Mechanical Handling Apparatus

A apparatus for handling a load. An elongate support plate for supporting the load is mounted to an elongate housing of a base from which two substantially upstanding side members extend. A load handling means provided in the housing is registered with the support plate, said load handling means having a retracted position. Other elements include a moving means provided in the housing. 1. A mechanical handling apparatus for handling a load , the apparatus comprising:an elongate housing, comprised of a base from which two substantially upstanding side members extend,an elongate support plate for supporting the load, said support plate being mounted with respect to the housing and having at least two apertures therein,a load handling means provided in the housing in register with the apertures in the support plate, said load handling means having a retracted position within the housing and a non-refracted position in which at least a portion thereof protrudes through the apertures in the support plate,a closed-end channel member provided in the housing, said channel member having an upper position adjacent to the support plate and a lower position adjacent to the base of the housing, anda moving means provided in the housing that is capable of moving both the load handling means and the channel member with respect to both the housing and the support plate,wherein the base of the housing is provided with a pair of elongate protrusions, which extend into the housing, between which the moving means is provided and onto which the channel member is capable of resting in its lower position.2. A mechanical handling apparatus as claimed in wherein the load handling means is moveable between its retracted position and its non-retracted position claim 1 , the channel member is moveable between its upper position and its lower position claim 1 , and the moving means is capable of moving both the load handling means and the channel member between their respective positions.3. A ...

SYSTEM AND METHOD FOR DESCRIBING SOFTWARE REQUIREMENT LOGIC

The present invention is a system to describe software requirement logic that includes a plurality of software requirements and an exclusive natural deduction style of formal reasoning that includes a plurality of connectives and a plurality of corresponding Latinate. The connectives include the group consisting of and, if-then, or, or not and the Latinate include the group consisting of conjunction, implication, disjunction or negation. The software requirements are included in a requirement phase and an implementation phase of a traditional software development cycle. The present invention also includes a method for describing software requirement logic.

CROSS-STORE ELECTRONIC DISCOVERY

An electronic discovery (eDiscovery) application is used in managing an electronic discovery process across different electronic data sources using a central interface. The eDiscovery application assists in managing: authentication support for the different data sources; accessing the different data sources; placing holds on content across the different data sources; searching and filtering content across the different data sources; gathering data across the data sources; and the like. The eDiscovery application may be configured as an application on premise, a cloud based service and/or a combination of a cloud based service and an application. 1. A method of electronic discovery across different data sources , comprising:determining different data sources to include in an electronic discovery process;determining an operation to perform on data that is included in the different data sources; andperforming the operation on the identified data across the different source using mechanisms provided by the data source, wherein at least a portion of the different data sources are actively servicing requests relating to the data stored therein.2. The method of claim 1 , further comprising performing a search across the different data stores using provided search capabilities when available from each of the different data stores.3. The method of claim 1 , wherein determining the operation to perform comprises determining that the operation is a hold command that when performed places a hold on the identified data that preserves the data in a current state and preserving the identified data in place within the data source when the data source allows in place preservation.4. The method of claim 2 , further comprising automatically exporting the data for preservation when the data source does not allow in place preservation of the identified data.5. The method of claim 1 , displaying a user interface that allows selection of the different data sources claim 1 , wherein the ...

LOCATING RELEVANT CONTENT ITEMS ACROSS MULTIPLE DISPARATE CONTENT SOURCES

Technologies are described herein for locating relevant content items across multiple disparate content sources. Query parameters are received from a user interface for defining a query for searching a number of content sources located on multiple, disparate content servers. A native search is executed on each of the content servers based on the received query parameters, and query statistics and other data regarding content items in the content sources matching the query parameters are received. The query statistics are aggregated across the content servers and presented in the user interface. The presentation of the query statistics may be broken out by each content source, by each query phrase segmented from the query, and the like. In addition, a preview of a number of content items matching the query parameters is presented based on the data received. 1. A system for locating content items in a plurality of content sources across different content servers , the system comprising:one or more processors;a memory coupled to the one or more processors; and present a user interface for defining a query for searching the plurality of content sources,', 'receive query parameters and a query scope regarding the query, the query scope comprising content sources located on at least two content servers of different types,', 'receive query statistics from searches executed by each of the at least two content servers based on the query parameters,', 'aggregate the query statistics from the at least two content servers and present the aggregated query statistics in the user interface, wherein the query statistics are shown regarding each of the plurality of content sources,', 'retrieve data regarding content items matching the query from the at least two content servers, and', 'present a preview of the content items matching the query in the user interface from the retrieved data., 'an e-discovery client application residing in the memory and comprising computer-executable ...

EFFICIENT IN-PLACE PRESERVATION OF CONTENT ACROSS CONTENT SOURCES

Technologies are described herein for providing efficient in-place preservation of content in multiple, disparate content sources without disrupting end-users' access to the content or content sources. A preservation request comprising a specification of a content source and a filter specification is received and the content source is marked as “on hold.” If a content item in the content source is modified or deleted, a copy of the current version of the content item is placed in a preservation storage area. A trim job may be run periodically that removes content items from the preservation storage area that do not match the filter specification. 1. A system for providing in-place preservation of content items in a content source , the system comprising:one or more processors;a memory coupled to the one or more processors; detect that a content item in the content source has been modified or deleted,', 'upon detecting that the content item has been modified or deleted, determine whether a hold is in effect for the content source,', 'upon determining that the hold is in effect for the content source, determine whether the content item has been deleted or modified,', 'upon determining that the content item has been deleted, place a current version of the content item in a preservation storage area,', 'upon determining that the content item has been modified, determine whether a modified date of the current version of the content item is less than or equal to a preservation date associated with the hold, and', 'upon determining that the modified date of the current version of the content item is less than or equal to the preservation date, place the current version of the content item in the preservation storage area; and, 'a hold manager module residing in the memory and comprising computer-executable instructions that, when executed by the one or more processors, cause the system to'} locate one or more content items in the preservation storage area that do not match ...

Nuclease-Mediated Targeting With Large Targeting Vectors

Compositions and methods are provided for making one or more targeted genetic modifications at a target genomic locus by employing homologous recombination facilitated by single or double-strand break at or near the target genomic locus. Compositions and methods for promoting efficiency of homologous recombination between an LTVEC and a target genomic locus in prokaryotic or eukaryotic cells using engineered nucleases are also provided. 1. A method for modifying a target genomic locus in a mammalian cell , comprising: (i) a nuclease agent that makes a single or double-strand break at or near a target genomic locus, and', '(ii) a large targeting vector (LTVEC) comprising an insert nucleic acid flanked with an upstream homology arm and a downstream homology arm; and, '(a) introducing into a mammalian cell(b) selecting a targeted mammalian cell comprising the insert nucleic acid in the target genomic locus.2. The method of claim 1 , wherein the mammalian cell is a pluripotent cell.3. The method of claim 1 , wherein the mammalian cell is an induced pluripotent stem (iPS) cell.4. The method of claim 2 , wherein the pluripotent cell is a mouse embryonic stem (ES) cell.5. The method of claim 2 , wherein the pluripotent cell is a hematopoietic stem cell.6. The method of claim 2 , wherein the pluripotent cell is a neuronal stem cell.7. The method of claim 1 , wherein the mammalian cell is a human fibroblast.8. The method of claim 1 , wherein the mammalian cell is a human cell isolated from a patient having a disease claim 1 , and wherein the human cell comprises at least one human disease allele in its genome.9. The method of claim 8 , wherein integration of the insert nucleic acid into the target genomic locus replaces the at least one human disease allele in the genome.10. The method of claim 1 , wherein combined use of the LTVEC with the nuclease agent results in an increased targeting efficiency compared to use of the LTVEC alone.11. The method of claim 10 , wherein the ...

HIGH POROSITY ACOUSTIC BACKING WITH HIGH THERMAL CONDUCTIVITY FOR ULTRASOUND TRANDUCER ARRAY

A backing block for an ultrasonic transducer array stack of an ultrasound probe is formed as a composite structure of graphite foam impregnated with an epoxy resin. The epoxy resin penetrates the porous foam structure at least part-way into the depth of the graphite foam block and, when cured, provides the backing block with good structural stability. The composite graphite foam backing block is bonded to the integrated circuit of a transducer to provide high thermal conductivity away from the transducer and good acoustic attenuation or scattering of rearward acoustic reverberations. 1. An ultrasonic transducer array assembly comprising:an array of transducer elements having a forward desired direction for the transmission of ultrasonic waves and a rearward undesired ultrasonic emission direction;an integrated circuit structurally coupled to the array of transducer elements;a composite foam backing block, located rearward of the array of transducer elements and integrated circuit, the composite foam backing block being formed of a foam material having a high thermal conductivity and a porous structure; andan epoxy resin filling at least some of the porous structure of the foam backing block,wherein ultrasonic emissions in the rearward direction is scattered or attenuated by the porous foam structure and epoxy, and heat is conducted away from the array of transducer elements and integrated circuit by the backing block material.2. The ultrasonic transducer array assembly of claim 1 , wherein the foam material further comprises a graphite foam.3. The ultrasonic transducer array assembly of claim 1 , wherein the composite foam backing block further comprises an exterior surface claim 1 , and wherein the epoxy resin fills the porous structure of the foam backing block adjacent to the exterior surface.4. The ultrasonic transducer array assembly of claim 1 , wherein the integrated circuit further comprises a beamformer ASIC coupled to the rearward side of the array of ...

METHODS AND COMPOSITIONS FOR TARGETED GENETIC MODIFICATION USING PAIRED GUIDE RNAS

Compositions and methods are provided for creating and promoting biallelic targeted modifications to genomes within cells and for producing non-human animals comprising the modified genomes. Also provided are compositions and methods for modifying a genome within a cell that is heterozygous for an allele to become homozygous for that allele. The methods make use of Cas proteins and two or more guide RNAs that target different locations within the same genomic target locus. Also provided are methods of identifying cells with modified genomes. 1. A method for modifying a genome within a cell that is heterozygous for a first allele , comprising: (a) a Cas protein or a nucleic acid encoding the Cas protein; and', '(b) a first guide RNA or a DNA encoding the first guide RNA, wherein the first guide RNA comprises a first tracrRNA and a first CRISPR RNA, wherein the first guide RNA hybridizes to a first CRISPR RNA recognition sequence, wherein the first allele is on a first homologous chromosome and the CRISPR RNA recognition sequence is centromeric to the locus corresponding to the first allele on a second homologous chromosome', 'wherein the Cas protein and the first guide RNA do not naturally occur together; and', 'wherein the Cas protein cleaves the first CRISPR RNA recognition sequence to generate a double-strand break and the cell is modified to become homozygous for the first allele; and, '(I) introducing into the cell(II) identifying a modified cell that is homozygous for the first allele.229.-. (canceled)30. The method of claim 1 , wherein loss of heterozygosity occurs telomeric of the double-strand break.31. The method of claim 1 , further comprising introducing into the cell a second guide RNA or a DNA encoding the second guide RNA claim 1 ,wherein the second guide RNA comprises a second tracrRNA and a second CRISPR RNA,wherein the second guide RNA hybridizes to a second CRISPR RNA recognition sequence centromeric to the locus corresponding to the first allele ...

METHODS AND COMPOSITIONS FOR TARGETED GENETIC MODIFICATION USING PAIRED GUIDE RNAS

Compositions and methods are provided for creating and promoting biallelic targeted modifications to genomes within cells and for producing non-human animals comprising the modified genomes. Also provided are compositions and methods for modifying a genome within a cell that is heterozygous for an allele to become homozygous for that allele. The methods make use of Cas proteins and two or more guide RNAs that target different locations within the same genomic target locus. Also provided are methods of identifying cells with modified genomes. 1114.-. (canceled)115. An in vitro method for making a biallelic modification to a genomic target locus in a genome within a cell , comprising: (a) a Cas protein or a nucleic acid encoding the Cas protein;', '(b) a first guide RNA or a DNA encoding the first guide RNA, wherein the first guide RNA hybridizes to a first CRISPR RNA recognition sequence within the genomic target locus;', '(c) a second guide RNA or a DNA encoding the second guide RNA, wherein the second guide RNA hybridizes to a second CRISPR RNA recognition sequence within the genomic target locus; and', '(d) a targeting vector comprising a nucleic acid insert flanked by a 5′ homology arm that hybridizes to a 5′ target sequence within the genomic target locus and a 3′ homology arm that hybridizes to a 3′ target sequence within the genomic target locus;', 'wherein the genome comprises a pair of first and second homologous chromosomes comprising the genomic target locus; and', 'wherein the Cas protein cleaves at least one of the first and second CRISPR RNA recognition sequences to generate at least one double-strand break; and, '(I) introducing into a population of cells(II) identifying a cell comprising a modified genomic target locus comprising a biallelic modification comprising a deletion and/or an insertion, wherein the identifying comprises: [ (i) a gain-of-allele assay to determine a copy number of a region of the nucleic acid insert in a genomic DNA sample ...

LOCKLESS MEASUREMENT OF EXECUTION TIME OF CONCURRENTLY EXECUTED SEQUENCES OF COMPUTER PROGRAM INSTRUCTIONS

A computer system supports measuring execution time of concurrent threads. A thread allocates a timing buffer in thread local storage. During execution, the thread also has access to a system timer which it can sample with microsecond or better precision with a single instruction. For any sequence of instructions within the thread for which execution time is to be measured, the sequence of instructions has an identifier and includes two commands, herein called a start command and an end command. The start command samples the system timer to obtain a start time, and stores the identifier and the start time in the timing buffer in the thread local storage. The end command samples the system timer to obtain an end time, and updates the data for the corresponding identifier in the timing buffer, to indicate an elapsed time for execution of the sequence of instructions. The start command and end command each can be implemented as a single executable instruction. 1. A computer comprising:a processing system comprising a processing unit and a memory accessible by threads executed by the processing system, and having a system timer, the processing system configured to:for a first thread to be executed by the processing system, allocate a first buffer in first thread local storage in the memory;for a second thread to be executed concurrently by the processing system, and different from the first thread, allocating a second buffer separate from the first buffer and in second thread local storage in the memory; sample the system timer at a time of execution of the first start command to provide a first start time; and', 'store, in the first buffer, an identifier of the first sequence of instructions and the first start time;, 'in response to execution of a first start command at a beginning of a first sequence of instructions for the first thread sample the system timer at a time of execution of the first end command to provide a first end time; and', 'store, in the first ...

IMAGING ASSEMBLY FOR INTRALUMINAL IMAGING

An intraluminal imaging device is provided. In one embodiment, the imaging device includes a flexible elongate member that may to be inserted into a body lumen within a patient. The flexible elongate member has a central longitudinal axis. The imaging device also has an imaging assembly that is disposed at a distal portion of the flexible elongate member. The imaging assembly comprises a flexible substrate and a plurality of ultrasound transducer elements. The plurality of ultrasound transducer elements are disposed on the flexible substrate. The flexible substrate is disposed around the central longitudinal axis of the flexible elongate member such that the ultrasound transducer elements are oriented to face away from the central longitudinal axis and the flexible substrate. 1. An intraluminal imaging device , comprising:a flexible elongate member configured to be inserted into a body lumen within a patient, the flexible elongate member comprising a central longitudinal axis; a flexible substrate; and', 'a plurality of ultrasound transducer elements disposed on the flexible substrate,', 'wherein the flexible substrate is disposed around the central longitudinal axis of the flexible elongate member such that the ultrasound transducer elements are oriented to face away from the central longitudinal axis and the flexible substrate., 'an imaging assembly disposed at a distal portion of the flexible elongate member, the imaging assembly comprising2. The intraluminal imaging device of claim 1 , wherein the imaging assembly further comprises:a support member, wherein the flexible substrate is positioned around the support member.3. The intraluminal imaging device of claim 2 , wherein the imaging assembly further comprising:a backing material disposed between the flexible substrate and the support member.4. The intraluminal imaging device of claim 2 , wherein the support member disposed longitudinally along the central longitudinal axis of the flexible elongate member.5. ...

COORDINATING FILE SYNCHRONIZATION BETWEEN A SYNC ENGINE AND ANOTHER APPLICATION THAT SUPPORTS DOCUMENT COLLABORATION

A synchronization engine detects a notification of a change to a file. It determines whether an application associated with the file has indicated that the file is to be synchronized by the application. If so, the changes to the file are synchronized between a cloud-based storage system and a local disk by the application. Collaborative metadata, associated with the synchronized file, is updated to indicate a state of a copy of the file on the local disk and a copy of the file in the cloud-based storage system. The collaborative metadata is stored by the synchronization engine. 1. A computing system , comprising:file synchronization logic that synchronizes changes to a file that has a corresponding cloud file stored on a cloud based storage system and a corresponding local file stored on a local file system;backoff processing logic that receives a backoff indicator corresponding to the file and determines, based on the backoff indicator, whether the file synchronization logic is to synchronize the changes to the file or to backoff and allow the changes to be synchronized by a co-authoring application andmetadata computing logic that maintains a first set of collaborative metadata indicative of content and a version of the cloud file and a second set of collaborative metadata indicative of content and a version of the local file.2. The computing system of wherein the backoff processing logic determines whether the file synchronization logic is to backoff by determining whether the file is open by a co-authoring application and claim 1 , if so claim 1 , indicates to the file synchronization logic that the file is locked.3. The computing system of wherein the computing system exposes a metadata interface that can be invoked by the co-authoring application to obtain and set the collaborative metadata for the local file.4. The computing system of wherein the metadata computing logic maintains the first set of collaborative metadata by generating a first hash value that ...

METHODS AND COMPOSITIONS FOR TARGETED GENETIC MODIFICATIONS AND METHODS OF USE

Methods and compositions are provided for generating targeted genetic modifications on the Y chromosome or a challenging target locus. Compositions include an in vitro culture comprising an XY pluripotent and/or totipotent animal cell (i.e., XY ES cells or XY iPS cells) having a modification that decreases the level and/or activity of an Sry protein; and, culturing these cells in a medium that promotes development of XY F0 fertile females. Such compositions find use in various methods for making a fertile female XY non-human mammal in an F0 generation. 156.-. (canceled)57. A method for modifying a target genomic locus on the Y chromosome in a cell , comprising:(a) providing a population of cells comprising a target genomic locus on the Y chromosome;(b) introducing into the population of cells of step (a) a large targeting vector comprising an insert polynucleotide flanked by first and second homology arms corresponding to first and second target sites located in the target genomic locus on the Y chromosome, wherein the sum total of the first and second homology arms is from 10 kb to 200 kb, and wherein the large targeting vector undergoes homologous recombination with the target genomic locus on the Y chromosome; and(c) identifying a cell from step (b) comprising in its genome the insert polynucleotide integrated at the target genomic locus on the Y chromosome.58. The method of claim 57 , wherein the cells in step (a) are mammalian cells.59. The method of claim 58 , wherein the cells in step (a) are mouse cells.60. The method of claim 59 , wherein the cells in step (a) are mouse embryonic stem (ES) cells.61. The method of claim 57 , wherein the target genomic locus on the Y chromosome is repeat-rich.62. The method of claim 57 , wherein the target genomic locus on the Y chromosome is a Sry gene claim 57 , a Uty gene claim 57 , an Eif2s3y gene claim 57 , a Ddx3y gene claim 57 , a Ube1y gene claim 57 , a Tspy gene claim 57 , a Usp9y gene claim 57 , a Zfy1 gene claim 57 ...

Ic die, probe and ultrasound system

An integrated circuit die is disclosed that comprises a substrate defining a plurality of circuit elements; a sensor region on the substrate, the sensor region comprising a layer stack defining a plurality of CMUT (capacitive micromachined ultrasound transducer) cells; and an interposer region on the substrate adjacent to the sensor region. The interposer region comprises a further layer stack including conductive connections to the circuit elements and the CMUT cells, the conductive connections connected to a plurality of conductive contact regions on an upper surface of the interposer region, the conductive contact regions including external contacts for contacting the integrated circuit die to a connection cable and mounting pads for mounting a passive component on the upper surface. A probe including such an integrated circuit die an ultrasound system including such a probe are also disclosed.

ULTRASOUND IMAGING DEVICE WITH THERMALLY CONDUCTIVE PLATE

A device for imaging within a body of a patient is provided. In one embodiment, the device includes a flexible elongate member that can be inserted into the body of the patient. The device also has an imaging assembly that is disposed at and extending a length of a distal portion of the flexible elongate member. The imaging assembly may include an array () of imaging elements that may have an outward surface and an inward surface. The imaging assembly may further include an integrated circuit () adjacent to the inward surface of the array of imaging elements. The device may further include a conductive plate () adjacent to and extending at least a portion of a length of the imaging assembly. The conductive plate may receive heat generated by at least one of the array of imaging elements or the integrated circuit. 1. A device for imaging within a body of a patient , comprising:a flexible elongate member configured to be inserted into the body of the patient; an array of imaging elements comprising an outward surface and an inward surface; and', 'an integrated circuit adjacent to the inward surface of the array of imaging elements; and, 'an imaging assembly disposed at and extending a length of a distal portion of the flexible elongate member, the imaging assembly comprisinga conductive plate adjacent to and extending at least a portion of a length of the imaging assembly, the conductive plate configured to receive heat generated by at least one of the array of imaging elements or the integrated circuit, andwherein the plate comprises a stiffness greater than a stiffness of the array of imaging elements such that the plate inhibits deflection of the array of imaging elements.2. (canceled)3. The device of claim 1 , wherein the plate comprises a metal.4. The device of claim 1 , wherein the plate is radiopaque.5. The device of claim 1 , wherein a cross section of the plate has a rectangular shape claim 1 , a t-shape claim 1 , or a semi-circular shape.6. The device of ...

LOCATING RELEVANT CONTENT ITEMS ACROSS MULTIPLE DISPARATE CONTENT SOURCES

Technologies are described herein for locating relevant content items across multiple disparate content sources. Query parameters are received from a user interface for defining a query for searching a number of content sources located on multiple, disparate content servers. A native search is executed on each of the content servers based on the received query parameters, and query statistics and other data regarding content items in the content sources matching the query parameters are received. The query statistics are aggregated across the content servers and presented in the user interface. The presentation of the query statistics may be broken out by each content source, by each query phrase segmented from the query, and the like. In addition, a preview of a number of content items matching the query parameters is presented based on the data received. 1. A system for locating content items in a plurality of content sources across different content servers , the system comprising:one or more processors;a memory coupled to the one or more processors; and receive query parameters and a query scope regarding a query, the query scope comprising content sources located on at least two content servers of different types;', 'initiate a segmentation process, wherein the segmentation process comprises iterative searches based on groupings of the query parameters;', 'receive data regarding content items located through the iterative searches executed by each of the at least two content servers based on the query parameters;', 'aggregate query statistics from the at least two content servers from the received data;', 'and', 'present the query statistics., 'an e-discovery client application residing in the memory and comprising computer-executable instructions that, when executed by the one or more processors, cause the system to2. The system of claim 1 , wherein the query statistics are presented regarding each of a plurality of query phrases segmented from a free-text ...

GENETIC MODIFICATION OF RATS

Compositions and methods are provided for making rat pluripotent and totipotent cells, including rat embryonic stem (ES) cells. Compositions and methods for improving efficiency or frequency of germline transmission of genetic modifications in rats are provided. Such methods and compositions comprise an in vitro culture comprising a feeder cell layer and a population of rat ES cells or a rat ES cell line, wherein the in vitro culture conditions maintain pluripotency of the ES cell and comprises a media having mouse leukemia inhibitory factor (LIF) or an active variant or fragment thereof. Various methods of establishing such rat ES cell lines are further provided. Methods of selecting genetically modified rat ES cells are also provided, along with various methods to generate a transgenic rat from the genetically modified rat ES cells provided herein. Various kits and articles of manufacture are further provided. 1118.-. (canceled)119. A method of making a genetically modified rat comprising: lacks expression of c-Myc;', 'forms spherical, free-floating colonies in culture;', 'is diploid; and', 'is germline competent;, '(a) providing a rat ES cell line comprising a population of rat ES cells obtained by culturing isolated rat ES cells on a feeder cell layer that is not modified to express leukemia inhibitory factor (LIF) with a medium comprising N2 supplement, B27 supplement, about 50 U/mL to about 150 U/mL LIF, and a combination of inhibitors consisting of MEK inhibitor PD0325901 and GSK3 inhibitor CHIR99021, wherein the population of rat ES cells(b) modifying the population of rat ES cells to comprise a targeted genetic modification;(c) identifying a rat ES cell clone comprising the targeted genetic modification;(d) introducing the rat ES cell clone into a rat host embryo; and(e) gestating the rat host embryo comprising the rat ES cell clone in a surrogate mother, wherein the surrogate mother produces F0 progeny comprising the targeted genetic modification, wherein ...

Nuclease-Mediated Targeting With Large Targeting Vectors

Compositions and methods are provided for making one or more targeted genetic modifications at a target genomic locus by employing homologous recombination facilitated by single or double-strand break at or near the target genomic locus. Compositions and methods for promoting efficiency of homologous recombination between an LTVEC and a target genomic locus in prokaryotic or eukaryotic cells using engineered nucleases are also provided. 164.-. (canceled)65. A method for modifying a target genomic locus in a mouse embryonic stem (ES) cell , comprising: (i) a zinc finger nuclease (ZFN) that makes a double-strand break at or near a target genomic locus; and', '(ii) a large targeting vector (LTVEC) comprising an insert nucleic acid flanked by an upstream homology arm and a downstream homology arm,', 'wherein the insert nucleic acid ranges from 5 kb to 30 kb in length,', 'wherein the sum total of the upstream and downstream homology arms is at least 10 kb in length,', 'wherein the upstream and downstream homology arms are between 5 kb and 200 kb in length, and', 'wherein the LTVEC ranges from 50 kb to 300 kb in length; and, '(a) introducing into the mouse ES cell(b) assaying the mouse ES cell for integration of the insert nucleic acid into the target genomic locus, wherein the integration results in deletion of an endogenous nucleic acid sequence at the target genomic locus and replacement with the insert nucleic acid; and(c) selecting a targeted mouse ES cell comprising the insert nucleic acid in the target genomic locus, wherein combined use of the LTVEC with the ZFN results in an increased targeting efficiency compared to use of the LTVEC alone.66. The method of claim 65 , wherein the targeting efficiency is increased at least two-fold compared to use of the LTVEC alone.67. The method of claim 65 , wherein:(I) the ZFN is an expression construct comprising a nucleic acid sequence encoding a ZFN protein, and wherein the nucleic acid is operably linked to a promoter ...

METHODS AND COMPOSITIONS FOR TARGETED GENETIC MODIFICATIONS AND METHODS OF USE

Methods and compositions are provided for generating targeted genetic modifications on the Y chromosome or a challenging target locus. Compositions include an in vitro culture comprising an XY pluripotent and/or totipotent animal cell (i.e., XY ES cells or XY iPS cells) having a modification that decreases the level and/or activity of an Sry protein; and, culturing these cells in a medium that promotes development of XY F0 fertile females. Such compositions find use in various methods for making a fertile female XY non-human mammal in an F0 generation. 1. A method for making a mouse XY embryonic stem (ES) cell line capable of producing a fertile XY female mouse in an F0 generation , comprising:(a) modifying a mouse XY ES cell to comprise a modification that decreases the level and/or activity of an Sry protein, wherein the mouse XY ES cell comprises a Y chromosome derived from a 129 strain; and(b) culturing the modified mouse XY ES cell under conditions that allow for making a mouse XY ES cell line capable of producing a fertile XY female mouse in an F0 generation.2. The method of claim 1 , further comprising:(c) introducing the modified mouse XY ES cell into a host embryo;(d) gestating the host embryo; and(e) obtaining an F0 XY female mouse, wherein upon attaining sexual maturity the F0 XY female mouse is fertile.3. The method of claim 1 , wherein the mouse XY ES cell is a VGF1 mouse ES cell.4. The method of claim 1 , wherein the decreased level and/or activity of the Sry protein results from a targeted genetic modification at the genomic locus comprising the Sry gene.5. The method of claim 4 , wherein the genetic modification in the Sry gene comprises a modification selected from the group consisting of:(I) an insertion of one or more nucleotides, a deletion of one or more nucleotides, a substitution of one or more nucleotides, a knockout, a knockin, a replacement of an endogenous nucleic acid sequence with a homologous, orthologous, or heterologous nucleic acid ...

METHODS AND COMPOSITIONS FOR THE TARGETED MODIFICATION OF A GENOME

Compositions and methods are provided for modifying a genomic locus of interest in a eukaryotic cell, a mammalian cell, a human cell or a non-human mammalian cell using a large targeting vector (LTVEC) comprising various endogenous or exogenous nucleic acid sequences as described herein. Further methods combine the use of the LTVEC with a CRISPR/Cas system. Compositions and methods for generating a genetically modified non-human animal comprising one or more targeted genetic modifications in their germline are also provided. 1. An in vitro method for modifying a genome at a genomic locus of interest in a rodent cell , comprising:contacting the rodent cell with a Cas9 protein, a CRISPR RNA that hybridizes to a CRISPR target sequence at the genomic locus of interest, a tracrRNA, and a large targeting vector (LTVEC) that is at least 10 kb in size and comprises an insert nucleic acid flanked by:(i) a 5′ homology arm that is homologous to a 5′ target sequence at the genomic locus of interest; and(ii) a 3′ homology arm that is homologous to a 3′ target sequence at the genomic locus of interest,wherein following contacting the rodent cell with the Cas9 protein, the CRISPR RNA, and the tracrRNA in the presence of the LTVEC, the genome of the rodent cell is modified to comprise a targeted genetic modification comprising deletion of a region of the genomic locus of interest wherein the deletion is at least 30 kb and/or insertion of the insert nucleic acid at the genomic locus of interest wherein the insertion is at least 30 kb.2. The method of claim 1 , wherein the CRISPR RNA and the tracrRNA are introduced as a single nucleic acid molecule comprising the CRISPR RNA and the tracrRNA.3. The method of claim 2 , wherein the single nucleic acid molecule comprises the CRISPR RNA and the tracrRNA fused together in the form of a single guide RNA (sgRNA).4. The method of claim 1 , wherein the CRISPR RNA and the tracrRNA are introduced separately.5. The method of claim 1 , wherein:(a) ...

ULTRASOUND TRANSDUCER ASSEMBLY AND METHOD OF MANUFACTURING THE SAME

The present invention relates to an ultrasound transducer assembly () comprising ultrasound transducer elements () for transmitting ultrasound waves in a general transmission direction (A). Each of or each of part of the ultrasound transducer elements () comprises a piezoelectric layer () having a top surface, a bottom surface and a side surface with respect to the general transmission direction (A), as well as a bottom electrode layer () and a top electrode layer (). A conductive layer () is applied at least partly on the side surface of at least one specific one () of the piezoelectric layers, such that the conductive layer () is connected to the top electrode layer () and the bottom electrode layer () of said specific piezoelectric layer (). 2. The ultrasound transducer assembly of claim 1 , wherein the ultrasound transducer element having the side surface conductive layer is a dummy element not operable to transmit or receive ultrasound waves.3. The ultrasound transducer assembly of claim 1 , wherein the ultrasound transducer element having the side surface conductive layer is the outermost ultrasound transducer element in the row of the ultrasound transducer elements.4. The ultrasound transducer assembly of claim 3 , wherein the side surface to which the conductive layer is applied is the side surface facing outward in the row of the ultrasound transducer elements.5. (canceled)6. The ultrasound transducer assembly of claim 1 , further comprising at least one de-matching layer applied to the bottom electrode layer.7. The ultrasound transducer assembly of claim 6 , wherein the conductive layer is further applied on the side surface of the de-matching layer.8. (canceled)9. The ultrasound transducer assembly of claim 1 , wherein each of the bottom electrode layers of the ultrasound transducers elements is connected to the semiconductor chip.10. The ultrasound transducer assembly of claim 1 , wherein the bottom electrode layer of the ultrasound transducer element ...

PRODUCTION OF FERTILE XY FEMALE ANIMALS FROM XY ES CELLS

Methods and compositions are described for making phenotypically female fertile animals from XY donor cells and suitable host embryos. Culture media and methods are provided for maintaining XY donor cells in culture that after introduction into a host embryo and gestation in a suitable host will result in fertile XY female animals. Methods and compositions are described for making fertile female animals in an F generation from a donor XY cell and a host embryo, as are methods for making F progeny that are homozygous for a modification from a heterozygous F fertile male and a heterozygous F fertile female sibling. 120-. (canceled)21. A method for generating an embryo comprising:(a) culturing a donor XY non-human embryonic stem (ES) cell in a medium comprising a base medium and supplements, wherein the base medium comprises a salt of an alkaline metal and a halide in a concentration of about 50-110 mM, a carbonic acid salt in a concentration of about 17-30 mM, and has an osmolality of about 200-329 mOsm/kg;(b) introducing the donor XY non-human ES cell derived from step (a) into a pre-morula host embryo; and(c) culturing the host embryo of step (b) to the blastocyst stage; wherein at least 90% of the cells of the non-human animal that develops from the host embryo are derived from the donor XY non-human ES cell.22. The method of claim 21 , further comprising:(d) introducing the host embryo of step (c) into a surrogate mother for gestation; and{'b': '0', '(e) obtaining an XY F non-human animal.'}23. The method of claim 22 , wherein the base medium comprises 50±5 mM NaCl claim 22 , 26±5 mM sodium bicarbonate claim 22 , and has an osmolality of about 218±22 mOsm/kg.24. The method of claim 22 , wherein the base medium comprises about 3 mg/mL NaCl claim 22 , about 2.2 mg/mL sodium bicarbonate claim 22 , and has an osmolality of about 218 mOsm/kg.25. The method of claim 24 , wherein the base medium further comprises about 4.5 mg/mL glucose.26. The method of claim 22 , ...

Methods and compositions for the targeted modification of a genome

Compositions and methods are provided for modifying a genomic locus of interest in a eukaryotic cell, a mammalian cell, a human cell or a non-human mammalian cell using a large targeting vector (LTVEC) comprising various endogenous or exogenous nucleic acid sequences as described herein. Further methods combine the use of the LTVEC with a CRISPR/Cas system. Compositions and methods for generating a genetically modified non-human animal comprising one or more targeted genetic modifications in their germline are also provided.

Production Of Fertile XY Female Animals By Silencing Of Genes On The Y Chromosome

Methods and compositions are provided for generating F0 fertile XY female animals. The methods and compositions involve making XY pluripotent or totipotent animal cells, in vitro cell cultures, or embryos that are capable of producing a fertile female XY animal in an F0 generation. Such cells, embryos, and animals can be made by silencing a region of the Y chromosome. Optionally, the cells can also be cultured in feminizing medium such as a low-osmolality medium and/or can be modified to decrease the level and/or activity of an Sry protein. Methods and compositions are also provided for silencing a region of the Y chromosome in an XY pluripotent or totipotent animal cell, or in vitro cell cultures, embryos, or animals derived therefrom, by maintaining an XY pluripotent or totipotent animal cell in a feminizing medium. Methods and compositions are also provided for maintaining a population of XY pluripotent or totipotent animal cells in a feminizing medium and selecting cells or clones having increased capabilities for producing a fertile female XY animal in an F0 generation. Methods and compositions are also provided for screening for compounds with feminizing activity or for optimizing concentrations of components in feminizing media. 1. A method for screening a target compound for feminizing activity in non-human mammalian XY pluripotent cells , comprising:(a) culturing a first population and a second population of non-human mammalian XY pluripotent cells in a medium comprising a base medium and supplements suitable for maintaining the pluripotency of the non-human mammalian XY pluripotent cells, wherein the first population is cultured in the presence of a target compound and the second population is cultured in the absence of the target compound;(b) assaying one or more of the non-human mammalian XY pluripotent cells in each of the first and second populations of non-human mammalian XY pluripotent cells for expression and/or activity of one or more of Ddx3y, Uty ...

ULTRASONIC MATRIX ARRAY PROBE WITH THERMALLY DISSIPATING CABLE AND BACKING BLOCK HEAT EXCHANGE

A matrix array probe including a transducer array and integrated circuitry coupled to the transducer elements dissipates heat generated by the array and integrated circuitry through the cover of the transducer probe. A pump in the probe connector pumps fluid through a closed loop system including inbound an outbound fluid conduits in the cable. The fluid conduits in the cable are separated by the cable electrical conductors for the probe. The heat transfer in the probe is done by a heat exchanger in the transducer backing block. Additional cooling may be provided by metal to metal contact with a chiller in the ultrasound system. 2. The ultrasonic transducer probe assembly of claim 1 , wherein the closed fluid loop further comprises an inbound fluid conduit and an outbound fluid conduit claim 1 ,wherein the inbound and outbound fluid conduits are coupled to the fluid channel of the thermally conductive backing block.3. The ultrasonic transducer probe assembly of claim 2 , further comprising first and second fluid ports claim 2 , coupled to the fluid channel of the thermally conductive backing block claim 2 ,wherein the inbound fluid conduit is coupled to the first fluid port and the outbound fluid conduit is coupled to the second fluid port.4. The ultrasonic transducer probe assembly of claim 1 , wherein the thermally conductive backing block is formed of a material having a thermal conductivity at least as great as that of graphite and comprises a composite structure of acoustic dampening material located in the thermally conductive backing block.5. The ultrasonic transducer probe assembly of claim 4 , wherein the composite structure comprises a plurality of holes in the backing block which are filled with acoustic dampening material.6. The ultrasonic transducer probe assembly of claim 5 , wherein the holes further comprise a plurality of cylindrical holes formed in the backing block and extending from a top surface of the backing block to a bottom surface of the ...

PATIENT DATA MANAGEMENT SYSTEM

A patient data management (“PDM”) system is disclosed herein. The PDM can provide doctors with an efficient and accurate means to extract medical diagnostic and treatment information from multi-perspective time based medical data. Further, the PDM provides a means to reduce computer processing time when training a neural network using medical data. In one aspect, a PDM system includes a preprocessor. The preprocessor receives patient data from a computer interface. In one non-limiting example, the preprocessor uses machine learning to extract patterns (“features”) from the data. The preprocessor formats the extracted features into a multidimensional tensor. In one non-limiting example, the PDM system includes a convolutional neural network (“CNN”). The preprocessor provides the tensor to the CNN. The CNN processes the tensor and extracts diagnostic and treatment information. 1. An electronic system for determining features of medical data , the system comprising a processor comprising instructions that when executed perform the following method:receiving, patient medical data;converting the received patient medical data into a plurality of tensors;extracting from deep canonical correlation, features of the medical data shared across the tensors; andanalyzing the features from the medical data using a neural network to discover patterns in the medical data.2. The system of claim 1 , wherein the patient medical data comprises a plurality of data types claim 1 , the data types comprising a plurality of data points.3. The system of claim 2 , wherein the method further comprises separating the data for each data type claim 2 , into a plurality of data clusters claim 2 , wherein the data clusters comprise disease related data points represented as one dimensional vectors claim 2 , each vector representing a clinical episode.4. The system of claim 3 , wherein the method further comprises combining claim 3 , the vectors for the plurality data types into a plurality of ...

GENETIC MODIFICATION OF RATS

Compositions and methods are provided for making rat pluripotent and totipotent cells, including rat embryonic stem (ES) cells. Compositions and methods for improving efficiency or frequency of germline transmission of genetic modifications in rats are provided. Such methods and compositions comprise an in vitro culture comprising a feeder cell layer and a population of rat ES cells or a rat ES cell line, wherein the in vitro culture conditions maintain pluripotency of the ES cell and comprises a media having mouse leukemia inhibitory factor (LIF) or an active variant or fragment thereof. Various methods of establishing such rat ES cell lines are further provided. Methods of selecting genetically modified rat ES cells are also provided, along with various methods to generate a transgenic rat from the genetically modified rat ES cells provided herein. Various kits and articles of manufacture are further provided. 1. An isolated rat embryonic stem (ES) cell obtainable by culturing isolated rat ES cells on a feeder cell layer with a medium comprising N2 supplement , B27 supplement , a MEK inhibitor , a GSK3 inhibitor , and about 50 U/mL to about 150 U/mL leukemia inhibitory factor (LIF) ,wherein the feeder cell layer is not modified to express LIF, andwherein the isolated rat ES cell:(i) is capable of being modified to comprise a targeted genetic modification and transmitting the targeted genetic modification through the germline;(ii) has a normal karyotype; and(iii) lacks expression of c-Myc.2. The isolated rat ES cell of claim 1 , wherein the isolated rat ES cell has been modified to comprise the targeted genetic modification and is capable of transmitting the targeted genetic modification through the germline.3. The isolated rat ES cell of claim 1 , wherein the isolated rat ES cell is derived from an ACI rat or a Dark Agouti (DA) rat.4. The isolated rat ES cell of claim 1 , wherein the isolated rat ES cell is a male (XY) rat ES cell.5. The isolated rat ES cell of ...

METHODS AND COMPOSITIONS FOR GENERATING OR MAINTAINING PLURIPOTENT CELLS

Methods and compositions are provided for generating or maintaining human iPS cells in culture. Methods include the use of a low osmolality medium to make human iPS cells, or use of a low osmolality medium to maintain human iPS cells. Methods for making targeted genetic modification to human iPS cells cultured in low osmolality medium are also included. Compositions include human iPS cells cultured and maintained using the low osmolality medium defined herein. 1. An in vitro culture comprising:(a) a population of hiPSCs; and (i) a leukemia inhibitory factor (LIF) polypeptide;', '(ii) a glycogen synthase kinase 3 (GSK3) inhibitor; and', '(iii) a MEK inhibitor;', 'wherein the base medium has an osmolality of about 180 mOsm/kg to about 250 mOsm/kg., '(b) a low osmolality medium comprising a base medium and supplements, wherein the low osmolality medium comprises2. The in vitro culture of claim 1 , wherein the hiPSCs:(a) comprise naïve or naïve-looking hiPSCs;(b) express one or more pluripotency markers;(c) display a morphology characterized by compact dome-shaped colonies;(d) can differentiate into cells of any one of the endoderm, ectoderm, or mesoderm germ layers;(e) have a doubling time of between about 16 hours and about 24 hours; or(f) any combination of (a) to (e).3. The in vitro culture of claim 1 , wherein the hiPSCs have a normal karyotype.4. The in vitro culture of claim 2 , wherein the pluripotency markers comprise NANOG claim 2 , alkaline phosphatase claim 2 , or a combination thereof.5. The in vitro culture of claim 1 , wherein the hiPSCs are derived from non-pluripotent cells transformed to express a pluripotent state.6. The in vitro culture of claim 5 , wherein the transformed cells express reprogramming genes comprising Oct4 claim 5 , Sox2 claim 5 , Klf4 claim 5 , Myc claim 5 , or any combination thereof.7. The in vitro culture of claim 5 , wherein the transformed cells comprise primed hiPSCs.8. The in vitro culture of claim 5 , wherein the transformed ...

TELEMETRY SYSTEM EXTENSION

A method of operating a telemetry system includes automatically populating a base field of a schema in an event definition using a logging library of the telemetry system for an event of an instrumented application, and automatically populating a conditional field of the schema in the event definition using the logging library in response to a selected condition for the event. 1. A method of operating a telemetry system , the method comprising:automatically populating a base field of a schema in an event definition using a logging library of the telemetry system for an event of an instrumented application; andautomatically populating a conditional field of the schema in the event definition using the logging library in response to a selected condition for the event.2. The method of wherein the base field is automatically populated with data in all events of the instrumented application.3. The method of wherein the data common to all events includes client system data.4. The method of wherein the conditional field is automatically populated with data related to an application environment condition.5. The method of wherein the application environment condition includes application platform claim 4 , operating system claim 4 , or cloud environment.6. The method of wherein the conditional field is populated with data in all events of the application environment condition.7. The method of wherein the conditional field is automatically populated with data related to an application usage condition.8. A method of operating a telemetry system claim 1 , the method comprising:automatically populating base fields of a first schema in an event definition using a logging library of the telemetry system for an event;automatically populating conditional fields of the first schema in the event definition using the logging library in response to a selected condition for the event; andpopulating fields in a second schema selected by an event author.9. The method of wherein populating ...

TELEMETRY DEFINITION SYSTEM

A method of operating a telemetry system includes automatically populating a first set of fields in a schema of an event definition using a logging library of the telemetry system, and populating a second set of fields in the schema selected by an event author. 1. A method of operating a telemetry system , the method comprising:automatically populating a first set of fields in a schema of an event definition using a logging library of the telemetry system; andpopulating a second set of fields in the schema selected by an event author.2. The method of wherein populating the second set of fields includes preselected fields from the telemetry system.3. The method of wherein the preselected fields are populated with data common to a plurality of applications.4. The method of wherein the preselected fields include a predefined name and data type.5. The method of wherein populating the second set of fields includes custom fields from the event author.6. The method of wherein the custom fields include custom name and custom data type.7. The method of wherein the first set of fields is automatically populated with data common to all events.8. The method of wherein the data common to all events includes client system data.9. The method of wherein the first set of fields in the schema includes an event envelope semantic.10. The method of wherein populating the second set of fields includes preselected fields from the telemetry system and custom fields from the event author.11. A telemetry system claim 1 , comprising: automatically populate a first set of fields in a schema of an event definition using a logging library of the telemetry system; and', 'populate a second set of fields in the schema selected by an event author., 'a computing device including a processor and a memory configured to12. The telemetry system of wherein populating the second set of fields includes preselected fields from the telemetry system.13. The telemetry system of wherein populating the second set ...

TELEMETRY REQUEST SYSTEM

A method of operating a telemetry system includes automatically populating a first set of fields in a schema of an event definition using a logging library of the telemetry system, and receiving the set of fields via a request message in an application protocol. 1. A method of operating a telemetry system , the method comprising:automatically populating a first set of fields in a schema of an event definition using a logging library of the telemetry system; andreceiving the set of fields via a request message in an application protocol.2. The method of comprising:populating a second set of fields in the schema selected by an event author.3. The method of wherein populating the second set of fields includes preselected fields from the telemetry system.4. The method of wherein the preselected fields are populated with data common to a plurality of applications.5. The method of wherein populating the second set of fields includes custom fields from the event author.6. The method of wherein the custom fields include custom name and custom data type.7. The method of wherein the set of fields is automatically populated with data common to all events.8. The method of wherein the data common to all events includes client system data.9. The method of wherein the request message includes a payload having the set of fields and a header.10. The method of wherein the payload is included in a data-interchange format.11. The method of wherein the application protocol is hypertext transfer protocol.12. A telemetry system claim 9 , comprising: automatically populate a set of fields in a schema of an event definition using a logging library of the telemetry system; and', 'receive the set of fields via a request message in an application protocol., 'a computing device including a processor and a memory configured to13. The telemetry system of wherein the computing device is configured to:populate a second set of fields in the schema selected by an event author.14. The telemetry system ...

METHOD FOR GENERATING A MENU FOR PRESENTING AUDIOVISUAL PROGRAMS PAID FOR BY SEVERAL USERS, DEVICE AND COMPUTER PROGRAM FOR IMPLEMENTING THE METHOD

A method is provided for generating a presentation menu for presenting audio and audiovisual contents on the screen of a receiver, which are downloadable from a broadcasting network or from dedicated sites. A user selects accessible contents and makes payment to make these contents available at the receiver. The receiver retrieves information on availability of all the contents from the receiver and requests display of a presentation menu presenting a list of available contents. Thus each user gets to know all the available contents from the receiver, including those purchased by other users. The presentation menu can visually associate each document with the identity of the user who made the document available. The presentation menu can display an indication that the replay of an available content has already begun and has been interrupted at a certain point in time. This point in time is made available at the display. 1. A method for generating a menu for presenting audio or audiovisual contents accessible by at least one digital network , comprising:receiving a set of identifiers of accessible contents capable, after payment, of being available at a receiver;retrieving information on availability of all the contents from the receiver; andgenerating signals for displaying on a display a menu presenting a list of all of said available contents.2. The method for generating a menu according to claim 1 , wherein the payment is done by several users making available certain contents for each of the users.3. The method for generating a menu according to claim 1 , wherein the display visually associates each document with an identity of a user who has made said document available from the receiver.4. The method for generating a menu according to claim 2 , wherein the payments are made by different payment means.5. The method for generating a menu according to claim 2 , wherein the display puts the available contents displayed into order according to the users having made ...

METHODS AND COMPOSITIONS FOR THE TARGETED MODIFICATION OF A GENOME

Compositions and methods are provided for modifying a genomic locus of interest in a eukaryotic cell, a mammalian cell, a human cell or a non-human mammalian cell using a large targeting vector (LTVEC) comprising various endogenous or exogenous nucleic acid sequences as described herein. Further methods combine the use of the LTVEC with a CRISPR/Cas system. Compositions and methods for generating a genetically modified non-human animal comprising one or more targeted genetic modifications in their germline are also provided. 1. A method for modifying a genome , comprising contacting the genome with a Cas protein , a CRISPR RNA that hybridizes to a target sequence , and a tracrRNA in the presence of a large targeting vector (LTVEC) , wherein the LTVEC is at least 10 kb and comprises a first nucleic acid flanked with a 5′ homology arm and a 3′ homology arm , wherein following contacting with the Cas protein , CRISPR RNA , and tracrRNA in the presence of the LTVEC , the genome is modified at a genomic locus of interest to contain the first nucleic acid.2. The method of claim 1 , wherein the genome is in a eukaryotic cell claim 1 , and the Cas protein claim 1 , the CRISPR RNA claim 1 , the tracrRNA claim 1 , and the LTVEC are introduced into the eukaryotic cell.3. The method of claim 2 , further comprising identifying a modified eukaryotic cell comprising a targeted genetic modification at the genomic locus of interest.4. The method of claim 2 , wherein the CRISPR RNA and the tracrRNA are introduced together in the form of a single guide RNA (gRNA).5. The method of claim 2 , wherein the CRISPR RNA and the tracrRNA are introduced separately.6. The method of claim 2 , wherein:(a) the Cas protein is introduced into the eukaryotic cell in the form of a protein, a messenger RNA (mRNA) encoding the Cas protein, or a DNA encoding the Cas protein;(b) the CRISPR RNA is introduced into the eukaryotic cell in the form of an RNA or a DNA encoding the CRISPR RNA; and(c) the tracrRNA ...

ULTRASONIC MATRIX ARRAY PROBE WITH THERMALLY DISSIPATING CABLE AND BACKING BLOCK HEAT EXCHANGE

A matrix array probe including a transducer array and integrated circuitry coupled to the transducer elements dissipates heat generated by the array and integrated circuitry through the cover of the transducer probe. A pump in the probe connector pumps fluid through a closed loop system including inbound an outbound fluid conduits in the cable. The fluid conduits in the cable are separated by the cable electrical conductors for the probe. The heat transfer in the probe is done by a heat exchanger in the transducer backing block. Additional cooling may be provided by metal to metal contact with a chiller in the ultrasound system. 1. An ultrasonic transducer probe assembly comprising:an acoustic stack comprising array of transducer elements configured to transmit and receive ultrasound energy;a thermally conductive backing block thermally and acoustically coupled to the acoustic stack and configured to reduce ultrasound energy received from the transducer elements, the thermally conductive backing block comprising a porous structure;a probe connector configured to connect the transducer probe to an ultrasound system;a cable connected between the probe case and the probe connector; and a fluid loop extending through the cable from the probe case to the probe connector;', 'a pump, coupled to the fluid loop, which pumps fluid through the loop; and', 'a heat exchanger configured to transfer heat generated by the acoustic stack by dissipation of the heat outside the closed fluid loop, wherein the heat exchanger comprises a fluid channel that is coupled to the fluid loop and is configured to allow fluid to pass through the porous structure of the thermally conductive backing block., 'a fluid-based cooling system comprising2. The ultrasonic transducer probe assembly of claim 1 , wherein the fluid loop comprises an inbound fluid conduit and an outbound fluid conduit coupled to the fluid channel of the thermally conductive backing block.3. The ultrasonic transducer probe ...

METHOD FOR PRODUCING A STACK OF METAL SHEETS, STACK OF METAL SHEETS, MACHINE COMPONENT, ELECTRIC MOTOR AND DRIVE TRAIN

In order to provide a method by means of which stacks of laminations can be produced in a simple and efficient manner, it is provided that the method comprises the following: coating one or more laminations with a bonding agent; bonding a plurality of laminations to form a sheet metal laminate by means of a first activation of the bonding agent; dividing the sheet metal laminate to produce a plurality of sheet metal laminate units and/or separating out a plurality of sheet metal laminate units from the sheet metal laminate; and bonding the plurality of sheet metal laminate units to form a stack of laminations by means of a second activation of the bonding agent, one or more parameters differing from one another in the first activation and the second activation. 2. Method according to claim 1 , wherein the first activation and/or the second activation are thermal activation.3. Method according to claim 1 , wherein the plurality of laminations which are bonded together is provided in a wound form and/or wherein the one or more laminations are unwound for coating with the bonding agent.4. Method according to claim 1 , wherein before and/or after the division of the sheet metal laminate claim 1 , a plurality of sheet metal laminate units are stacked one on top of the other in a stacking direction claim 1 , such that in particular a stack of sheet metal laminate units is produced.5. Method according to claim 1 , wherein the plurality of laminations is provided in a pre-coated form claim 1 , in particular pre-coated on both sides.6. Method according to claim 1 , wherein the one or more laminations are each coated with the bonding agent on both sides.7. Method according to claim 1 , wherein a ratio between a thickness of the one or more laminations and a layer thickness of the bonding agent is in a range of approximately 20:1 to approximately 250:1 claim 1 , in particular of approximately 25:1 to approximately 210:1.8. Method according to claim 1 , wherein the first ...

METHOD FOR PRODUCING A STACK OF METAL SHEETS FOR AN ELECTRIC MOTOR

To provide a method by means of which stacks of metal sheets can be produced in an easy and efficient way, it is proposed that the method comprises the following: coating one or more metal sheets with a bonding substance; bonding multiple metal sheets to form a sheet-metal laminate by a first activation of the bonding substance; cutting up the sheet-metal laminate to produce multiple sheet-metal laminate units and/or cutting out multiple sheet-metal laminate units from the sheet-metal laminate; and bonding the multiple sheet-metal laminate units to form a stack of metal sheets by a second activation of the bonding substance, wherein the bonding substance comprises a resin material and an elastomer material. 1. Method for producing a stack of metal sheets , in particular a laminated electrical steel core , wherein the method comprises the following:coating one or more metal sheets with a bonding substance;bonding multiple metal sheets to form a sheet-metal laminate by a first activation of the bonding substance;cutting up the sheet-metal laminate to produce multiple sheet-metal laminate units and/or cutting out multiple sheet-metal laminate units from the sheet-metal laminate; andbonding the multiple sheet-metal laminate units to form a stack of metal sheets by a second activation of the bonding substance,wherein the bonding substance comprises a resin material and an elastomer material.2. Method according to claim 1 , wherein a proportion of the elastomer material is in a range of from approximately 1 vol. % to approximately 25 vol. % claim 1 , in particular from approximately 5 vol. % to approximately 20 vol. % claim 1 , based on a total volume of the bonding substance or based on a total volume of a bonding substance/solvent mixture.3. Method according to claim 1 , wherein the elastomer material comprises or is formed from a synthetic rubber material claim 1 , in particular an acrylonitrile butadiene rubber.4. Method according to claim 1 , wherein a Shore hardness ...

METHODS AND COMPOSITIONS FOR TARGETED GENETIC MODIFICATION USING PAIRED GUIDE RNAS

Compositions and methods are provided for creating and promoting biallelic targeted modifications to genomes within cells and for producing non-human animals comprising the modified genomes. Also provided are compositions and methods for modifying a genome within a cell that is heterozygous for an allele to become homozygous for that allele. The methods make use of Cas proteins and two or more guide RNAs that target different locations within the same genomic target locus. Also provided are methods of identifying cells with modified genomes. 1. A method for making a biallelic modification to a genome within a cell , comprising contacting the genome with:(a) a first Cas protein;(b) a first CRISPR RNA that hybridizes to a first CRISPR RNA recognition sequence within a genomic target locus;(c) a second CRISPR RNA that hybridizes to a second CRISPR RNA recognition sequence within the genomic target locus;(d) a tracrRNA; and(e) a targeting vector comprising a nucleic acid insert flanked by a 5′ homology arm that hybridizes to a 5′ target sequence and a 3′ homology arm that hybridizes to a 3′ target sequence, provided that if the cell is a one-cell stage embryo the targeting vector is no more than 5 kb in length;wherein the genome comprises a pair of first and second homologous chromosomes comprising the genomic target locus; andwherein the first Cas protein cleaves at least one of the first and second CRISPR RNA recognition sequences to generate at least one double-strand break in at least one of the first and second homologous chromosomes.2. The method of claim 1 , further comprising identifying a cell comprising the modified genome.3. The method of claim 2 , wherein the nucleic acid insert comprises a selection cassette adjacent to a first homology arm that hybridizes to a first target sequence claim 2 ,wherein the first homology arm is the 5′ homology arm and the first target sequence is the 5′ target sequence, or wherein the first homology arm is the 3′ homology arm ...

TELEMETRY SYSTEM EXTENSION

A method of operating a telemetry system includes automatically populating a base field of a schema in an event definition using a logging library of the telemetry system for an event of an instrumented application, and automatically populating a conditional field of the schema in the event definition using the logging library in response to a selected condition for the event. 1. A method of operating a telemetry system to collect telemetry data of an instrumented application , the method comprising:implementing an event ingestion pipeline to shuttle events through multiple components of the telemetry system;determining quality of the event ingestion pipeline by ingesting telemetry data to a schema in an event definition;automatically populating a base field with telemetry data using a filter declared in a logging library of the telemetry system for an event of the instrumented application, the base field of the schema;automatically populating conditional fields with telemetry data using a second filter in the logging library in response to selected conditions for the event, the conditional fields of the schema; andproviding events in the event ingestion pipeline to real-time systems or batch processing systems in a format to allow analytical applications to query for telemetry data according to the telemetry data in the base field and the conditional fields.2. The method of wherein the base field is automatically populated with data in all events of the instrumented application.3. The method of wherein the data common to all events includes client system data.4. The method of wherein at least one of the conditional fields is automatically populated with data related to an application environment condition.5. The method of wherein the application environment condition includes application platform claim 4 , operating system claim 4 , or cloud environment.6. The method of wherein the at least one of the conditional fields is populated with data in all events of the ...

Methods and Compositions for the Targeted Modification of a Genome

Compositions and methods are provided for modifying a genomic locus of interest in a eukaryotic cell, a mammalian cell, a human cell or a non-human mammalian cell using a large targeting vector (LTVEC) comprising various endogenous or exogenous nucleic acid sequences as described herein. Further methods combine the use of the LTVEC with a CRISPR/Cas system. Compositions and methods for generating a genetically modified non-human animal comprising one or more targeted genetic modifications in their germline are also provided.

METHODS AND COMPOSITIONS FOR THE TARGETED MODIFICATION OF A GENOME

Compositions and methods are provided for modifying a genomic locus of interest in a eukaryotic cell, a mammalian cell, a human cell or a non-human mammalian cell using a large targeting vector (LTVEC) comprising various endogenous or exogenous nucleic acid sequences as described herein. Further methods combine the use of the LTVEC with a CRISPR/Cas system. Compositions and methods for generating a genetically modified non-human animal comprising one or more targeted genetic modifications in their germline are also provided. 1. A method for modifying a genome in a mouse cell or a human cell at a genomic locus of interest , comprising contacting the genome with a Cas protein , a CRISPR RNA that hybridizes to a CRISPR target sequence at the genomic locus of interest , and a tracrRNA , (i) a 5′ homology arm that is homologous to a 5′ target sequence at the genomic locus of interest; and', '(ii) a 3′ homology arm that is homologous to a 3′ target sequence at the genomic locus of interest,, 'wherein the genome is contacted in the presence of a large targeting vector (LTVEC) that is at least 10 kb and comprises an insert nucleic acid flanked withwherein the insert nucleic acid is at least 30 kb and/or the 5′ target sequence and the 3′ target sequence are separated by at least 30 kb;wherein following contacting with the Cas protein, CRISPR RNA, and tracrRNA in the presence of the LTVEC, the genome comprises a targeted genetic modification at the genomic locus of interest, wherein the modified genomic locus of interest comprises the insert nucleic acid.2. The method of claim 1 , wherein the contacting comprises introducing the Cas protein claim 1 , the CRISPR RNA claim 1 , the tracrRNA claim 1 , and the LTVEC into the mouse cell or the human cell.3. The method of claim 2 , wherein the CRISPR RNA and the tracrRNA are introduced as a single nucleic acid molecule comprising the CRISPR RNA and the tracrRNA.4. The method of claim 3 , wherein the single nucleic acid molecule ...

GENETIC MODIFICATION OF RATS

Compositions and methods are provided for making rat pluripotent and totipotent cells, including rat embryonic stem (ES) cells. Compositions and methods for improving efficiency or frequency of germline transmission of genetic modifications in rats are provided. Such methods and compositions comprise an in vitro culture comprising a feeder cell layer and a population of rat ES cells or a rat ES cell line, wherein the in vitro culture conditions maintain pluripotency of the ES cell and comprises a media having mouse leukemia inhibitor factor (LIF) or an active variant or fragment thereof. Various methods of establishing such rat ES cell lines are further provided. Methods of selecting genetically modified rat ES cells are also provided, along with various methods to generate a transgenic rat from the genetically modified rat ES cells provided herein. Various kits and articles of manufacture are further provided. 1. An isolated rat ES cell of a strain selected from ACI or DA , wherein the isolated rat ES cell is and capable of transmitting its genome through the germline.2. The isolated rat ES cell of claim 1 , wherein the cell is derived from an ACI rat.3. The isolated rat ES cell of claim 1 , wherein the cell is derived from a Dark Agouti (DA) rat.2.4. The isolated rat ES cell of claim 1 , wherein the cell is euploid and capable of transmitting a targeted genetic modification through the germline.5. The isolated rat ES cell of claim 4 , wherein the rat ES cell comprises a germline transmission efficiency of the targeted genetic modification of at least 3%.6. The isolated rat ES cell of claim 4 , wherein the rat ES cell has a germline transmission efficiency of the targeted genetic modification of at least 60%.7. The isolated rat ES cell of claim 1 , wherein the rat ES cell exhibits a targeting efficiency of homologous recombination of at least 2%.8. The isolated rat ES cell of claim 1 , wherein the rat ES cell is capable of transmitting a targeted genetic ...

Material deposition device and method of use

A material deposition device includes a solution supply component, a gas supply component, and a co-axial discharge mechanism. The co-axial discharge mechanism includes a solution discharge mechanism, and a gas discharge mechanism co-axial with the solution discharge mechanism. The material deposition device further includes an alignment component that aligns the solution discharge mechanism in a center of the gas discharge mechanism; and an orifice plate with a number of turbulence inducing structures that induce turbulence in gas exiting the gas discharge mechanism.

TILED CMUT DIES WITH PITCH UNIFORMITY

A large aperture CMUT transducer array is formed of a plurality of adjacently located tiles of CMUT cells. The adjacent edges of the tiles are formed by an anisotropic etch process, preferably a deep reactive ion etching process which is capable of cutting through the die and its substrate while maintaining vertical edges in close proximity to the CMUT cells at the edge of the tile. This enables the CMUT cells of continuous rows or columns to exhibit a constant pitch over multiple CMUT cell tiles. The tiles also contain interconnect electrodes along an edge for making electrical connections to the tiles with flex circuit. 2. The CMUT transducer array of claim 1 , wherein the edge is a nonlinear etched edge in lateral proximity to a plurality of CMUT cells.3. The CMUT transducer array of claim 1 , wherein the edge is etched by an anisotropic etch process.4. The CMUT transducer array of claim 3 , wherein the anisotropic etch process further comprises a deep reactive ion etching process.5. The CMUT transducer array of claim 2 , wherein the tiles exhibit symmetry such that a nonlinear edge of a first tile can be positioned adjacent to either of two edges of a second tile while retaining a constant CMUT cell pitch from the first tile to the second tile.6. The CMUT transducer array of claim 1 , wherein a tile further comprises a plurality of interconnect electrodes located on the substrate along an edge and electrically coupled to CMUT cells of the tile.7. The CMUT transducer array of claim 6 , wherein the tiles exhibit symmetry such that an etched edge of a first tile can be located adjacent to an etched edge of a second tile while retaining a constant CMUT cell pitch from the first tile to the second tile claim 6 ,wherein the first and second tiles each have a plurality of interconnect electrodes located along an edge, andwherein the interconnect electrode edges are on opposite sides of a respective tile, with refrence to the adjacently located etched edges.8. The CMUT ...

Optical Sensor and Method

An optical sensor has a waveguide having a core, a cladding having an outer surface and a long period fiber grating. The core, the cladding and the long period fiber grating collectively provide at least two resonant wavelengths. The optical sensor also has binding sites on the outer surface of the cladding for binding to elements to be detected to the outer surface of the cladding. The cladding may be thinned down to a thickness sufficiently low produce the resonant wavelengths. The binding sites include agents for binding to the elements to be detected with the agents being covalently bonded to the surface of the cladding. Example binding sites can include bacteriophages for detecting bacteria, Palladium for detecting hydrogen, or synthetic DNA for detecting viruses of certain molecules for example.

VETO-BASED MODEL FOR MEASURING PRODUCT HEALTH

The performance of a cloud-based software product over time is determined by collecting telemetry data representing whether different features of online sessions of the software product are operating properly. The telemetry data represents shared performance metrics of the software product across different participants and components participating in an online session. The collected telemetry data is correlated with session identifiers identifying the online session from which the telemetry data was collected. The telemetry data for an online session is processed to establish a unit of failure when the telemetry data indicates that the online session operated outside of predefined performance metrics. The unit of failure is a function of vetoes applied to a candidate list of online sessions indicating that the online session may have problems. The performance of the software product may be determined as a function of the unit of failure over time. 1. A computer-implemented method of determining the performance of a cloud-based software product over time , comprising:collecting telemetry data representing whether different features of online sessions of the software product are operating properly, where the telemetry data represents shared performance metrics of the software product across different participants and components participating in an online session;correlating the collected telemetry data with session identifiers identifying the online session from which the telemetry data was collected;processing the telemetry data for an online session to establish a unit of failure when the telemetry data indicates that the online session operated outside of predefined performance metrics; anddetermining the performance of the software product as a function of the unit of failure over time.2. A method as in claim 1 , further comprising defining user experience metrics for the software product claim 1 , inventorying telemetry data needed for measuring performance of ...

System and Method for Identification and Characterization of Transglutaminase Species

In one aspect, the present disclosure provides a system and method for the identification and characterization of a transglutaminase. Further, the present disclosure provides transglutaminase enzymes for forming isopeptide bonds, methods of forming isopeptide bonds in the presence of transglutaminases, and substrate tags for use with transglutaminases. 1. A substrate tag for a microbial transglutaminase , the substrate tag comprising one of an acyl-donor tag having at least 80% sequence identity to the peptide sequence YRYRQ (SEQ ID NO:1) , and an amine donor tag having at least 80% sequence identity to the peptide sequence RYESK (SEQ ID NO:2).2Kutzneria albida. The substrate tag of claim 1 , wherein the microbial transglutaminase has at least 80% sequence identity to the microbial transglutaminase (SEQ ID NO:6).3. The substrate tag of claim 1 , further comprising a detectable label.4. The substrate tag of claim 3 , wherein the detectable label is selected from a biotin moiety claim 3 , a fluorescent dye claim 3 , a ruthenium label claim 3 , a radiolabel claim 3 , and a chemiluminescent label.5. The substrate tag of claim 1 , the acyl-donor tag having the peptide sequence APRYRQRAA (SEQ ID NO:24).6Kutzneria albida. A kit for forming an isopeptide bond in the presence of a microbial transglutaminase claim 1 , the kit comprising an isolated microbial transglutaminase having at least 80% sequence identity to the microbial transglutaminase (SEQ ID NO:6).7. The kit of claim 6 , further comprising one of a first substrate including an acyl-donor tag having at least 80% sequence identity to the peptide sequence YRYRQ (SEQ ID NO:1) claim 6 , and a second substrate including an amine-donor tag having at least 80% sequence identity to the peptide sequence RYESK (SEQ ID NO:2).8. The kit of claim 7 , wherein at least one of the first substrate and the second substrate includes a detectable label.9. The kit of claim 8 , wherein the detectable label is selected from a biotin ...

Reclosable Wrapper for Sanitary Products and Related Methods

A wrapped sanitary product comprises a wrapper and a sanitary product that provides for discreet storage and removal of a sanitary product, and/or discreet placement of a soiled sanitary product into a vacated wrapper to be discreetly disposed thereafter. The wrapper is formed such that an interior space is created to store a sanitary product. The wrapper has a storage configuration, and accessible configuration, and a second storage configuration. The wrapper has a port that provides access to the interior space and the sanitary product therein. The wrapper has a flap that can comprise a sticker or a tab, or both. The flap is sealed to the wrapper in a storage configuration, is at least partially removable from the wrapper in an accessible configuration, and is reclosable to the wrapper in a second storage configuration. 1. A wrapper for sanitary products , comprising:an interior face that is disposed opposite to an exterior face, said interior and exterior faces having a first end that is disposed opposite to a second, end and a first side that is disposed opposite to a second side, wherein said wrapper forms an interior space defined by said interior face, the at least partial joining of said first side and said second side, the at least partial joining of said first end onto itself and the at least partial joining of said second end onto itself; wherein said wrapper has a port such that said interior space is at least partially accessible from outside of said wrapper, said port is sized, shaped and positioned to permit discreet removal of a sanitary product from within said wrapper, said wrapper having a flap that is sealable to said wrapper to provide a complete closure around said interior space;wherein said wrapper has a storage configuration wherein said flap is in a sealed position such that said interior space is not accessible by said port;wherein said wrapper has an accessible configuration wherein said flap is at least partially removed from said port ...

GPU BASED SHADER CONSTANT FOLDING

Embodiments described herein provide a general purpose graphics processing device, comprising a general purpose graphics processing compute block to process a workload including graphics or compute operations, a memory, and a constant folding unit comprising a processing unit to receive a first input shader and metadata for the first input shader, receive a first constant buffer comprising runtime constants for the first input shader, and generate an improved shader from the first input shader and the runtime constants. Other embodiments may be described and claimed. 1. A general purpose graphics processing device , comprising:a general purpose graphics processing compute block to process a workload including graphics or compute operations, the general purpose graphics processing compute block comprising a plurality of processing units comprising one or more registers;a shared memory communicatively coupled to the plurality of execution units; and receive a first input shader comprising shader code for execution on the general purpose graphics processing compute block and metadata for the first input shader;', 'load the shader code and metadata into the intermediate storage block;', 'load the metadata from the intermediate storage block to the one or more registers of the plurality of processing units prior to execution of the first input shader;', 'receive a first constant buffer comprising runtime constants for the first input shader; and', 'remove at least a portion of the shader code from the first input shader to generate an improved shader from the first input shader and the runtime constants., 'a constant folding unit comprising an intermediate storage block and a processing unit to2. The general purpose graphics processing device of claim 1 , the processing unit to:load a constant fold pass from the memory; andexecute the constant folding pass.3. The general purpose graphics processing device of claim 2 , the processing unit to:read a current version of ...

TELEMETRY RESPONSE SYSTEM

A method of operating a telemetry system includes receiving an automatically populated set of fields in a schema of an event definition, and providing a response message in an application protocol. The set of fields are automatically populated using a logging library of the telemetry system. 1. A method of operating a telemetry system , the method comprising:receiving an automatically populated set of fields in a schema of an event definition, the set of fields automatically populated using a logging library of the telemetry system; andproviding a response message in an application protocol.2. The method of comprising:populating a second set of fields in the schema selected by an event author.3. The method of wherein populating the second set of fields includes preselected fields from the telemetry system.4. The method of wherein the preselected fields are populated with data common to a plurality of applications.5. The method of wherein populating the second set of fields includes custom fields from the event author.6. The method of wherein the set of fields is automatically populated with data common to all events.7. The method of wherein the response message includes a response code and return object.8. The method of wherein the response message includes a header field associated with the response code.9. The method of wherein the response code is selected from a set of status codes.10. The method of wherein the return object is included in a data-interchange format.11. The method of wherein the application protocol is hypertext transfer protocol.12. A telemetry system claim 7 , comprising: receive an automatically populated a set of fields in a schema of an event definition, the set of fields automatically populated using a logging library of the telemetry system; and', 'provide a response message in an application protocol., 'a computing device including a processor and a memory configured to13. The telemetry system of claim 12 , wherein the computing device is ...

CAPACITIVE MICRO-MACHINED ULTRASOUND TRANSDUCER CELL

The invention relates to a capacitive micro-machined ultrasound transducer (CMUT) cell () comprising a cell floor () having a first electrode (); a cell membrane () having a second electrode () which opposes the first electrode and vibrates during transmission or reception of acoustic energy; a transmitter/receiver coupled to the first and second electrodes which causes the cell membrane to vibrate at an acoustic frequency and/or receives signals at an acoustic frequency; and an acoustic lens (), overlaying the cell membrane, and having an inner surface opposing the cell membrane and an outer, patient-facing surface. According to the present invention the acoustic lens comprises at least one layer of a material selected from the group of: polybudatiene, polyether block amide (PEBAX), polydimethylsiloxane (PDMS) and buthylrubber. 1. A capacitive micro-machined ultrasound transducer cell comprising:a cell floor having a first electrode;a cell membrane having a second electrode which opposes the first electrode and vibrates during transmission or reception of acoustic energy;an acoustic lens, overlaying the cell membrane, and having an inner surface opposing the cell membrane and an outer surface;whereinthe acoustic lens comprises at least one layer of, polydimethylsiloxane (PDMS).2. The CMUT cell according to claim 1 , wherein the acoustic lens further comprises at least one of the following layers:(i) a moisture barrier layer;(ii) a layer of adhesive material;(iii) a layer of conductive material coupled to act as a radio frequency shield;(iv) an acoustic wave focusing layer;(v) a durable exterior layer located as the outer surface.3. The CMUT cell according to claim 2 , wherein the acoustic lens further comprises at least one layer of liquid.4. (canceled)5. The CMUT cell according to claim 14 , wherein the layer of polydimethylsiloxane is one of cured and uncured PDMS.6. The CMUT cell according to claim 1 , wherein the acoustic lens further comprises at least one ...

LATENCY-REDUCED DOCUMENT CHANGE DISCOVERY

Latency-reduced document change discovery in a co-authoring session is provided. When a co-authoring session is established between clients for co-authoring a document, a communication channel that is separate from a content channel is established between each client in the co-authoring session and a notification service. When a client uploads edits made to the document to a server-stored and managed master copy of the document, the client sends a notification on the separate channel to the other clients via the notification service, notifying the other clients that document changes have been made and are available to download from the content service. The other clients are enabled to discover document changes in real-time or in near real-time to when the changes are saved to the master copy of the document, and download the client edits for merging the changes with a local copy of the document. 1. A computer-implemented method for latency-reduced document change discovery in a co-authoring session , comprising:instantiating a local copy of a document at a first client computing device, wherein a master copy of the document is stored in a storage repository managed by a content service;receiving, at the first client computing device, an indication of a save event in association with the local copy of the document;generating an upload request including client edits made to the local copy of the document at the first client computing device for updating the master copy of the document with the client edits;transmitting the upload request to the content service;generating a notification indicating that the master copy of the document is being updated with the client edits; andtransmitting the notification to a notification service for broadcasting the notification to other client computing devices associated with the co-authoring session, such that the other client computing devices discover that the master copy of the document has changed.2. The computer-implemented ...

TARGETED MODIFICATION OF RAT GENOME

Compositions and methods are provided for modifying a rat genomic locus of interest using a large targeting vector (LTVEC) comprising various endogenous or exogenous nucleic acid sequences as described herein. Compositions and methods for generating a genetically modified rat comprising one or more targeted genetic modifications in their germline are also provided. Compositions and methods are provided which comprise a genetically modified rat or rat cell comprising a targeted genetic modification in the rat interleukin-2 receptor gamma locus, the rat ApoE locus, the rat Rag2 locus, the rat Rag1 locus and/or the rat Rag2/Rag1 locus. The various methods and compositions provided herein allows for these modified loci to be transmitted through the germline. 136.-. (canceled)37. A method for targeted modification of a genomic locus of interest in a population of pluripotent rat cells to produce a genetically modified rat , comprising: wherein the pluripotent rat cells lack expression of c-Myc;', 'wherein the pluripotent rat cells form spherical, free-floating colonies in culture;', 'wherein the pluripotent rat cells are diploid; and', 'wherein the pluripotent rat cells are germline competent;, '(a) providing a population of pluripotent rat cells obtained by culturing isolated rat embryonic stem cells on a feeder cell layer that is not modified to express leukemia inhibitory factor (LIF) with a medium comprising N2 supplement, B27 supplement, about 50 U/mL to about 150 U/mL LIF, and a combination of inhibitors consisting of MEK inhibitor PD0325901 and GSK3 inhibitor CHIR99021;'}(b) introducing into the pluripotent rat cells a large targeting vector (LTVEC) comprising an insert nucleic acid flanked by a 5′ homology arm homologous to a first nucleic acid sequence at the genomic locus of interest and a 3′ homology arm homologous to a second nucleic acid sequence at the genomic locus of interest, wherein the sum total of the 5′ and the 3′ homology arms is at least 10 kb; and ...

Methods And Compositions For Modifying A Targeted Locus

Methods and compositions are provided for modifying one or more target loci in a cell. Such methods comprise providing a cell comprising a first polynucleotide encoding a first selection marker operably linked to a first promoter active in the cell, wherein the first polynucleotide further comprises a first recognition site for a first nuclease agent. A first nuclease agent is introduced into a cell, wherein the first nuclease agent induces a nick or double-strand break at the first recognition site. Further introduced into the cell is a first targeting vector comprising a first insert polynucleotide flanked by a first and a second homology arm that correspond to a first and a second target site located in sufficient proximity to the first recognition site. At least one cell is then identified comprising in its genome the first insert polynucleotide integrated at the target locus. 153.-. (canceled)54. A method for serial modification of a target locus in a cell , comprising:(a) providing the cell comprising the target locus, wherein the cell is a mouse embryonic stem (ES) cell or a rat ES cell, wherein the target locus comprises a first selection cassette comprising: (1) a nucleic acid encoding a first selection marker; and (2) a first nuclease recognition site for a first nuclease agent, wherein the first nuclease recognition site is located in a coding region of the first selection marker or any non-protein-coding region of the first selection marker; (i) the first nuclease agent, wherein the first nuclease agent induces a nick or a double-strand break at the first nuclease recognition, thereby disrupting expression or activity of the first selection marker; and', '(ii) a first targeting vector comprising a first insert polynucleotide flanked by a first homology arm corresponding to a first target site located in the target locus and a second homology arm corresponding to a second target site located in the target locus, wherein the first insert polynucleotide ...

PRODUCTION OF FERTILE XY FEMALE ANIMALS FROM XY ES CELLS

Methods and compositions are described for making phenotypically female fertile animals from XY donor cells and suitable host embryos. Culture media and methods are provided for maintaining XY donor cells in culture that after introduction into a host embryo and gestation in a suitable host will result in fertile XY female animals. Methods and compositions are described for making fertile female animals in an F0 generation from a donor XY cell and a host embryo, as are methods for making F1 progeny that are homozygous for a modification from a heterozygous F0 fertile male and a heterozygous F0 fertile female sibling. 120-. (canceled)21. A method for increasing the efficiency of generating embryonic stem (ES) cell-derived mice in an F0 generation , comprising: (i) a base medium; and', '(ii) supplements suitable for growing the mouse ES cells in culture and maintaining pluripotency,', 'wherein the base medium comprises sodium bicarbonate in a concentration of 1.5-2.2 mg/mL, comprises fetal bovine serum, and has an osmolality of 218-322 mOsm/kg;, '(a) maintaining a donor XY mouse ES cell in a medium comprising(b) injecting a donor XY mouse ES cell from step (a) into a pre-morula stage host mouse embryo;(c) introducing the host mouse embryo of step (b) into a recipient female mouse and gestating the host mouse embryo; and(d) obtaining an F0 XY mouse progeny.22. The method of claim 21 , wherein the base medium further comprises sodium chloride in a concentration of 3.0-6.4 mg/mL.23. The method of claim 22 , wherein the base medium comprises 3 mg/mL sodium chloride and 2.2 mg/mL sodium bicarbonate and has an osmolality of 218 mOsm/kg.24. The method of claim 23 , wherein the base medium further comprises 4.5 mg/mL glucose.25. The method of claim 22 , wherein the base medium comprises 5.1 mg/mL sodium chloride and 1.5 mg/mL sodium bicarbonate and has an osmolality of 261 mOsm/kg.26. The method of claim 22 , wherein the base medium comprises 6.4 mg/mL sodium chloride and 1.5 ...

TARGETED MODIFICATION OF RAT GENOME

Compositions and methods are provided for modifying a rat genomic locus of interest using a large targeting vector (LTVEC) comprising various endogenous or exogenous nucleic acid sequences as described herein. Compositions and methods for generating a genetically modified rat comprising one or more targeted genetic modifications in their germline are also provided. Compositions and methods are provided which comprise a genetically modified rat or rat cell comprising a targeted genetic modification in the rat interleukin-2 receptor gamma locus, the rat ApoE locus, the rat Rag2 locus, the rat Rag1 locus and/or the rat Rag2/Rag1 locus. The various methods and compositions provided herein allows for these modified loci to be transmitted through the germline. 1. A method for modifying a genomic locus of interest in a non-human pluripotent cell , comprising (i) a large targeting vector (LTVEC) comprising a first nucleic acid flanked with a 5′ homology arm and a 3′ homology arm, wherein the sum total of the 5′ and 3′ homology arms of the LTVEC is at least 10 kb;', '(ii) a first expression construct comprising a first promoter operably linked to a second nucleic acid encoding a Cas protein,', '(iii) a second expression construct comprising a second promoter operably linked to a third nucleic acid encoding a guide RNA (gRNA) comprising a nucleotide sequence that hybridizes to a target sequence and a trans-activating CRISPR RNA (tracrRNA), wherein the first and the second promoters are active in the non-human pluripotent cell; and', '(b) identifying a modified non-human pluripotent cell comprising a targeted genetic modification at the genomic locus of interest., '(a) introducing into the non-human pluripotent cell2. The method of claim 1 , wherein the LTVEC is from about 20 kb to about 30 kb claim 1 , from about 30 kb to about 40 kb claim 1 , from about 40 kb to about 50 kb claim 1 , from about 50 kb to about 75 kb claim 1 , or from about 75 kb to about 100 kb.3. The method ...

Targeted modification of rat genome

Compositions and methods are provided for modifying a rat genomic locus of interest using a large targeting vector (LTVEC) comprising various endogenous or exogenous nucleic acid sequences as described herein. Compositions and methods for generating a genetically modified rat comprising one or more targeted genetic modifications in their germline are also provided. Compositions and methods are provided which comprise a genetically modified rat or rat cell comprising a targeted genetic modification in the rat interleukin-2 receptor gamma locus, the rat ApoE locus, the rat Rag2 locus, the rat Rag1 locus and/or the rat Rag2/Rag1 locus. The various methods and compositions provided herein allows for these modified loci to be transmitted through the germline.

COORDINATING FILE SYNCHRONIZATION BETWEEN A SYNC ENGINE AND ANOTHER APPLICATION THAT SUPPORTS DOCUMENT COLLABORATION

A computing system includes at least one processor and memory storing instructions executable by the at least one processor, wherein the instructions, when executed, cause the computing system to instruct a synchronization engine to synchronize first and second versions of a file, the first version being stored on a first storage system and the second version being stored on a second storage system, receive a backoff indicator corresponding to the file, based on the backoff indicator, instruct the synchronization engine to backoff synchronizing changes to the file, and allow the changes to the file to be synchronized by a co-authoring application, maintain a first set of collaborative metadata indicative of content of the first version of the file, and maintain a second set of collaborative metadata indicative of content of the second version of the file. 1. A computing system comprising:at least one processor; and instruct a synchronization engine to synchronize first and second versions of a file, the first version being stored on a first storage system and the second version being stored on a second storage system;', 'receive a backoff indicator corresponding to the file;', 'based on the backoff indicator, instruct the synchronization engine to backoff synchronizing changes to the file, and allow the changes to the file to be synchronized by a co-authoring application; and', 'maintain a first set of collaborative metadata indicative of content of the first version of the file; and', 'maintain a second set of collaborative metadata indicative of content of the second version of the file., 'memory storing instructions executable by the at least one processor, wherein the instructions, when executed, cause the computing system to2. The computing system of claim 1 , wherein the instructions cause the computing system to:determine whether the synchronization engine is to backoff synchronizing changes by determining that the file is open by the co-authoring application ...

NON-RECTANGULAR TRANSDUCER ARRAYS AND ASSOCIATED DEVICES, SYSTEMS, AND METHODS

The present disclosure advantageously describes ultrasound imaging arrays that comprise ergonomic, non-rectangular shapes, as well as associated systems and methods. Non-rectangular transducer arrays allow for ergonomic probe shapes that improve patient comfort, maneuverability of the ultrasound device, and operator workflow. For example, an ultrasound imaging device can include an array of acoustic elements comprising a non-rectangular perimeter. The array includes a plurality of active elements configured to emit ultrasound energy and receive echoes corresponding to the emitted ultrasound energy, and a plurality of buffer elements surrounding the plurality of active elements at the non-rectangular perimeter of the array of acoustic elements. An edge seal comprising a sealing material is positioned at least partially around the plurality of buffer elements, and a buffer element of the plurality of buffer elements is spaced from at least one other buffer element by the sealing material of the edge seal. 1. An ultrasound imaging device , comprising: a plurality of active elements configured to emit ultrasound energy and receive echoes corresponding to the emitted ultrasound energy; and', 'a plurality of buffer elements surrounding the plurality of active elements at the non-rectangular perimeter of the array of acoustic elements; and, 'an array of acoustic elements comprising a non-rectangular perimeter, wherein the array of acoustic elements further comprisesan edge seal comprising a sealing material positioned at least partially around the plurality of buffer elements,wherein a buffer element of the plurality of buffer elements is spaced from at least one other buffer element by the sealing material of the edge seal.2. The device of claim 1 , wherein the non-rectangular perimeter comprises a curved segment.3. The device of claim 1 , wherein the non-rectangular perimeter comprises a polygon.4. The device of claim 1 , wherein each buffer element of a first portion of ...

INTRALUMINAL IMAGING DEVICES WITH A REDUCED NUMBER OF SIGNAL CHANNELS

An imaging assembly for an intraluminal imaging device is provided. In one embodiment, the imaging assembly includes an imaging array positioned at a distal portion of the intraluminal imaging device. The imaging array may have a plurality of imaging elements arranged into subarrays. The imaging assembly also may include a micro-beam-former integrated circuit (IC) coupled to the imaging array at the distal portion of the intraluminal imaging device. The micro-beam-former IC includes a plurality of microchannels that may separately beam-form signals received from imaging elements of at least two subarrays. The imaging assembly further includes two or more signal lines that may couple to the micro beam-former IC. Each signal line may correspond to a specific subarray and may receive the beam-formed signals specific to corresponding subarray. 1. An imaging assembly for an intraluminal imaging device , comprising:an imaging array positioned at a distal portion of the intraluminal imaging device and including a plurality of imaging elements arranged into a plurality of subarrays;a micro-beam-former integrated circuit (IC) positioned at the distal portion of the intraluminal imaging device and comprising a plurality of microchannels configured to separately beam-form signals received from imaging elements of at least two subarrays of the plurality of subarrays; andtwo or more signal lines coupled to the micro-beam-former IC, each signal line corresponding to a subarray of the at least two subarrays and configured to receive the beam-formed signals specific to the corresponding subarray.2. The assembly of claim 1 , wherein the microchannels each comprise a delay for alignment of the signals received from the imaging elements of the subarray.3. The device of claim 1 , wherein the imaging elements are ultrasound transducers mounted to the micro-beam-former IC.4. The device of claim 1 , wherein the imaging array is a two dimensional array.5. The device of claim 1 , further ...

METHODS AND COMPOSITIONS FOR MODIFYING A TARGETED LOCUS

Methods and compositions are provided for modifying one or more target loci in a cell. Such methods comprise providing a cell comprising a first polynucleotide encoding a first selection marker operably linked to a first promoter active in the cell, wherein the first polynucleotide further comprises a first recognition site for a first nuclease agent. A first nuclease agent is introduced into a cell, wherein the first nuclease agent induces a nick or double-strand break at the first recognition site. Further introduced into the cell is a first targeting vector comprising a first insert polynucleotide flanked by a first and a second homology arm that correspond to a first and a second target site located in sufficient proximity to the first recognition site. At least one cell is then identified comprising in its genome the first insert polynucleotide integrated at the target locus. 1. A method for modifying a target locus in a cell , comprising:(a) providing a cell comprising a first target locus comprising a first polynucleotide encoding a first selection marker operably linked to a first promoter, wherein the first polynucleotide further comprises a first recognition site for a first nuclease agent, (i) one or more expression constructs encoding a first nuclease agent which is operably linked to a promoter active in the cell, wherein the first nuclease agent induces a nick or a double-strand break at a first recognition site in the first polynucleotide, thereby disrupting expression or activity of the first selection marker; and', '(ii) a first targeting vector comprising a first insert polynucleotide comprising a second polynucleotide that encodes a second selection marker operably linked to a second promoter, wherein the first insert nucleic acid is flanked by a first and a second homology arm corresponding to a first and a second target site located in the first target locus; and, '(b) introducing into the cell(c) identifying a modified cell comprising the first ...

METHODS AND COMPOSITIONS FOR GENERATING A MOUSE

Methods of generating modified embryos and mammals by introduction of donor cells into an early stage embryo are provided, such that the resulting embryo and animal generated therefrom has a significant contribution to all tissues from the donor cells and is capable of transmitting the donor cell DNA. 120.-. (canceled)21. An in-vitro culture comprising a pre-morula mouse embryo which comprises a mouse donor cell introduced under the zona pellucida , wherein the donor cell comprises an ES cell or ES-like cell from an inbred mouse which is heterozygous or homozygous for a genetic modification.22. The in vitro culture of claim 21 , wherein the donor cell comprises an ES cell.23. The in vitro culture of claim 21 , wherein the pre-morula embryo is an 8-cell stage embryo.25. The method of claim 24 , further comprising introducing the embryo of (b) into a surrogate mouse mother for gestation.26. The method of claim 24 , wherein at least 95% of the cells of a mouse that develops from the blastocyst are derived from the donor cells.27. The method of claim 26 , wherein at least 99% of the cells of a mouse that develops from the blastocyst are derived from the donor cells.28. The method of claim 24 , wherein the pre-morula host mouse embryo is from an inbred strain or an outbred strain.29. The method of claim 24 , wherein the pre-morula host mouse embryo is an 8-cell stage embryo.30. The method of claim 24 , wherein the pre-morula host mouse embryo comprises a zona pellucida claim 24 , and wherein the non-human mammalian donor cells are introduced into the host mouse embryo through an opening in the zona pellucida.31. The method of claim 24 , wherein the culture of step (b) is conditioned by a growth factor.32. The method of claim 31 , wherein the growth factor comprises a protein of the Wnt family.33. The method of claim 32 , wherein the protein of the Wnt family comprises Wnt3a.34. The method of claim 24 , further comprising gestation of the genetically modified mouse embryo ...

Transducer arrays with air kerfs for intraluminal imaging

An imaging assembly for an intraluminal device is provided. In one embodiment, the imaging assembly includes: an array of ultrasound transducer elements spaced apart by air kerfs; a plurality of buffer elements surrounding the array of ultrasound transducer elements, wherein the plurality of buffer elements are spaced apart by gaps; and a sealing material filling portions of the gaps between the plurality of buffer elements.

ATTACHMENT PART FOR A POWER TOOL AND A TOOL ASSEMBLY

An attachment part for a power tool includes an elongated housing including an upper housing part, a lower housing part and an interconnection structure that interconnects the upper and lower housing parts. An input gear for connection to an output shaft of a power tool is arranged at a first end of the housing. An output gear with an output interface is arranged at a second end of the housing. The interconnecting structure includes a sleeve member extending through a first central bore at the first end of the upper housing part, which sleeve member receives the input gear, and a fixation member extending through a second central bore at the first end of the lower housing part and which is arranged to be secured to the sleeve member to clamp the upper and lower housing parts. A tool assembly includes a power tool and the attachment part. 115-. (canceled)16. An attachment part for a power tool , the attachment part comprising:an elongated housing including an upper housing part and a lower housing part;an interconnection structure that interconnects the upper and lower housing parts;an input gear for connection to an output shaft of a power tool, wherein the input gear is arranged at a first end of the housing; andan output gear with an output interface, wherein the output gear is arranged at a second end of the housing; a sleeve member extending through a first central bore at the first end of the upper housing part, wherein the sleeve member receives the input gear; and', 'a fixation member extending through a second central bore at the first end of the lower housing part and which is arranged to be secured to the sleeve member for clamping the upper and lower housing parts,', 'wherein the sleeve member has an opening arranged to allow the input gear to mesh with the output gear or with an auxiliary gear arranged between the input gear and the output gear., 'wherein the interconnection structure comprises17. The attachment part according to claim 16 , wherein at ...

METHODS AND COMPOSITIONS FOR TARGETED GENETIC MODIFICATIONS AND METHODS OF USE

Methods and compositions are provided for generating targeted genetic modifications on the Y chromosome or a challenging target locus. Compositions include an in vitro culture comprising an XY pluripotent and/or totipotent animal cell (i.e., XY ES cells or XY iPS cells) having a modification that decreases the level and/or activity of an Sry protein; and, culturing these cells in a medium that promotes development of XY F0 fertile females. Such compositions find use in various methods for making a fertile female XY non-human mammal in an F0 generation. 129.-. (canceled)30. A method for modifying a target genomic locus on the Y chromosome in a mouse embryonic stem (ES) cell , comprising:(a) providing the cell comprising the target genomic locus on the Y chromosome, wherein the target genomic locus comprises a recognition site for a nuclease agent, and wherein the cell is in a culture comprising a DMEM base medium; (i) the nuclease agent, wherein the nuclease agent induces a nick or double-strand break at the recognition site; and', '(ii) a large targeting vector comprising an insert polynucleotide flanked by first and second homology arms corresponding to first and second target sites located in the target genomic locus, wherein the sum total of the first homology arm and the second homology arm is at least 10 kb, and wherein the targeting vector undergoes homologous recombination with the target genomic locus; and, '(b) introducing into the cell(c) identifying at least one cell comprising in its genome the insert polynucleotide integrated at the target genomic locus, wherein integration of the insert polynucleotide introduces a genetic modification comprising replacement of an endogenous nucleic acid sequence with an exogenous nucleic acid sequence at the target genomic locus.3156.-. (canceled)57. The method of claim 30 , wherein the sum total of the first homology arm and the second homology arm is less than 150 kb.58. The method of claim 30 , wherein the nuclease ...

System and Method for Identification and Characterization of Transglutaminase Species

In one aspect, the present disclosure provides a system and method for the identification and characterization of a transglutaminase. Further, the present disclosure provides transglutaminase enzymes for forming isopeptide bonds, methods of forming isopeptide bonds in the presence of transglutaminases, and substrate tags for use with transglutaminases. 1. A substrate tag for a microbial transglutaminase , the substrate tag comprising one of an acyl-donor tag having at least 80% sequence identity to the peptide sequence YRYRQ (SEQ ID NO:1) , and an amine donor tag having at least 80% sequence identity to the peptide sequence RYESK (SEQ ID NO:2).2Kutzneria albida. The substrate tag of claim 1 , wherein the microbial transglutaminase has at least 80% sequence identity to the microbial transglutaminase (SEQ ID NO:6).3. The substrate tag of claim 1 , further comprising a detectable label.4. The substrate tag of claim 3 , wherein the detectable label is selected from a biotin moiety claim 3 , a fluorescent dye claim 3 , a ruthenium label claim 3 , a radiolabel claim 3 , and a chemiluminescent label.5. The substrate tag of claim 1 , the acyl-donor tag having the peptide sequence APRYRQRAA (SEQ ID NO:24).6Kutzneria albida. A kit for forming an isopeptide bond in the presence of a microbial transglutaminase claim 1 , the kit comprising an isolated microbial transglutaminase having at least 80% sequence identity to the microbial transglutaminase (SEQ ID NO:6).7. The kit of claim 6 , further comprising one of a first substrate including an acyl-donor tag having at least 80% sequence identity to the peptide sequence YRYRQ (SEQ ID NO:1) claim 6 , and a second substrate including an amine-donor tag having at least 80% sequence identity to the peptide sequence RYESK (SEQ ID NO:2).8. The kit of claim 7 , wherein at least one of the first substrate and the second substrate includes a detectable label.9. The kit of claim 8 , wherein the detectable label is selected from a biotin ...

SYSTEM AND METHOD FOR IDENTIFICATION AND CHARACTERIZATION OF TRANSGLUTAMINASE SPECIES

In one aspect, the present disclosure provides a system and method for the identification and characterization of a transglutaminase. Further, the present disclosure provides transglutaminase enzymes for forming isopeptide bonds, methods of forming isopeptide bonds in the presence of transglutaminases, and substrate tags for use with transglutaminases. In another aspect, the present disclosure provides glutamine-containing substrates (or Q-tag substrates) that are more resistant to proteases/clipping and therefore, more stable, than other Q-tag substrates, and their uses in substrate tags for cross-linking to an amine-donor tag via an isopeptide bond mediated by a microbial transglutaminase. 1. A structure , a microbial transglutaminse , a first substrate tag , and a second substrate tag ,wherein the first substrate tag is attached to the structure;wherein the first substrate tag comprises an acyl-donor tag having at least 80% sequence identity to any one of the peptide sequences selected from the group consisting of YRYRQ (SEQ ID NO:1), PRYRQ (SEQ ID NO:38), GGGYRYRQGGGP (SEQ ID NO:105), GGGSYRYRQGGGS (SEQ ID NO:106), GGGSPRYRQGGGS (SEQ ID NO:107), GGGSRWRQRGGGS (SEQ ID NO:108), GGGSRVRQRGGGS (SEQ ID NO:109), GGGSPKFRQGGGS (SEQ ID NO:110), GGGSPKQRQGGGS (SEQ ID NO:111), RWRQR (SEQ ID NO:112), RVRQR (SEQ ID NO:113), PKFRQ (SEQ ID NO:114), and PKQRQ (SEQ ID NO:115);wherein the second substrate tag comprises an amine-donor tag;wherein the structure is selected from a recombinant protein, a detectable label, and a chemically synthesized structure;{'i': 'Kutzneria albida', 'wherein the microbial transglutaminase has at least 80% sequence identity to the microbial transglutaminase (SEQ ID N0:6); and'}wherein the microbial transglutaminase cross-links the first substrate tag to the second substrate tag by forming an isopeptide bond between the acyl-donor tag and the amine-donor tag.2. The structure claim 1 , the microbial transglutaminase claim 1 , the first substrate tag ...

SEALING SYSTEM AND MOTOR VEHICLE COMPONENT COMPRISING SAID SEALING SYSTEM

In order to improve a sealing system, particularly for sealing against hot gas, it is proposed that it comprise a sealing element or a plurality of sealing elements and a support device for the sealing element or for the sealing elements, wherein the sealing system is constructed such that the one or at least one sealing element is arranged on the support device with play in at least one sealing state of the sealing system. 1. A sealing system , the sealing system comprising a sealing element or a plurality of sealing elements and a support device for the sealing element or for the sealing elements , wherein the sealing system is formed in such a way that at least in a sealing state of the sealing system the one or at least one sealing element is arranged on the support device with play.2. The sealing system in accordance with claim 1 , the sealing system being for sealing against a hot gas.3. The sealing system in accordance with claim 1 , wherein it is formed in such a way that at least in the sealing state the one or at least one sealing element and the support device are arranged such as to be moveable relative to each other.4. The sealing system in accordance with claim 1 , wherein the one or at least one sealing element is arranged on the support device such as to be moveable relative thereto.5. The sealing system in accordance with claim 1 , wherein an expansion space is arranged between the one or at least one sealing element and the support device.6. The sealing system in accordance with claim 1 , wherein an expansion space is arranged between the one or at least one sealing element and the support device in the form of a radial expansion space in a direction that is radial to the seal axis.7. The sealing system in accordance with claim 1 , wherein it comprises at least one stop claim 1 , and in that the play of the one or the at least one sealing element is up to the at least one stop.8. The sealing system in accordance with claim 1 , wherein it comprises ...

Grinder for processing plant material

A grinder having a lid and a container. The container has an interior surface defining a cavity, and at least one container tooth extending outward from the interior surface into the cavity. The container tooth extends across at least a portion of the interior surface from adjacent a center portion of the interior surface to adjacent a peripheral edge of the interior surface. The lid has a lower surface that is configured to be at least partially received within the cavity. The lid includes at least one lid tooth that extends outward from the lower surface. The lid tooth extends across at least a portion of the lower surface from adjacent a center portion of the lower surface to adjacent a peripheral edge of the lower surface.

ROBUST ULTRASOUND TRANSDUCER PROBES HAVING PROTECTED INTEGRATED CIRCUIT INTERCONNECTS

An ultrasound probe is formed with protected interconnects, thereby resulting in a more robust probe. The interconnects are mounted between an array of transducer elements and an integrated circuit. The array of transducer elements are coupled to the interconnect via flip chip bumps or other structures. Underfill material fixedly positions the interconnects to the integrated circuit. A method of making the transducer assembly is provided. 1. An ultrasonic transducer array assembly comprising:an array of transducer elements comprising a plurality of layers;an integrated circuit structurally coupled to the array of transducer elements;a backing block positioned on an opposing side of the integrated circuit from the array of transducer elements; andan interconnect,characterized in that interconnect is fixedly positioned between the integrated circuit and at least one layer of the plurality of layers.2. The ultrasonic transducer array assembly of claim 1 , wherein the interconnect comprises a flexible circuit.3. The ultrasonic transducer array assembly of claim 1 , wherein the interconnect comprises a wire bond coupled to a flexible circuit.4. The ultrasonic transducer array assembly of claim 1 , wherein the interconnect is positioned between the integrated circuit and all of the plurality of layers.5. The ultrasonic transducer array assembly of claim 1 , wherein the interconnect is positioned between the integrated circuit and one of the plurality of layers.6. The ultrasonic transducer array assembly of claim 1 , wherein the integrated circuit is structurally coupled to the array of transducer elements with stud bumps.7. The ultrasonic transducer array assembly of claim 1 , wherein the integrated circuit is structurally coupled to the array of transducer elements with subtractively created bumps.8. The ultrasonic transducer array assembly of claim 1 , wherein the backing block comprises a porous foam material filled with resin.9. The ultrasonic transducer array ...

SIEVE SEAL AND METHOD FOR OPERATION THEREOF

A sieve seal as a component embodied of one piece, consisting of a seal, which holds a sieve body so that it is enclosed over an inner free cross-sectional area. The present invention also relates to a method for sustained operation of a sieve seal of this kind. In order to provide a remedy in the event of a clogging and/or soot formation and an accumulation of deposits in the sieve seal, it is proposed that the sieve body is embodied for an electric current to flow through at least part of it in such a way that a temperature that is sufficient to eliminate at least significant parts of the deposits is achieved or a corresponding temperature threshold is exceeded. 1. A sieve seal for an EGR branch of an internal combustion engine , the sieve seal , as comprises:a one-piece component consisting of;a seal; anda sieve body positioned so that the sieve body is enclosed over an inner free cross-sectional area of the seal, wherein the sieve body is designed for an electric current to flow through at least part of the sieve body in such a way that a temperature of the sieve body of up to approx. 600° C. that is sufficient for thermal elimination of at least significant parts of deposits in the sieve seal is achieved.2. The sieve seal according to claim 1 , wherein the sieve body includes at least one heating wire.3. The sieve seal according to claim 2 , wherein the at least one heating wire is provided as a heating element in or on the sieve body or is separately mounted at a short distance from the sieve body.4. The sieve seal according to claim 1 , further comprising multiple heating wires provided in claim 1 , at claim 1 , and/or on the sieve body.5. The sieve seal according to one of the preceding claims claim 1 , wherein essentially the entire sieve body allows the electric current flow through the sieve body in order to be used as a heating fabric.6. The sieve seal according to claim 5 , wherein a tap of the sieve body for introducing or applying a current flow is ...

PRODUCTION OF FERTILE XY FEMALE ANIMALS FROM XY ES CELLS

Methods and compositions are described for making phenotypically female fertile animals from XY donor cells and suitable host embryos. Culture media and methods are provided for maintaining XY donor cells in culture that after introduction into a host embryo and gestation in a suitable host will result in fertile XY female animals. Methods and compositions are described for making fertile female animals in an F0 generation from a donor XY cell and a host embryo, as are methods for making F1 progeny that are homozygous for a modification from a heterozygous F0 fertile male and a heterozygous F0 fertile female sibling. 120.-. (canceled)21. A method for making and breeding a fertile female XY mouse in an F0 generation , comprising: (i) a base medium; and', '(ii) supplements suitable for growing the mouse ES cells in culture and maintaining pluripotency,', 'wherein the donor XY mouse ES cell does not comprise a Tdy-negative sex reversal genetic modification, and wherein the base medium comprises sodium bicarbonate in a concentration of about 1.5-2.2 mg/mL and has an osmolality of about 218-322 mOsm/kg;, '(a) maintaining a donor XY mouse ES cell in a medium comprising(b) introducing a donor XY mouse ES cell from step (a) into a pre-morula stage host mouse embryo;(c) introducing the host mouse embryo of step (b) into a recipient female mouse and gestating the host mouse embryo;(d) obtaining an F0 XY mouse progeny comprising an F0 XY phenotypically female mouse, wherein upon attaining sexual maturity the F0 XY female mouse is fertile; and(e) breeding the F0 XY fertile female mouse to produce progeny.22. The method of claim 21 , wherein the base medium further comprises sodium chloride in a concentration of about 3.0-6.4 mg/mL.23. The method of claim 22 , wherein the base medium comprises about 3 mg/mL sodium chloride and about 2.2 mg/mL sodium bicarbonate and has an osmolality of about 218 mOsm/kg.24. The method of claim 23 , wherein the base medium further comprises about ...

INTRA-CARDIAC ECHOCARDIOGRAPHY INTERPOSER

An imaging catheter assembly is provided. The imaging catheter assembly includes an interposer including a multi-layered substrate structure, wherein the multi-layered substrate structure includes a first plurality of conductive contact pads coupled to a second plurality of conductive contact pads via a plurality of conductive lines; an imaging component coupled to the interposer via the first plurality of conductive contact pads; and an electrical cable coupled to the interposer via the second plurality of conductive contact pads and in communication with the imaging component. 1. An imaging catheter assembly , comprising:an interposer including a proximal end, a distal end, and a multi-layered substrate structure, wherein the multi-layered substrate structure includes a first plurality of conductive contact pads coupled to a second plurality of conductive contact pads via a plurality of conductive lines;an imaging component coupled to the interposer via the first plurality of conductive contact pads, wherein the imaging component includes an ultrasound transducer array including a proximal end and a distal end, wherein the distal end of the interpose is proximal to the proximal end of the ultrasound transducer array; andan electrical cable coupled to the interposer via the second plurality of conductive contact pads and in communication with the imaging component.2. The imaging catheter assembly of claim 1 , wherein the interposer includes:a top conductive layer including the first plurality of conductive contact pads and the second plurality of conductive contact pads;a base substrate material layer; andat least one intermediate conductive layer positioned between the top conductive layer and the base substrate material layer, wherein the plurality of conductive lines extend through the at least one intermediate conductive layer.3. The imaging catheter assembly of claim 2 , wherein the base substrate material layer includes at least one of ceramic claim 2 , glass ...

Methods and compositions for generating a mouse

Methods of generating modified embryos and mammals by introduction of donor cells into an early stage embryo are provided, such that the resulting embryo and animal generated therefrom has a significant contribution to all tissues from the donor cells and is capable of transmitting the donor cell DNA.

METHODS AND COMPOSITIONS FOR THE TARGETED MODIFICATION OF A GENOME

Compositions and methods are provided for modifying a genomic locus of interest in a eukaryotic cell, a mammalian cell, a human cell or a non-human mammalian cell using a large targeting vector (LTVEC) comprising various endogenous or exogenous nucleic acid sequences as described herein. Further methods combine the use of the LTVEC with a CRISPR/Cas system. Compositions and methods for generating a genetically modified non-human animal comprising one or more targeted genetic modifications in their germline are also provided.

ES Cell-Derived Mice From Diploid Host Embryo Injection

Genetically modified mice and nucleic acid constructs for making the genetically modified mice are described. A first mouse having a gene encoding an activator (such as a Cre recombinase) operably linked to a developmentally-regulated promoter (such as a Nanog promoter) is provided. A second mouse having a toxic responder gene (such as a gene encoding diphtheria toxin A) is provided, where the toxic gene is expressed only in the presence of an activator. Embryos from a mating of the first and the second mouse are provided as host embryos suitable for generating mice from donor cells introduced into the host embryos. Ablating the ICM of a mouse embryo physically, chemically, or genetically is described, as well as making FO generation mice that are substantially or in full derived from donor cells, employing a host mouse embryo with an ablated or nonproliferating ICM. 110.-. (canceled).11. A method for making a mouse from one or more mouse donor cells and a host embryo , comprising: (i) a site-specific recombinase gene operably linked to a Nanog promoter that expresses the site-specific recombinase gene in a host cell of the inner cell mass (ICM) but not in the trophectoderm during development of the embryo; and,', '(ii) a gene whose expression prevents proliferation of the host ICM cell, wherein expression of the gene is induced by the presence of the site-specific recombinase; and, and', '(b) gestating the embryo of step (a) in a pseudopregnant mouse., '(a) introducing the one or more mouse donor cells into a mouse host embryo, wherein the mouse donor cells are selected from the group consisting of embryonic stem (ES) cells, pluripotent stem (PS) cells, and induced pluripotent stem (iPS) cells, wherein the host embryo comprises12. The method of claim 11 , wherein the site-specific recombinase is a Cre recombinase or a modified Cre recombinase.13. (canceled)14. The method of claim 11 , wherein the embryo stage is selected from a 2-cell stage claim 11 , a 4-cell ...

METHODS AND COMPOSITIONS FOR GENERATING A MOUSE

Methods of generating modified embryos and mammals by introduction of donor cells into an early stage embryo are provided, such that the resulting embryo and animal generated therefrom has a significant contribution to all tissues from the donor cells and is capable of transmitting the donor cell DNA. 1. A method for generating a mammal homozygous for a genetic modification , comprising:(a) introducing a female eukaryotic donor cell into an early stage host embryo, wherein the eukaryotic donor cell is an embryonic stem (ES) cell or an ES-like cell heterozygous for the genetic modification;(b) culturing the embryo of (a) to the blastocyst stage;(c) introducing the embryo of (b) into a surrogate mother for gestation, wherein a modified female mammal is generated having at least 90% cellular contribution from the female donor cell;(a′) introducing a male eukaryotic donor cell into an early stage host embryo, wherein the eukaryotic donor cell is an embryonic stem (ES) cell or an ES-like cell heterozygous for the genetic modification;(b′) culturing the embryo of (a′) to the blastocyst stage;(c′) introducing the embryo of (b′) into a surrogate mother for gestation, wherein a modified male mammal is generated; and(d) breeding a sexually mature modified male mammal and a sexually mature modified female mammal of (c and c′), wherein a mammal homozygous for the genetic modification is generated.2. The method of claim 1 , wherein the female eukaryotic donor cell of step (a) is derived from the same cell line of the male eukaryotic donor cell of step (a′).3. The method of claim 1 , wherein the female eukaryotic donor cell of step (a) is an XO cell and the modified female mammal of step (c) is an XO mammal.4. The method of claim 1 , wherein the early stage embryo is a pre-morula stage cell or an 8-cell embryo.5. The method of claim 1 , wherein the cell is a mouse ES cell from an inbred strain.6. The method of claim 5 , wherein the inbred strain is selected from the group ...

SHAPE SENSING FOR FLEXIBLE ULTRASOUND TRASNDUCERS

A transducer device includes a transducer array () configured on a substrate (). The substrate is configured to flex in accordance with a surface. The transducer array includes elements for transmitting and/or receiving acoustic energy. A shape sensing optical fiber () is disposed within the array and configured to shape sense a position of the elements in the array. Stiffeners () are connected to the array and configured to flex in accordance with the surface and provide a limit to an amount of flexure. 1. A transducer device , comprising:a transducer array configured on a substrate, the substrate configured to flex in accordance with a surface, the transducer array including a plurality of elements for transmitting and/or receiving acoustic energy;at least one shape sensing optical fiber configured to shape sense a position of at least one element in the array; anda plurality of stiffeners configured to flex in accordance with the surface and provide a limit to an amount of flexure and connected to the substrate such that the substrate is disposed between the plurality of stiffeners and the transducer array.2. The device as recited in claim 1 , wherein the stiffeners extend longitudinally in one direction and limit bending to only one axis.3. The device as recited in claim 2 , wherein the at least one shape sensing optical fiber extends perpendicularly to longitudinal gaps between the stiffeners.4. The device as recited in claim 1 , wherein the stiffeners extend longitudinally with gaps perpendicular to the longitudinal direction and permit bending in at least two axes.5. The device as recited in claim 4 , wherein the at least one shape sensing optical fiber extends perpendicularly to longitudinal gaps and the gaps perpendicular to the longitudinal direction between the stiffeners.6. The device as recited in claim 1 , wherein the substrate includes integrated circuits and the elements electrically connect to the integrated circuits.7. The device as recited in ...

IDENTIFICATION OF TRANSGLUTAMINASE SUBSTRATES AND USES THEREFOR

According to one aspect, the present disclosure provides a method of identifying a substrate of a transglutaminase using a peptide array comprising a plurality of peptides. The method includes the steps of contacting the peptides in the peptide array with the transglutaminase, allowing the transglutaminase to bind to the peptides, and identifying the substrate of the transglutaminase. 1. A method for crossing-linking a protein , the method comprising the steps of:incorporating at least one heterologous transglutaminase substrate peptide sequence into the protein; andcross-linking the protein by contacting the protein with a transglutaminase,wherein the heterologous transglutaminase peptide sequence comprises the sequence motif [YF][VA]LQG.2. The method of claim 1 , wherein the heterologous transglutaminase peptide sequence comprises the sequence motif GDYALQGPG (SEQ ID NO: 79).3. The method of claim 1 , further comprising incorporating a transglutaminase lysine substrate peptide into the protein.4. The method of claim 3 , wherein the lysine substrate peptide comprises a sequence motif selected from SK[LS]K and [KR][ST]KL.5. The method of claim 1 , wherein the step of cross-linking further comprises labeling the protein with at least one label selected from Cy5 claim 1 , Biotin claim 1 , and Ruthenium.6. A method of cross-linking at least two compounds claim 1 , the method comprising the steps of:incorporating a heterologous transglutaminase glutamine substrate peptide comprising the sequence motif [YF][VA]LQG into a first compound; andcross-linking the first compound with a second compound by contacting the first compound and the second compound with a transglutaminase.7. The method of claim 6 , wherein the heterologous transglutaminase glutamine substrate peptide comprises the sequence motif GDYALQGPG (SEQ ID NO: 79)8. The method of claim 6 , further comprising the step of incorporating a heterologous transglutaminase lysine substrate peptide into the second ...

REAL-TIME SHARING OF DOCUMENT EDITS

Systems and methods for enabling the real-time sharing of document edits are disclosed herein. Documents being edited may use backing stores that are not originally compatible to share edits in a coauthoring environment and thus require additional attention before coauthoring edits can be shared in real-time. The systems and methods described may provide for the analysis of high level functions within the document editor to determine the underlying activities. Both the high level functions and underlying activities may be analyzed to determine whether it is safe to implement the changes they represent in real-time on an endpoint. When it is determined that the changes are safe to implement, the changes will be implemented and further real-time edits will be shared. When it is determined that the edits are not safe to implement, real-time updates will be suspended until the next selected-time update, at which time real-time sharing will recommence. 1. A system for improving the functionality of a computing device participating in a coauthoring environment by recording document model changes at an editor for safe transmission over a network in real-time to an endpoint in accordance with a document model , comprising:a backing store listener, operable to receive a change to a backing store of the document model to observe low level activities that comprise the change;a recording module, operable to receive the low level activities observed by the backing store listener to create a record of the change;a safety analyzer, operable to analyze the record of the change and determine whether the change is safe to implement in real-time; anda gating module, operable to translate the change into a schema intelligible by the endpoint, and further operable to, in response to determining that the change is safe to implement in real-time, transmit the schema to the endpoint.2. The system of claim 1 , wherein the recording module is further operable to group multiple low level ...

COMPACT ULTRASOUND TRANSDUCER WITH DIRECT COAX ATTACHMENT

An ultrasound device includes a transducer array () formed on a first side of a substrate (). A through via () passes through a thickness of the substrate between the first side and a second side, opposite the first side. A conductor () is electrically coupled to the through via on the second side to provide signals to and from the transducer array. 1. An ultrasound device , comprising:a substrate comprising a transducer array and microbeamforming circuitry configured to partially beamform signals from the transducer array, the transducer array being on a first side of a substrate;at least one through via passing through a thickness of the substrate between the first side and a second side, opposite the first side; anda conductor electrically coupled to the at least one through via on the second side to provide signals to and from the transducer array.2. The device as recited in claim 1 , wherein the transducer array includes capacitive micromachined ultrasound transducer elements.3. The device as recited in claim 1 , wherein the substrate includes an interposer substrate and the array includes a one dimensional array of transducer elements.4. The device as recited in claim 1 , wherein the substrate includes an application specific integrated circuit and the array includes a matrix array of transducer elements.5. The device as recited in claim 4 , wherein the substrate includes a decoupling capacitor mounted on the second side of the substrate.6. The device as recited in claim 1 , wherein the conductor includes a center conductor of a coaxial cable.7. The device as recited in claim 1 , wherein the substrate includes a plurality of through vias claim 1 , and the conductor includes a center conductor and a ground shield of a coaxial cable such that the center conductor and the ground shield are connected to different through vias.8. The device as recited in claim 1 , further comprising a conductive bump connected to the at least one through via claim 1 , the ...

ACOUSTIC PROBE WITH COMPONENTS OF ACOUSTIC ELEMENTS HAVING DIFFERENT PITCHES THAN EACH OTHER

An acoustic probe includes a plurality of acoustic array components separated and spaced apart from each other. Each of the acoustic array components includes: an array of acoustic element circuits disposed contiguous to each other at a first pitch; a plurality of pads each corresponding to one of the acoustic element circuits and formed within a circuitry area of the corresponding acoustic element circuit, the pads being disposed at a second pitch; a plurality of interconnection bumps each corresponding to one of the pads and being disposed in electrical connection with the corresponding pad, wherein the interconnection bumps are disposed at a third pitch; and a plurality of acoustic transducer elements on the interconnection bumps. The acoustic transducer elements are disposed at a fourth pitch. At least two of the first, second, third, and fourth pitches are different than each other. 1. A device , comprising: an array of acoustic element circuits disposed contiguous to each other at a first pitch in at least a first direction;', 'a plurality of pads each corresponding to one of the acoustic element circuits and formed within a circuitry area of the corresponding acoustic element circuit, the pads being arranged at a second pitch in at least the first direction;', 'a plurality of interconnection bumps each corresponding to one of the pads and being disposed directly on, and in electrical connection with the corresponding pad, wherein the interconnection bumps are disposed at a third pitch in at least the first direction; and', 'a plurality of acoustic transducer elements disposed directly on the interconnection bumps, wherein the acoustic transducer elements are disposed at a fourth pitch in at least the first direction,', 'wherein at least two of the first, second, third, and fourth pitches are different than each other., 'an acoustic probe having a plurality of acoustic array components separated and spaced apart from each other, each of the acoustic array ...

Genetic modification of rats

Compositions and methods are provided for making rat pluripotent and totipotent cells, including rat embryonic stem (ES) cells. Compositions and methods for improving efficiency or frequency of germline transmission of genetic modifications in rats are provided. Such methods and compositions comprise an in vitro culture comprising a feeder cell layer and a population of rat ES cells or a rat ES cell line, wherein the in vitro culture conditions maintain pluripotency of the ES cell and comprises a media having mouse leukemia inhibitory factor (LIF) or an active variant or fragment thereof. Various methods of establishing such rat ES cell lines are further provided. Methods of selecting genetically modified rat ES cells are also provided, along with various methods to generate a transgenic rat from the genetically modified rat ES cells provided herein. Various kits and articles of manufacture are further provided.

Targeted modification of rat genome

Compositions and methods are provided for modifying a rat genomic locus of interest using a large targeting vector (LTVEC) comprising various endogenous or exogenous nucleic acid sequences as described herein. Compositions and methods for generating a genetically modified rat comprising one or more targeted genetic modifications in their germline are also provided. Compositions and methods are provided which comprise a genetically modified rat or rat cell comprising a targeted genetic modification in the rat interleukin-2 receptor gamma locus, the rat ApoE locus, the rat Rag2 locus, the rat Rag1 locus and/or the rat Rag2/Rag1 locus. The various methods and compositions provided herein allows for these modified loci to be transmitted through the germline.

TORQUE IMPULSE WRENCH

An impulse wrench includes a housing, an electric motor with a rotor, a hydraulic pulse unit with an inertia drive member and an output shaft, and a coupling rigidly connecting the rotor to the inertia drive member to form an integrated rotating structure. The coupling includes a male coupling portion on the inertia drive member and a female coupling portion on the rotor, such that the male coupling portion is received in the female coupling portion to form the coupling. The male and female coupling portions have external and internal threaded sections, respectively, where an axial clamping force is accomplished at relative rotation of the rotor and the inertia drive member. The male coupling portion and the female coupling portion are provided with mating conical surfaces which are brought together by the axial clamping force to form a rigid connection between the rotor and the inertia drive member. 12-. (canceled)3. An impulse wrench comprising a housing , an electric motor with a rotor , a hydraulic pulse unit with an inertia drive member and an output shaft , and a coupling rigidly connecting the rotor to the inertia drive member to form an integrated rotating structure , wherein:the coupling comprises a male coupling portion on the inertia drive member and a female coupling portion on the rotor,the male coupling portion is arranged to be received in the female coupling portion to form the coupling,the male coupling portion has an external threaded section, and the female coupling portion has an internal threaded section, wherein an axial clamping force is accomplished at relative rotation of the rotor and the inertia drive member, andthe male coupling portion and the female coupling portion are provided with mating conical surfaces which are brought together by the axial clamping force to form a rigid connection between the rotor and the inertia drive member.4. The impulse wrench according to claim 3 , wherein the male coupling portion is provided with an ...

Methods and compositions for modifying a targeted locus

Methods and compositions are provided for modifying one or more target loci in a cell. Such methods comprise providing a cell comprising a first polynucleotide encoding a first selection marker operably linked to a first promoter active in the cell, wherein the first polynucleotide further comprises a first recognition site for a first nuclease agent. A first nuclease agent is introduced into a cell, wherein the first nuclease agent induces a nick or double-strand break at the first recognition site. Further introduced into the cell is a first targeting vector comprising a first insert polynucleotide flanked by a first and a second homology arm that correspond to a first and a second target site located in sufficient proximity to the first recognition site. At least one cell is then identified comprising in its genome the first insert polynucleotide integrated at the target locus.

METHODS AND COMPOSITIONS FOR TARGETED GENETIC MODIFICATIONS AND METHODS OF USE

Methods and compositions are provided for generating targeted genetic modifications on the Y chromosome or a challenging target locus. Compositions include an in vitro culture comprising an XY pluripotent and/or totipotent animal cell (i.e., XY ES cells or XY iPS cells) having a modification that decreases the level and/or activity of an Sry protein; and, culturing these cells in a medium that promotes development of XY F0 fertile females. Such compositions find use in various methods for making a fertile female XY non-human mammal in an F0 generation. 1. A method for making a non-human mammalian XY embryonic stem (ES) cell line capable of producing a fertile XY female non-human mammal in an F0 generation , comprising:(a) modifying a non-human mammalian XY embryonic stem (ES) cell to comprise a modification that decreases the level and/or activity of an Sry protein; and(b) culturing the modified non-human mammalian XY ES cell under conditions that allow for making a non-human mammalian XY ES cell line capable of producing a fertile XY female non-human mammal in an F0 generation.2. A method for making a fertile XY female non-human mammal in an F0 generation , comprising:{'claim-ref': {'@idref': 'CLM-00001', 'claim 1'}, '(a) introducing the modified non-human mammalian XY ES cell of into a host embryo;'}(b) gestating the host embryo; and(c) obtaining an F0 XY female non-human mammal, wherein upon attaining sexual maturity the F0 XY female non-human mammal is fertile.3. The method of claim 1 , wherein the non-human mammalian XY ES cell is from a rodent.4. The method of claim 3 , wherein the rodent is a mouse or rat.5. The method of claim 4 , wherein the mouse XY ES cell is from a 129 strain or a C57BL/6 strain.6. The method of claim 5 , wherein the mouse XY ES cell comprises a Y chromosome derived from the 129 strain or wherein the mouse XY ES cell is a VGF1 mouse ES cell.78.-. (canceled)9. The method of claim 1 , wherein the decreased level and/or activity of the Sry ...

FIBER-OPTIC FLUORESCENCE SENSOR FOR HIGHLY SENSITIVE AND SPECIFIC DETECTION OF CHEMICAL HAZARDS

There is described a fiber-optic sensor for measuring a light signal from a fluorescible sample comprising heavy metal ions, for example. The fiber-optic sensor comprises an optical fiber having a side surface by which the light signal from the fluorescible sample is inputted. The optical fiber is corrugated to form at least two gratings on the side surface of the optical fiber. Each grating comprises periodically longitudinally spaced-apart valleys on the surface of the optical fiber, and is longitudinally spaced apart from any other grating of the at least two gratings. 1. A fiber-optic sensor for measuring a light signal from a fluorescible sample , the fiber-optic sensor comprising: comprising periodically longitudinally spaced-apart valleys on the surface of the un-cladded portion of the core and', 'being longitudinally spaced apart from any other grating of the at least two gratings., 'an optical fiber comprising a core having a portion which is un-cladded on a side of the optical fiber, the un-cladded portion of the core forming a surface by which the light signal from the fluorescible sample is inputted, the un-cladded portion of the core being corrugated on the surface to form at least two gratings on the side surface of the un-cladded portion of the core, each grating'}2. (canceled)3. The fiber-optic sensor of claim 1 , wherein the optical fiber is a large-core optical fiber thereby being highly multi-mode.4. The fiber-optic sensor of claim 3 , wherein each grating is configured to couple high-order modes to low-order modes.5. The fiber-optic sensor of claim 4 , wherein the light signal from the fluorescible sample comprises leaky modes claim 4 , the grating converting the leaky modes into bound core modes that can propagate within a cladded segment of the optical fiber for eventual detection at a detection device provided at an end of the optical fiber.6. The fiber-optic sensor of claim 5 , wherein each grating is characterized by parameters comprising: a ...

SYSTEM AND METHOD FOR IDENTIFICATION AND CHARACTERIZATION OF TRANSGLUTAMINASE SPECIES

In one aspect, the present disclosure provides a system and method for the identification and characterization of a transglutaminase. Further, the present disclosure provides transglutaminase enzymes for forming isopeptide bonds, methods of forming isopeptide bonds in the presence of transglutaminases, and substrate tags for use with transglutaminases. In another aspect, the present disclosure provides glutamine-containing substrates (or Q-tag substrates) that are more resistant to proteases/clipping and therefore, more stable, than other Q-tag substrates, and their uses in substrate tags for cross-linking to an amine-donor tag via an isopeptide bond mediated by a microbial transglutaminase. 1Kutzneria albida. A kit for forming an isopeptide bond in the presence of a microbial transglutaminase , the kit comprising a recombinant protein construct including an isolated microbial transglutaminase having at least 80% sequence identity to the microbial transglutaminase (SEQ ID NO:6) , wherein the isolated microbial transglutaminase was expressed and isolated in the presence of ammonium , and a first substrate including an acyl-donor tag having at least 80% sequence identity to the peptide sequence RYRQR (SEQ ID NO:14).2. The kit of claim 1 , wherein the acyl-donor tag has the peptide sequence of APRYRQRAA (SEQ ID NO:24).3. The kit of claim 1 , wherein the acyl-donor tag has the peptide sequence of RVRQR (SEQ ID NO:113).4. The kit of claim 1 , further comprising a second substrate including an amine-donor tag having at least 80% sequence identity to the peptide sequence RYESK (SEQ ID NO:2).5. The kit of claim 4 , wherein at least one of the first substrate and the second substrate includes a detectable label.6. The kit of claim 5 , wherein the detectable label is selected from a biotin moiety claim 5 , a fluorescent dye claim 5 , a ruthenium label claim 5 , a radiolabel claim 5 , and a chemiluminescent label.7. The kit of claim 1 , wherein the ammonium was present at a ...

Fkbp domain with transglutaminase recognition site

The present disclosure relates to a recombinant transglutaminase (TG) substrate having an amino acid sequence of the FKBP domain of an FKBP polypeptide, wherein the “insert-in-flap” (IF) domain thereof is, at least in part, replaced by an amino acid sequence (“Q-tag”) of 5 to 20 amino acids with a sequence having at least 80% sequence identity to the YRYRQ portion of the peptide sequence X 1 -YRYRQ-X 2 (SEQ ID NO. 1), and wherein said TG substrate is a substrate for the TG function of the Kutzneria albida TG. The present disclosure furthermore relates to uses of said substrate.

METHODS AND COMPOSITIONS FOR GENERATING OR MAINTAINING PLURIPOTENT CELLS

Methods and compositions are provided for generating or maintaining human iPS cells in culture. Methods include the use of a low osmolality medium to make human iPS cells, or use of a low osmolality medium to maintain human iPS cells. Methods for making targeted genetic modification to human iPS cells cultured in low osmolality medium are also included. Compositions include human iPS cells cultured and maintained using the low osmolality medium defined herein. 1. A method for modifying a target genomic locus in a human induced pluripotent stem cell (hiPSC) , comprising:(a) providing a population of naïve hiPSCs that display a morphology characterized by compact, dome-shaped colonies,wherein the hiPSCs are cultured in a low osmolality medium comprising a base medium and supplements, (i) a leukemia inhibitory factor (LIF) polypeptide;', '(ii) a glycogen synthase kinase 3 (GSK3) inhibitor; and', '(iii) a MEK inhibitor, and, 'wherein the low osmolality medium compriseswherein the low osmolality medium has an osmolality of about 200 mOsm/kg to about 250 mOsm/kg; '(c) identifying a genetically modified hiPSC comprising in its genome the insert nucleic acid integrated at the target genomic locus.', '(b) introducing into the population of hiPSCs a targeting vector comprising an insert nucleic acid flanked by 5′ and 3′ homology arms corresponding to 5′ and 3′ target sites at the target genomic locus; and'}231.-. (canceled)32. A method for modifying a target genomic locus in a human induced pluripotent stem cell (hiPSC) , comprising:(a) providing a population of naïve hiPSCs that display a morphology characterized by compact, dome-shaped colonies,wherein the hiPSCs are cultured in a low osmolality medium comprising a base medium and supplements, (i) a leukemia inhibitory factor (LIF) polypeptide;', '(ii) a glycogen synthase kinase 3 (GSK3) inhibitor; and', '(iii) a MEK inhibitor, and, 'wherein the low osmolality medium compriseswherein the low osmolality medium has an ...

SYSTEMS AND METHODS FOR CONTINGENCY NET ASSET VALUE PRICING

Systems and methods for contingency NAV pricing are disclosed. In one embodiment, in an information processing apparatus comprising at least one computer processor, a method for contingency Net Asset Value (cNAV) pricing may include (1) receiving a daily Net Asset Value (NAV) for a fund and performance data for a plurality of benchmarks; (2) selecting one of the plurality of benchmarks that has a benchmark performance that is similar to a fund performance of the fund for a period of time; (3) determining a correlation factor between the fund performance and the selected benchmark performance; and (4) calculating a cNAV based on a prior day's NAV for the fund, a movement for the selected benchmark, and the correlation factor in response to a daily NAV for the fund being unavailable. 1. A method for contingency Net Asset Value (cNAV) pricing , comprising: receiving a daily Net Asset Value (NAV) for a fund and performance data for a plurality of benchmarks;', 'selecting one of the plurality of benchmarks that has a benchmark performance that is similar to a fund performance of the fund for a period of time;', 'determining a correlation factor between the fund performance and the selected benchmark performance; and', "calculating a cNAV based on a prior day's NAV for the fund, a movement for the selected benchmark, and the correlation factor in response to a daily NAV for the fund being unavailable."], 'in an information processing apparatus comprising at least one computer processor2. The method of claim 1 , wherein the selected benchmark comprises one of an index and a commonly-traded instrument.3. The method of claim 1 , wherein the selected benchmark comprises one of the S&P 500 Index claim 1 , the Dow Jones Industrial Average claim 1 , the Hang Seng Index claim 1 , the Nikkei 225 Index claim 1 , the FTSE 100 Index claim 1 , and the DAX Index.4. The method of claim 1 , wherein the step of reconciling the cNAV with the current NAV when the current NAV for the fund is ...

Sieving device has laminar functional layer, particularly provided for use in transmission guide plate, where functional layer is provided with sieve portions with pre-selected sieve openings

The sieving device has a laminar functional layer (3), particularly provided for use in a transmission guide plate. The functional layer is provided with sieve portions with pre-selected sieve openings (19). The sieve portions cover a medium flow for separating particle impurities. The medium flow crosses the functional layer. The sieve part is an integral part of the functional layer.

HOLDER FOR DETACHABLY FASTENING A FLAT DEVICE TO A MOTOR VEHICLE SEAT

The invention relates to a holder () for detachably fastening a flat, approximately rectangular device—such as a tablet computer or a smartphone—to a motor vehicle seat (), wherein the holder has a fastening device () for the detachable plug-in fastening of the holder to a plug-in receptacle () allocated to the motor vehicle seat, and wherein the holder has a holding device () for detachably holding the device to the holder, wherein the fastening device and the holding device are connected to one another via a coupling element (), wherein the coupling element is connected to the fastening device via a first joint and to the holding device via a second joint, wherein the joints are designed as swivel joints with a first swivel joint () and a first swivel axis () and with a second swivel joint () and a second swivel axis (), wherein the first swivel axis and the second swivel axis are oriented parallel to one another. 110201012101820102410122436361224423844403840. A holder () for detachably fastening a flat , approximately rectangular device to a motor vehicle seat () , wherein the holder () has a fastening device () for the detachable plug-in fastening of the holder () to a plug-in receptacle () allocated to the motor vehicle seat () , and wherein the holder () has a holding device () for detachably holding the device on the holder () , wherein the fastening device () and the holding device () are connected to one another via a coupling element () , wherein the coupling element () is connected to the fastening device () via a first joint and to the holding device () via a second joint , wherein the joints are designed as swivel joints with a first swivel joint () and a first swivel axis () and with a second swivel joint () and a second swivel axis () , wherein the first swivel axis () and the second swivel axis () are oriented parallel to one another.210384010. The holder () of claim 1 , wherein the first swivel axis () and the second swivel axis () are oriented ...

INTRA-CARDIAC ECHOCARDIOGRAPHY INTEPOSER

An imaging catheter assembly is provided. The imaging catheter assembly includes an interposer including a multi-layered substrate structure, wherein the multi-layered substrate structure includes a first plurality of conductive contact pads coupled to a second plurality of conductive contact pads via a plurality of conductive lines; an imaging component coupled to the interposer via the first plurality of conductive contact pads; and an electrical cable coupled to the interposer via the second plurality of conductive contact pads and in communication with the imaging component. 1. An apparatus , comprising: an imaging component; and', 'an interposer configured to transmit an electrical signal associated with the imaging component, wherein the interposer comprises a multi-layered substrate structure,, 'an intraluminal imaging device comprisingwherein the imaging component is not formed on the multi-layered substrate structure, and a top layer comprising a first contact pad and a second contact pad;', 'a base layer; and', 'an intermediate layer disposed between the top layer and the base layer, wherein the intermediate layer comprises a conductive line coupled to the first contact pad and the second contact pad such that the electrical signal is transmitted via the first contact pad, the conductive line, and the second contact pad., 'wherein the multi-layered substrate structure comprises2. The apparatus of claim 1 , wherein the intraluminal imaging device comprises:a first conductor coupled to the imaging component and the first contact pad; andan electrical cable comprising a second conductor coupled to the second contact pad.3. The apparatus of claim 2 ,wherein the first contact pad and the second contact pad comprise a same material,wherein the first conductor comprises a wirebonding between the imaging component and the first contact pad, andwherein the second conductor is soldered to the second contact pad.4. The apparatus of claim 2 ,wherein the intraluminal ...

in vitro culture, hipscs population, method for modifying a genomic target locus, and, hipsc.

a presente invenção refere-se aos métodos e composições que são fornecidos para gerar ou manter as células humanas ips em cultura. os métodos incluem o uso de um meio de baixa osmolalidade para fazer células humanas ips, ou usar um meio de baixa osmolalidade para manter as células humanas ips. métodos para fazer a modificação genética direcionada às células humanas ips cultivadas no meio de baixa osmolalidade também estão incluídos. as composições incluem células humanas ips cultivadas e mantidas usando o meio de baixa osmolalidade aqui definido. The present invention relates to methods and compositions which are provided for generating or maintaining human ips cells in culture. Methods include using a low osmolality medium to make human ips cells, or using a low osmolality medium to maintain human ips cells. Methods for making genetic modification directed to human ips cells grown in the low osmolality medium are also included. The compositions include human ips cells cultured and maintained using the low osmolality medium defined herein.

tongue

Method and system for classifying a scenario

Living cells can be used to identify or quantify bioactive conditions, including without limitation, chemicals, biological pathogens, and environmental conditions, such as pH, in samples based on changes in, for example, cell color, morphology and/or physiology. Such changes can be directly detected or detected with the aid of instrumentation. One embodiment of the method comprises exposing a system to a bioactive condition, such as a chemical agent, a biological pathogen, an environmental condition, such as pH, etc., and combinations of such conditions. The system then exhibits a response to the bioactive condition. The response of the system, or a portion thereof, to the bioactive condition is then represented, such as by digital images. The method then involves attempting to classify a scenario by database comparison. Classification can be in terms of numeric or non-numerical classifiers. Typically, the system comprises living cells. Living cells useful for practicing the method experience a detectable change in response to an interaction with a bioactive condition. A likely living cell for use with the method and apparatus of the present invention is a chromatophore. The present method has a number of uses, including classifying unknown drug candidates, classifying unknown toxins, classifying chemical warfare agents, etc. The method a can be implemented using a computer program encoding the method. Moreover, a computer-readable medium is described on which is stored a computer program having instructions for executing the method. A cytosensor apparatus also is described.

Process for the production of a sheet metal stack, sheet metal stack, machine component and electric motor

Um ein Verfahren bereitzustellen, mittels welchem sich auf einfache und effiziente Art und Weise Blechstapel herstellen lassen, wird vorgeschlagen, dass das Verfahren Folgendes umfasst: Beschichten eines oder mehrerer Bleche mit einem Verbindungsstoff; Verbinden mehrerer Bleche zu einem Blechlaminat durch eine erste Aktivierung des Verbindungsstoffs; Zerteilen des Blechlaminats zum Herstellen mehrerer Blechlaminateinheiten und/oder Herausteilen mehrerer Blechlaminateinheiten aus dem Blechlaminat; und Verbinden der mehreren Blechlaminateinheiten zu einem Blechstapel durch eine zweite Aktivierung des Verbindungsstoffs, wobei der Verbindungsstoff ein Harzmaterial und ein Elastomermaterial umfasst. In order to provide a method by means of which sheet metal stacks can be produced in a simple and efficient manner, it is proposed that the method comprises the following: coating one or more sheets with a connecting material; Connecting a plurality of metal sheets to form a sheet metal laminate by a first activation of the connecting material; Dividing the sheet metal laminate to produce a plurality of sheet metal laminate units and / or cutting out a plurality of sheet metal laminate units from the sheet metal laminate; and connecting the plurality of sheet laminate units to form a sheet stack by a second activation of the connecting material, wherein the connecting material comprises a resin material and an elastomer material.

Genetic modification of rats

Compositions and methods are provided for making rat pluripotent and totipotent cells, including rat embryonic stem (ES) cells. Compositions and methods for improving efficiency or frequency of germline transmission of genetic modifications in rats are provided. Such methods and compositions comprise an

Methods for generating a rodent having a genetic modification

Methods of generating modified embryos and mammals by introduction of donor cells into an early stage embryo are provided, such that the resulting embryo and animal generated therefrom has a significant or complete contribution to all tissues from the donor cells and is capable of transmitting the donor cell DNA.