Abstract: Systems and methods are described for employing event context to improve threat detection. Systems and methods of embodiments of the disclosure measure both process deviation and path deviation to determine whether processes are benign or represent threats. Both a process deviation model and a path deviation model are deployed. The process deviation model determines the similarity of a process to past processes, and the path deviation model estimates whether processes have been called out of turn. In this manner, systems and methods of embodiments of the disclosure are able to detect both whether a process is in itself unusual, and whether it is called at an unusual time. This added context contributes to improved threat detection.

Abstract: Compositions and methods for conditionally regulating activities of CRISPR-Cas systems. In some embodiments, the methods comprise providing an inactive guide RNA comprising a regulatory domain bound by a lock nucleic acid different from the guide RNA; and displacing the lock nuclei acid from the regulatory domain by a trigger nucleic acid, thereby activating the guide RNA, wherein the activated guide RNA forms a complex with a Cas enzyme.

Abstract: The need to control the activity and fidelity of CRISPR-associated nucleases has resulted in the demand for inhibitory anti-CRISPR molecules. Current small-molecule inhibitor discovery platforms are not generalizable to multiple nuclease classes, only target the initial step in the catalytic activity, and require high concentration of nuclease, resulting in inhibitors with suboptimal attributes, including poor potency. Herein, Applicants report a high-throughput discovery pipeline consisting of a FRET-based assay that is generalizable to contemporary and emerging nucleases, operates at low nuclease concentration, and targets all catalytic steps. Applicants applied this pipeline to identify BRD7586, a cell-permeable small-molecule inhibitor of SpCas9, that is 2-fold more potent than current inhibitors. Furthermore, unlike the reported inhibitors, BRD7586 enhanced SpCas9 specificity and its activity was independent of the genomic loci, DNA repair pathway, or mode of nuclease delivery.

Abstract: The present disclosure relates to bifunctional chemical conjugation molecules, which find utility as modifiers of target substrates. The present disclosure includes multifunctional compounds comprising an enzyme binding moiety, a chemical linker moiety, and a target binding moiety, which may further include an electrophilic reactive group. Molecules according to the present invention find use making substrate modifications such as post-translational modifications to proteins that are not the natural substrate of the enzyme. Diseases or disorders may be treated or prevented with molecules of the present disclosure.

Abstract: Compositions and methods are provided for the inhibition of the function of RNA guided endonucleases, including the identification and use of such inhibitors.

Abstract: The embodiments disclosed herein utilize fluorescence polarization based preliminary screen to identify a putative set of Cas inhibitors from an initial set of candidate inhibitors. The primary screening assay is followed by secondary screening assay to validate the putative set of inhibitors selected by the preliminary screen. In some embodiments, the present disclosure includes compositions and methods are provided for the inhibition of the function of RNA guided endonucleases, including the identification and use of such inhibitors.

Abstract: The present disclosure relates to chimeric small molecules, which find utility as modifiers of target substrates according to the formula A-L1-E-B or A-L1-E-L2-B, wherein A is a kinase binding moiety; B is a target binding moiety; L1 and L2 are each a linker; and E is an electrophilic reactive group. Molecules according to the present invention find use making substrate modifications such as post-translational modifications to targets that are not the natural substrate of the kinase; accordingly, diseases or disorders may be treated or prevented with molecules of the present disclosure.

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: The present disclosure relates to multifunctional chemical conjugation molecules, which find utility as modifiers of target substrates. The present disclosure includes multifunctional compounds comprising a localizing moiety, a chemical linker moiety, an activator moiety, a first orienting adaptor interconnecting the chemical linker moiety on one end to the activator moiety, and optionally a second orienting adaptor interconnecting the chemical linker molecule on a different end to the localizing moiety. Molecules according to the present invention find use making post-translational modifications to macromolecules that are not the natural substrate of the activator moiety. Diseases or disorders may be treated or prevented with molecules of the present disclosure.

Abstract: An engineered cell is provided that may include one or more polynucleotides inserted into a sequence of a secretory protein of the cell, which may be a ?-cell.

Abstract: The present inventions generally relate to site-specific delivery of nucleic acid modifiers and includes novel DNA-binding proteins and effectors that can be rapidly programmed to make site-specific DNA modifications. The present inventions also provide synthetic all-in-one genome editor (SAGE) systems comprising designer DNA sequence readers and a set of small molecules that induce double-strand breaks, enhance cellular permeability, inhibit NHEJ and activate HDR, as well as methods of using and delivering such systems.

Abstract: The present inventions generally relate to site-specific delivery of nucleic acid modifiers and includes novel DNA-binding proteins and effectors that can be rapidly programmed to make site-specific DNA modifications. The present inventions also provide a synthetic all-in-one genome editor (SAGE) systems comprising designer DNA sequence readers and a set of small molecules that induce double-strand breaks, enhance cellular permeability, inhibit NHEJ and activate HDR, as well as methods of using and delivering such systems.

Abstract: The present inventions generally relate to site-specific delivery of nucleic acid modifiers and includes novel DNA-binding proteins and effectors that can be rapidly programmed to make site-specific DNA modifications. The present inventions also provide synthetic all-in-one genome editor (SAGE) systems comprising designer DNA sequence readers and a set of small molecules that induce double-strand breaks, enhance cellular permeability, inhibit NHEJ and activate HDR, as well as methods of using and delivering such systems.

Abstract: 3D cell cultures and devices for 3D cell culture, and methods of use thereof are provided. In some embodiments, the 3D cell culture comprise pancreatic ? cells and can be generated in multi-well plates, allowing for high throughput assays on the cell culture.

Abstract: Compositions and methods are provided for the inhibition of the function of RNA guided endonucleases, including the identification and use of such inhibitors. Methods of identifying inhibitor compounds of RNA guided nucleases, assays for detecting nuclease activity and compounds for use therein are also provided.

Abstract: The disclosure includes non-naturally occurring or engineered CRISPR Cas variant proteins comprising one or more functional domains and degrader compositions specifically targeting the CRISPR Cas variant proteins; compositions, systems and methods of using the CRISPR Cas variant proteins comprising one or more functional domains and degrader compounds for spatio-temporal control are also provided.

Abstract: The disclosure includes non-naturally occurring or engineered DNA- or RNA-guided nuclease systems, comprising CRISPR enzymes associated with at least one destabilization domain (DD) and photocaged stabilization ligands with at least one photocage molecule, along with compositions, systems and complexes involving such systems, nucleic acid molecules and vectors encoding the same, delivery systems involving the same, uses thereof.

Abstract: Systems, apparatuses, and methods for providing a more effective customer service support system. A trained model may be created or generated by a process that includes acquiring a corpus of documents (such as customer generated messages), generating keyphrases from each document in the corpus of documents, generating word embeddings from each document in the corpus of documents, performing a clustering operation on the word embeddings, assigning each document in the corpus to a duster and labeling each duster, and training a machine learning or text classification model using the most relevant documents in a cluster and the label assigned to that cluster. The methods include a processing flow that provides multiple ways for a customer to navigate and select their desired intent or purpose in seeking customer assistance. As part of the processing flow, the trained machine learning model and intent tree data are provided to a customer seeking assistance.

Abstract: The disclosure includes non-naturally occurring or engineered DNA- or RNA-guided nuclease systems, comprising guide-binding adaptors each associated with at least one destabilization domain (DD), along with compositions, systems and complexes involving such systems, nucleic acid molecules and vectors encoding the same, delivery systems involving the same, uses therefor.

Abstract: Systems, apparatuses, and methods for providing a more effective customer service support system. In some embodiments, the systems, apparatuses, and methods include a user interface (UI) and process flow for implementing a conversation-based customer service support system. The user interface and associated processing enable a user/customer to quickly and accurately select an intent, goal, or purpose of their customer service request. In some embodiments, this is achieved by a set of user interface displays or screens and an underlying logic that provide a user with multiple ways of selecting, identifying, or describing the intent, goal, or purpose of their request for service or assistance.