Abstract: Nucleotide sequences of interest, which may be as yet unknown sequences, comprised in a biological sample may often be present in diminishingly small amounts, meaning there are difficulties in detecting, sequencing and identifying these sequences. A method of enrichment of the sequences of interest prior to sequencing of a sample overcomes the problem. In such a method a library of nucleic acid guides is generated from a portion of the sample itself, and the guides are used with a guide-dependent endonuclease such as an Argonaute, usually a prokaryotic Argonaute (pAgo) in a reaction which cleaves the nucleic acids recognised by the guides in another portion of the same sample, but which spares the low abundance sequences for which no guides have been generated. In this way a sample enriched for rarer or low abundance sequences is provided and used in subsequent steps of detection of sequences present, including sequencing of the enriched sample.

Abstract: The present disclosure relates to therapeutic methods and clinically useful molecular switches, for which activity or degradation of a switch-presenting polypeptide can be precisely induced via administration or withdrawal of an FDA-approved drug. Certain aspects of the disclosure relate to an engineered drug-inducible heterodimeric system including a first polypeptide presenting a CRBN polypeptide disrupted for or lacking a DDB1-interacting domain and a second polypeptide presenting a CRBN polypeptide substrate, where binding between the CRBN polypeptide and the CRBN polypeptide substrate are inducible via administration of an FDA-approved thalidomide analog immunomodulatory drug (IMiD). Another aspect of the disclosure relates to a chimeric antigen receptor (CAR) that presents a minimal fragment of the CRBN polypeptide substrate IKZF3 capable of triggering proteasomal degradation of CAR upon administration of an FDA-approved IMiD.

Abstract: The invention relates to methods for determining the sequence of a genomic region of interest comprising a target nucleotide sequence comprising, fragmenting a crosslinked DNA, ligating the fragmented cross linked DNA, reversing the crosslinking and determining at least part of the sequences of ligated DNA fragments which comprise a target nucleotide sequence.

Abstract: A computer-implemented method comprising detecting, by an application in a focussed operating mode, a trigger event; determining, using machine learning (ML) content classification applied to content associated with the trigger event, that content associated with the trigger event does not match a permitted topic associated with the focussed operating mode; and based on determining that the second content does not match the permitted topic applicable to the focussed operating mode, suppressing, by the application in the focussed operating mode, notification of the second trigger event.

Abstract: The present disclosure relates to therapeutic methods and clinically useful molecular switches, for which activity or degradation of a switch-presenting polypeptide can be precisely induced via administration or withdrawal of an FDA-approved drug. Certain aspects of the disclosure relate to an engineered drug-inducible heterodimeric system including a first polypeptide presenting a CRBN polypeptide disrupted for or lacking a DDB 1-interacting domain and a second polypeptide presenting a CRBN polypeptide substrate, where binding between the CRBN polypeptide and the CRBN polypeptide substrate are inducible via administration of an CFDA-approved thalidomide analog immunomodulatory drug (IMiD). Another aspect of the disclosure relates to a chimeric antigen receptor (CAR) that presents a minimal fragment of the CRBN polypeptide substrate IKZF3 capable of triggering proteasomal degradation of CAR upon administration of an FDA-approved IMiD.

Abstract: The invention relates to methods for determining the sequence of a genomic region of interest comprising a target nucleotide sequence comprising, fragmenting a crosslinked DNA, ligating the fragmented cross linked DNA, reversing the crosslinking and determining at least part of the sequences of ligated DNA fragments which comprise a target nucleotide sequence.

Abstract: The disclosure includes compositions comprising synthetic zinc finger degrons, and their use with non-naturally occurring or engineered programmable nucleases. Compositions specifically targeting the engineered programmable nucleases for control of gene editing outcomes, and compositions, systems and method of use are further detailed.

Abstract: Described herein are compositions and methods for modulating protein abundance in a target-specific manner via degron tags.

Abstract: The present disclosure relates to therapeutic methods and clinically useful molecular switches, for which activity or degradation of a switch-presenting polypeptide can be precisely induced via administration or withdrawal of an FDA-approved drug. Certain aspects of the disclosure relate to an engineered drug-inducible heterodimeric system including a first polypeptide presenting a CRBN polypeptide disrupted for or lacking a DDB1-interacting domain and a second polypeptide presenting a CRBN polypeptide substrate, where binding between the CRBN polypeptide and the CRBN polypeptide substrate are inducible via administration of an FDA-approved thalidomide analog immunomodulatory drug (IMiD). Another aspect of the disclosure relates to a chimeric antigen receptor (CAR) that presents a minimal fragment of the CRBN polypeptide substrate IKZF3 capable of triggering proteasomal degradation of CAR upon administration of an FDA-approved IMiD.

Abstract: The invention relates to methods for determining the sequence of a genomic region of interest comprising a target nucleotide sequence comprising, fragmenting a crosslinked DNA, ligating the fragmented cross linked DNA, reversing the crosslinking and determining at least part of the sequences of ligated DNA fragments which comprise a target nucleotide sequence.

Abstract: The present invention relates to a method of ordering nucleic acid molecule fragment sequences derived from a pool of potentially diverse RNA molecules comprising optionally reverse transcribing the RNA molecules to provide a pool of cDNA molecules, segregating nucleic acids from said template RNA or cDNA pool, selecting for potentially different templates with a distinctive nucleic acid feature shared by the segregated templates, thereby providing at least a first subpool of nucleic acids, optionally once or more further segregating nucleic acids from said template RNA or cDNA, selectively segregating nucleic acids with a different distinctive nucleic acid feature, thereby providing one or more further subpool(s) of nucleic acids, generating fragments of said segregated nucleic acid molecules by fragmenting or obtaining fragment copies of said segregated nucleic acid molecules, wherein the fragments of each subpool or combined subpools remain separable from fragments of other subpools or other combined su