>

In decision step 1225, it is determined whether another synthesis cycle is needed by successively. if

<p dir="rtl">20 If another synthesis cycle is needed, then the method 1200 continues to step 1230. If another synthesis cycle is not needed, then the method 1200 terminates. At step 1230, a denaturation reaction and a cleavage reaction are performed. The debinding reaction is used to remove a hindrance group on the introduced nucleotide to add the next nucleotide in the synthesis cycle by the following sequence. The cleavage reaction is used to remove single-molecule magnetic tags from nucleotides</p>

<p dir="rtl">25 which are entered and re-referenced to the background levels. The method 1200 goes back to step 1210.</p>

<p dir="rtl">1.4 Rice DNA polymerase functionalized deoxyribonucleic acid in magnetic biosensing</p>

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Synthesis by succession

In yet another embodiment, unlabeled oligonucleotides and an activated doxyribonucleic acid polymer are used to mark the base in the synthesis scheme by succession to a magnetic biosensor. In one example, a rice doxyribonucleic acid polymer is tagged with a single-molecule magnet and...

<p dir="rtl">5 Design oligonucleotides to have different insertion rates during synthesis by sequencing. For example, A is modified to have a first input rate, G is modified to have a second input rate, C is modified to have a third input rate, and T is modified to have a fourth input rate. Because the insertion rate is different for each nucleotide, the rice doxyribonucleic acid polymerase that is temporally associated with an insertion site (group) is a function of the base that was inserted. An example of nucleotide insertion rates is shown in</p>

<p dir="rtl">10 Table 1.</p>

Table 1. Nucleotide insertion rates

Nucleotide input rate (ms)

Deoxyadenosine triphosphate 10

Deoxyguanosine triphosphate 100

<p dir="rtl">15 Deoxycytidine Tariphosphate 500</p>

Dioxythymidine triphosphate 1000

In one example, the 3′ hydroxyl group of the designed nucleotide is not protected by the disability group. In another example, the 3′ hydroxyl group of the designed nucleotide is protected by the disability group.

<p dir="rtl">20 In one or more embodiments, such as that shown in relation to Figure 13, the synthesis protocol can include attaching magnetic particles to a rice polymer. The magnetic particle can be, for example, nano-sized magnetic particles or single-molecular magnets. More specifically, in one or more embodiments, the method of synthesis may include respectively providing a detector including an array of magnetically responsive sensors. The detector could be similar to what is</p>

<p dir="rtl">25 Explained here. Each of the magnetically responsive sensors can be placed near a corresponding blank to detect an external magnetic field from it. The detector may also include a plurality of strands</p>

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A DNA template placed in certain corresponding spaces. Mold strands can be transferred to a surface. Alternatively, the template strands can be specified to a specific size, such as a gel eye or gel matrix.

The method may further include performing a plurality of synthesis cycles by sequentially giving a complementary strand by adding nucleotides along each template strand using a rice polymer. Maybe

<p dir="rtl">5 Polymers have corresponding magnetic particles attached to them that give off magnetic fields</p>

debate. When the polymerase adds nucleotides to the template strands, the polymerase can be placed in the designated space. Therefore, sensors capable of detecting magnetic fields from magnetic particles could be attached to the polymer.

Each synthesis cycle may include series detection of changes in electrical resistance at

<p dir="rtl">10 Magnetically responsive sensor. More specifically, the changes detected can be caused by the presence of magnetic particles at specific gaps when the polymerase adds nucleotides. The method may also include determining sequences of complementary strands as described herein. Figure 13 shows a flow chart of an example method 1300 for tagging a base in a synthesis scheme by sequence for a magnetic biosensor using a labeled rice doxyribonucleic acid polymer.</p>

<p dir="rtl">15 With single-molecule magnets and nucleotides with different insertion rates. In this example, the nucleotides are unspliced and include insertion rates as shown in Table 1.</p>

At step 1310, nucleotides are inserted into complementary growing strands into the synthesis cycle by stranding. The nucleotide can be C, G, A, or T. In one example, four nucleotides with the same input time are streamed separately. Therefore, it monitors the polymer input link

<p dir="rtl">20 (Possibly from about 30 ms to about 100 ms.) In another example, four nucleotides with different insertion times are streamed at the same time.</p>

At step 1315, signals from the monomolecular magnet rice polymer are detected. For example, using the magnetic sensor 130 of the flow cell 100, a signal from a rice doxyribonucleic acid polymer tagged with a single-molecule magnet is detected at each nucleotide insertion site.

<p dir="rtl">25 A first light frequency is used to turn on the single-molecule rice polymer magnet and the signal is detected at all locations (assemblies) with the input C, G, A, or T. A second light frequency is used to turn off</p>

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Bonus polymolecular magnets return the signal to background levels.

At step 1320, base alerts are performed based on the input modifier oligonucleotide using bio-informatics software. In this example, input A is detected by a first duration signal (e.g., approximately 10 ms), input G is detected by a second duration signal (e.g., approximately 5 100 ms), input C is detected by a third duration signal (e.g., about 500 ms), and the T input is detected by a signal of duration four (e.g., about 1000 ms).

In decision step 1325, it is determined whether another synthesis cycle is needed by successively. If another synthesis cycle is needed, then the method returns to step 1310. If no further synthesis cycle is needed, then method 1300 terminates.

<p dir="rtl">10 The present application embodiments will not, however, be limited to the embodiments shown in Figures 1a through 13. Magnetic sensors (e.g., massive magnetoresistance-based and/or tunneling magnetoresistance-based sensors) may be used in combination with other architectures, Mechanisms, and/or systems to support the serial synthesis scheme of a magnetic biosensor; examples of which are illustrated by reference to Figures 14a through 18.</p>

<p dir="rtl">15 Figures 14a and 14b illustrate a plane view and a cross-sectional view, respectively, of the magnetic sensor array 110 in combination with an example of a semi-hydrophobic region in the flow cell or catart motor 1400. The flow cell or catart motor 1400 includes the magnetic sensor array 110 over a circuit board. Printed 112 relative to an upper substrate 114 and conductive layer 150, as shown by reference to a flow cell 100 according to Figures 1a, 1b, and 4.</p>

<p dir="rtl">20 The flow cell or catart drive 1400 also includes a semi-hydrophobic region 1410 over the magnetic sensor array 110. In this example, the semi-hydrophobic region 1410 includes a substrate 1418. The substrate 1418 can be, for example, a glass substrate or a CMOS substrate. In one example, the substrate 1418 is a silicon dioxide (SiO2) substrate. The hydrophobic region 1410 also includes a plurality of nanowells 1412 placed</p>

<p dir="rtl">25 with a pattern in the substrate 1418. The inside of the micro-eyes 1412 is coated with a hydrophobic layer 1414 thus forming a hydrophilic micro-eyes 1412. The surface of the substrate 1418 is coated outside the micro-eyes</p>

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1412 with a hydrophobic layer 1416. Also, oligonucleotide primers 142 are provided within each of the microeyes 1412.

The hydrophilic layer 1414 within the microfoils 1412 can be any hydrophilic material suitable for implementing surface chemistry in a train engine. In one example, the hydrophobic layer is 1414 words

<p dir="rtl">5 For polyacrylamide gel polish, such as a mixture of norbornene, norbornylene, or norcamphene and poly(5)-N-azido pentyl acetamide (acrylamide-co-acrylamide), also known as poly(5)-N-azido</p>

Acetamidyl pentyl(acrylamide-co-acrylamide). In another example, the hydrophobic layer 1414 includes poly(5)-N-azido acetamidyl pentyl(acrylamide-co-acrylamide-co-acrylonitrile), also known as poly(5)-N-azido Acetamidyl pentyl(acrylamide-co-acrylamide-PAN). In some embodiments, 10 may be modified to poly(5)-N-azido acetamidyl pentyl(acrylamide-co-acrylamide and/or poly(5)-N-azido

PAN to be thermally responsive, thus forming a thermally responsive polyacrylamide gel. More details about poly(5)-N-azidoacetamidyl pentyl(acrylamide-co-acrylamide) can be found here. With reference to George et al., US Patent Application No. 784,368/13, titled “Polymer Coatings,” filed on March 4, 15, 2013, the full disclosure of which is incorporated by reference.

The hydrophobic layer 1416 fills the interfacial space between the microscopic eyes 1412. The hydrophobic layer 1416 can be any hydrophobic material suitable for implementing surface chemistry in a train engine. In one example, the hydrophobic layer 1416 is fluoro octyl-trichloro-silane (FOTS), formally known as 1,1,2,2-tetrihydro(FOTS). 20 octyl (1-2-tetrahydrooctyl)trichlorosilane,1,2,tridecafluoro. In another example, the hydrophobic layer 1416 is a fluorophobic material (i.e., a hydrophobic fluoropolymer), such as ALX2010, available from

. aka AGC, Japan), Ltd. (Tokyo, Asahi Glass Co., Ltd.

In the flow cell or cat-art motor 1400, the micro-eyes 1412 are arranged in rows and columns having positions 25 essentially corresponding to the rows and columns of the magnetic sensor 130 of the sensor array.

Magnetic 110. Each minute eye 1412 includes a specific depth and diameter. In one example, it includes:

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Micro-eyes 1412 are about 350 nanometers deep and about 400 nanometers in diameter. In another example, microeyes 1412 include a depth of about 350 nm and a diameter of about 500 nm.

Figures 15a and 15b illustrate a planar view and a cross-sectional view, respectively, of the magnetic sensor array 110 in combination with another example of a semi-hydrophobic region 1410 in the flow cell or

<p dir="rtl">5 Cat Art Engine 1400. In this example, the polarity of the hydrophobic layer 1414 and the hydrophobic layer 1416 are reversed. Specifically, instead of having the hydrophilic layer 1414 located in an eye relative to the plane of the hydrophobic layer 1416, the hydrophobic layer 1414 is placed on the base relative to to the level of the hydrophobic layer 1416. For example, the fine eyes 1412 of the semi-hydrophobic region 1410 in Figures 14a and 14b are replaced with basic bases 1420. Above the basic bases 1420 is the hydrophobic layer</p>

<p dir="rtl">10 For water 1414 and the starting oligonucleotide materials 142, thus forming a hydrophilic base 1420. In this example of a flow cell or train engine 1400, a hydrophilic base 1420 is arranged in rows and columns having positions corresponding essentially to the magnetic sensor rows and columns 130 of the sensor array. Magnetic 110.</p>

Figures 16a and 16b show a plane view and a cross-sectional view, respectively, of part of an engine

<p dir="rtl">15 ART 1600 which includes the magnetic sensor array 110 to support, for example, a synthesis scheme</p>

By succession to a magnetic biosensor. A train engine 1600 includes a lower bracket 1610 and an upper bracket 1612 separated by a distillation gap 1614. The distillation gap 1614 contains a filling fluid 1616. The filling fluid 1616 is, for example, a low-viscosity oil, such as silicone oil or hexadecane filling fluid. The lower substrate 1610 includes an electrode device 1605 including, for example, a plurality of

<p dir="rtl">20 Distillation electrodes 1618 (e.g., electrowetting electrodes) feed a plurality of reservoir electrodes 1620. Distillations are performed over distillation electrodes 1618 on a distillation surface.</p>

The magnetic sensor array 110 sized around the same as the distillation electrodes 1618 can be provided in one or more distillation electrode lines 1618, as shown. In this example, parts of the upper substrate 1612 near the distillation electrodes 1618 may include

<p dir="rtl">25 A ground reference plane or electrode (not shown), while portions of the upper bracket 1612 close to the magnetic sensor array 110 may include a Vdd reference plane or electrode (not shown).</p>

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(shown). The droplet 1630 (e.g., a sample or droplet reagent) can be transported via distillation processes along the distillation electrodes 1618 and to the magnetic sensor array 110, whereby magnetic biosensing operations, such as those shown by reference in Figures 5 through 13, can then be performed.

In some embodiments, one or more of the magnetically responsive sensors may be movable

<p dir="rtl">5 Relative to a sample substrate that contains the biological or chemical sample on it. For example, a series synthesis system may include a readout arm and a magnetically responsive sensor attached to the arm. The magnetically responsive sensor can include at least one of a massive magnetoresistance sensor or a tunneled magnetoresistance sensor.</p>

The system can also include a sample substrate having a substrate surface. The surface of the substrate is prepared to include a set of

<p dir="rtl">10 Nucleic acid template strands arranged in specific spaces along the surface of the substrate. At least one of the reading heads and the sample substrate are configured to move relative to the other to position the magnetically responsive sensor near designated voids in an operational relationship. More specifically, the magnetically responsive sensor is positioned so that it can detect external magnetic fields generated by magnetic particles. The system also includes a readout circuit that is communicatively coupled to the transponder</p>

<p dir="rtl">15 Magnetically. The reading circuit is configured to emit signals that respond to the electrical resistance of the magnetically responsive sensor when positioned at one of the specified spaces. The reading circuit may be similar to the reader circuit 106 (Figure 1).</p>

Figure 17 shows a plane view of this system. More specifically, Figure 17 illustrates a turntable-based device 1700 wherein a single movable magnetic sensor is provided to support, for example, a chart

<p dir="rtl">20 Series synthesis of a magnetic biosensor. The turntable-based device 1700 includes a disc substrate or sample substrate (1710), which may, for example, be a plastic compact disc (CD) substrate. A plurality of concentric tracks (or notches) 1712 is provided. (grooves into the surface of a disc substrate 1710. The rotating disc-based instrument 1700 also includes a magnetic reading arm 1714 on a movable arm 1716.</p>

<p dir="rtl">25 Specifically, there is a pivot point on one end of the movable arm 1716 and the magnetic reading head 1714 is located on the opposite end of the movable arm 1716. The magnetic reading head 1714 includes</p>

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1714 A single magnetic sensor, such as a sensor based on massive magnetoresistance and/or tunneling magnetoresistance, such as a single magnetic sensor 130 as shown by reference to Figures 1a to 4. It is configured, however, such that the magnetic readout can include more than One magnetically responsive sensor.

<p dir="rtl">5 In a turntable-based device 1700, a turntable substrate 1710 is rotatable using standard CD technology. The co-centered tracts 1712 may be assembled with a combination of, for example, oligonucleotide primers 142 (not shown). Again, the oligonucleotide primers 142 are grasping primers upon which single-stranded deoxyribose DNA fragments are hybridized and can be amplified to form assemblies. Clonal doxyribonucleic acid template for synthesis by sequencing.</p>

<p dir="rtl">10 In one example, there are about 10 tracks sharing the 1712 position with about 100 assemblies/path, which amounts to about 1000 assemblies/disk. By rotating the disc substrate 1710, the reagents can be dispersed and distributed onto co-centric paths 1712 using centripetal force. Thus, using the magnetic sensor of the magnetic reader 1714, magnetic biosensing can be performed, for example, at about 10 revolutions/min. The distance between the magnetic reading heads should be equal</p>

<p dir="rtl">15 1714 and magnetic particles introduced or captured during the nucleotide synthesis insertion reaction</p>

By properly formatting them for good detection. Aspects of the 1700 rotary disc-based instrument include an inexpensive substrate (e.g., a CD substrate), reusable savings on microfluidic pumping beds, rapid fluidization properties, and a sensor due to disc activation, suitable for performing synthesis by series.

<p dir="rtl">20 Although the 1700 uses a rotating disc. It is adapted to use other traffic types. For example, the sample substrate may involve sliding. The slide and/or readout position may be readable to position the magnetically responsive sensors relative to designated clearances. For example, the sliding and/or reading heads can be coupled to a motor.</p>

Optical detection systems are compared to traditional systems in synthesis applications using series devices

<p dir="rtl">25 Currently disclosed methods of synthesis using a magnetic sensor array support a scheme for synthesis of a magnetic biosensor that gives certain advantages, such as, e.g.</p>

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Example but not limited to:

<p dir="rtl">(1) Small size - a magnetic sensor array occupies a much smaller area than optomechanical devices. For example, a 1 GB magnetic sensor array can occupy an area of approximately 13 cm x 3 cm x 0.1 cm, which can</p>

<p dir="rtl">5 Optical mechanical devices occupy an area of about 2 cm x 5.08 cm x 5.08 cm;</p>

<p dir="rtl">(2) Simplicity and low cost - the magnetic biosensing system requires only a control device, where the optical detection systems have switching relays, optical components, and a control device;</p>

<p dir="rtl">(3) Rigidity - the magnetic biosensing system does not have delicate moving parts, as conventional detection systems do; and</p>

<p dir="rtl">10 (4) Speed - The magnetic biosensing scheme can be about 6.5x faster</p>

than a CMOS imaging system and about 100x faster than XTen opto-mechanical devices. For example, magnetic biosensing can support a data rate of 3.2 Gbit/s; 1.6 billion transfers per second per I/O, which amounts to 1.6 billion assemblies per second.

Figures 18a and 18b show a plane view and a cross-sectional view, respectively, of the sensor array.

<p dir="rtl">15 Magnetic 110 in a flow cell or CatArt motor 1800. The flow cell or CatArt motor 1800 includes a magnetic sensor array 110 over a printed circuit board 112 relative to an upper substrate 114 and a conductive layer 150, as shown by reference to a flow cell 100 in accordance with Figures 1a, 1b. , and 4.</p>

The flow cell or catart engine 1800 also includes a semi-hydrophobic region 1410 above the matrix.

<p dir="rtl">20 Magnetic sensor 110. In this example, the hydrophobic region 1810 includes the substrate 1818. The substrate 1818 can be, for example, a glass substrate or a CMOS substrate. In one example, substrate 1818 is a silicon dioxide substrate. The semi-hydrophobic region 1810 also includes a plurality of eyes 1812 (e.g., micro-eyes) disposed in a pattern in the substrate 1818. The interior of the micro-eyes 1812 is coated with the hydrophobic layer 1814 thus forming</p>

<p dir="rtl">25 Hydrophilic micro-eyes 1812. The surface of the substrate 1818 located outside the micro-eyes 1812 with the hydrophobic layer 1816. Also, oligonucleotide starting materials 142 are provided within each of the micro-eyes</p>

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.1812

The hydrophilic layer 1814 within the microfoils 1812 can be any hydrophilic material suitable for implementing surface chemistry in a train engine. In one example, the hydrophilic layer 1814 is a polyacrylamide gel polish, such as a mixture of norbornene, norborneneline, or norcamphene(and poly)-N5(5)-azidoacetamidyl pentyl(acrylamide-co-acrylamide), also known as poly(5)-5). N-azido

Acetamidyl pentyl(acrylamide-co-acrylamide). In another example, the hydrophobic layer 1814 includes poly(5)-N-azido acetamidyl pentyl(acrylamide-co-acrylamide-co-acrylonitrile), also known as poly(5)-N-azido Acetamidyl pentyl(acrylamide-co-acrylamide-PAN). In some embodiments, poly(5)-N-azidoacetamidyl pentyl(acrylamide-co-acrylamide) and/or poly(5)-N-azidoacetamidyl 10-pentyl(acrylamide) can be modified co-acrylamide-PAN to be thermally responsive, thus forming a thermally responsive polyacrylamide gel. More details about poly(5)-N-azidoacetamidylpentyl(acrylamide-co-acrylamide) can be found by referring to George et al., US Patent Application No. 784,368/13, titled “Polymer Coatings,” filed at 4 March, 2013, and the full disclosure is hereby incorporated by reference.

<p dir="rtl">15 The hydrophobic layer 1816 fills the interfacial space between the microscopic eyes 1812. The hydrophobic layer 1816 can be any hydrophobic material suitable for implementing surface chemistry in a train engine. In one example, the hydrophobic layer 1816 is fluoro-octyl-trichloro-silane, formally known as (t-tridecafluoro-1,1,2,2-tetrahydrooctyl)trichlorosilane. In another example, The hydrophobic layer 1816 is a photoresist material treated with fluorine (i.e., a hydrophobic fluoropolymer),</p>

<p dir="rtl">20 Such as the light-insulating material ALX2010, available from Japan), Ltd. (Tokyo, Asahi Glass Co.,</p>

.aka AGC

In the flow cell or cat-art engine 1800, the micro-eyes 1812 are equipped in an array having positions essentially corresponding to the array 110 of the magnetic sensor 130. As shown in Figure 18b, each of the micro-eyes can be an individual rice polymer 1820 transported to a specific area. 1822 in the 25 minute eye 1812. The polymerase 1820 can be moved to the designated area 1822 using a tether, e.g.

Those described above. Each of the 1820 polymerases is configured to hold a template strand of the starting material

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attached to it. In Figure 18b, the serial synthesis protocol is partially complete.

With the 1820 rice polymer transferred to the surface, models can perform many of the protocols described above where nucleotides are labeled with magnetic particles. For example, the operations described above in Figures 7-12 can be performed with rice polymer transferred to the surface. As shown here, it can

<p dir="rtl">5 The magnetically responsive sensor 130 tests the change in electrical resistance with the addition of a magnetic particle attached to the nucleotide to the complementary strand. For each cycle, the models can deliver one nucleotide at a time so that four separate secondary cycles must be executed. Alternatively, models can simultaneously deliver two or more nucleotides at a time. In other embodiments, however, the synthesis protocol may be performed by succession with individual vascular interactions.</p>

<p dir="rtl">10 Although the example above is illustrated with polymer rice transferred to a surface in an eye, it is configured such that the polymer rice is selectively placed along a flat surface.</p>

Referring to Figure 19, a tunneling magnetoresistance device 1905 at three different phases 1951, 1952, 1953 for the synthesis protocol is illustrated by respectively. The device may form a tunneled magnetoresistance 1905 magnetically responsive sensor which may be part of an array

<p dir="rtl">15 Sensor integrated by flow cell and/or catart motor. The tunneling magnetoresistance device 1905 includes a first ferromagnetic layer 1910 or storage layer), including a nonmagnetic layer 1912, and a second ferromagnetic layer 1914. The nonmagnetic layer 1912 is a thin insulating layer, such as aluminum oxide (Al2O3). As shown above, When the first and second magnetic iron layers were separated 1910, 1914 by the non-magnetic layer</p>

<p dir="rtl">20 1912, Electrical resistance of the multilayer in the direction perpendicular to the membrane changes dependent on</p>

Directions for the magnetization processes of the ferromagnetic layers 1910, 1914 due to spin-based electron tunneling between the two ferromagnetic layers 1910, 1914. Also illustrated is a tunneling magnetoresistance device 1905 which includes the separation layer 1916 of Ru, the backflow compensation layer 1918, and the magnetic layer. Anti-ferrous metal 1920. A magnetic resistance device is coupled

<p dir="rtl">25 1905 tunneled electrically and placed it between a writing line (for example, a conductive path) 1922 and a reading line 1924.</p>

As shown above, when the directions of magnetization processes the two layers of magnetic iron

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1910, 1914 opposite each other (as shown in the third stage 1953), it is not possible to conduct electron tunneling with the opposite spin orientation relative to the magnetization of the ferromagnetic layer. Therefore, the tunneling electron current becomes smaller (i.e., higher resistance) compared to the case of the same directions of magnetization processes. When the directions of the magnetization processes of the two layers of magnetic iron 1910 and 1914 are the same (as shown in

<p dir="rtl">5 During the first and second phases (1951, 1952), the possibility of the formation of an electronic tunnel between the two will become</p>

The number of layers of magnetic iron through the insulating layer is larger, and results in a larger tunneling current (i.e., lower resistance).

Models can implement one or more of the methods described here. For example, prior to the first stage 1951, template strands 1928 may be transferred to a specific area of the surface of the substrate 1926 and the attached primers

<p dir="rtl">10 With it. During the first phase 1951, nucleotides 1930 can be incorporated within the complementary strand and, thus, magnetosomes 1932 can be provided for appending to the introduced nucleotides 1930. Alternatively, nucleotides 1930 can be magnetosomes 1932 appended thereto with nucleotides 1930 added to the complementary strand. .</p>

The magnetic particle 1932 may include a magnetic property capable of switching the first ferromagnetic layer 15 1910 such that the first ferromagnetic layer 1910 maintains

On its magnetization after the removal of the magnetic particle 1932 as shown at the second stage 1952. More specifically, the magnetization is not transient, but permanent until the magnetization is changed by the writing line 1922. This process could be similar to the process of non-volatile memory. In these embodiments, the tunneling magnetoresistance device 1905 may be read at certain times and for a certain period of time through the reading line 1924. In

<p dir="rtl">20 In these embodiments, the tunneling magnetoresistance device 1905 may be able to achieve a higher signal-to-noise ratio than tunneling magnetoresistance devices that do not include storage layers that maintain their magnetic states. After reading the tunneling magnetoresistance device 1905, the writing line 1922 can be an electric current flowing through it to change the magnetization of the first ferromagnetic layer 1910. The series synthesis protocol can thus repeat the series synthesis cycle.</p>

<p dir="rtl">25 The foregoing detailed description of embodiments refers to the accompanying figures, which explain particular embodiments in accordance with the present disclosure. The various structures and operations do not depart from the perspective of the present disclosure. Will be</p>

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Understand that there are many details that can be changed without going out of perspective. Furthermore, the above description is provided for illustrative purposes only, and is not for the purpose of limitation.

The following protections refer to specific examples of the current application. Therefore, protection elements are integrated into the detailed description.

5

Relay list:

AA "A"

<p dir="rtl">"B" Low resistance</p>

<p dir="rtl">"C" high resistance</p>

<p dir="rtl">10 “D” Low resistance (high expenditure current)</p>

“E” High impedance (low expenditure current)

"and" the homogeneous field of MACS (oe)

“g” MACS number

“H” signal (ultraviolet)

<p dir="rtl">15 “i” homogeneous field on the sensor (oe)</p>

"Y" beginning

"K" Yes

"L" No

"M" expiration

20 "n" end

“S” insertion of the first nucleotide (deoxyadenosine triphosphate)

615, 655 bases

610 Biotin

670 Fasten

<p dir="rtl">25 710 Introduction of the first nucleotide (deoxyadenosine triphosphate)</p>

715 Inserting nano-sized magnetic particles and detecting a first signal

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<p dir="rtl">720 Unblocking and splitting nano-sized particles after introducing a second nucleotide (for example, deoxyadenosine triphosphate)</p>

725 Inserting nano-sized magnetic particles and detecting the second signal

<p dir="rtl">730 Unblocking and cleaving nano-sized particles after the introduction of a third nucleotide (for example, dioxycytidine)</p>

<p dir="rtl">5 tarry phosphate)</p>

735, 745 Insertion of nano-sized magnetic particles and detection of a third signal

<p dir="rtl">750 Unblocking and splitting of nano-sized particles after the introduction of a third nucleotide (for example, dioxythymidine triphosphate)</p>

750 Synthesis cycle by succession to add another quaternary base?

<p dir="rtl">10 755 Unblocking and splitting nano-sized particles</p>

810 Introduction of nucleotides

815 Detecting the first signal to distinguish the base

820 Flow of nano-sized anti-digoxigenin particles and SS moiety solution through the flow cell

825 Detect a second signal to distinguish the base

<p dir="rtl">15 835, 1025, 1135, 1225, 1325 Synthesis cycle by other series?</p>

840, 1030, 1140, 1230 blocking/slitting jaw

815 First reveal

820 Anti-digoxigenin NP SS cleavage method

825 Second reveal

<p dir="rtl">20 810 Enter “G” not marked</p>

Biotin - A-LN3-SS

Biotin C-LN3

T-LN3-DIG

1010 Introduction of nucleotides

<p dir="rtl">25 1015 Signal detection</p>

1010, 1220 Alerts are made based on a magnetic volume using a bioinformatics program.

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1110 Introduction of tagged nucleotides with a single-molecule magnet

1115 Detect the first base (for example, A) using the first set of light on/off frequencies

1120 Detect a second base (for example, G) using a first set of light on/off frequencies

1125 Detect a third base (for example, C) using a first set of light on/off frequencies

<p dir="rtl">5 1130 Detection of base four (for example, T) using the first set of light on/off sequences</p>

1210 Introduction of tagged nucleotides with a single-molecule magnet

1215 Detecting signals using TAKARART to close/open a light using

1310 Introduction of nucleotides

1315 Detection of single-molecule magnetic signal of rice polymer

<p dir="rtl">10 1310 Base alerts on the nucleotide insertion rate are implemented using a bioinformatics program</p>

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