Abstract: The present invention relates to compounds of formula (I): or a pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, wherein X1, X2, X3, X4, X5, W1, W2, W3, and W4 are as described herein. The present invention relates generally to inhibitors of histone deacetylase and to methods of making and using them. In one aspect, the invention relates to selective HDAC3 inhibitors useful for protecting ?-cells and improving insulin resistance. The selective HDAC3 inhibitors are also useful for promoting cognitive function and enhancing learning and memory formation.

Abstract: The present specification provides compositions and methods that are capable of directly installing an insertion or deletion of a given nucleotide at a specified genetic locus. The compositions and methods involve the novel combination of the use an engineered RNA enzyme (i.e., “ribozyme”) that is capable of site-specifically inserting or deleting a single nucleotide at a genetic locus and the use of a nucleic acid programmable DNA binding protein (napDNAbp) (e.g., Cas9) to target the engineered ribozyme to a specified genetic locus, thereby allowing for the direct installation of an insertion of deletion at the specified genetic locus by the engineered ribozyme.

Abstract: Provided herein are methods to determine the original abundance of mutant alleles of one or more barcoded target sequences following mutation enrichment and sequencing.

Abstract: The invention provides for systems, methods, and compositions for targeting nucleic acids. In particular, the invention provides non-naturally occurring or engineered DNA-targeting systems comprising a novel DNA-targeting CRISPR effector protein and at least one targeting nucleic acid component like a guide RNA. Methods for making and using and uses of such systems, methods, and compositions and products from such methods and uses are also disclosed and claimed.

Abstract: The present disclosure provides for base editors which satisfy a need in the art for installation of targeted transversions of thymine (T) to adenine (A), or correspondingly, trans versions of adenine (A) to thymine (T). The nucleobase editor domains include a nucleic acid programmable DNA binding protein and an adenosine methyltransferase domain. The base editors may be engineered through the use of continuous or non-continuous evolution systems, such as phage-assisted continuous evolution (PACE). In particular, the present disclosure provides for evolved adenine-to-thymine (or thymine-to-adenine) base editor variants that overcome deficiencies in the art for base editors that can install single-base A:T to T:A transversion mutations. In some embodiments, methods for targeted nucleic acid editing are provided. In some embodiments, pharmaceutical compositions comprising, and vectors and kits for the generation of, targeted base editors are provided.

Abstract: Described are methods for enhancing exon skipping in a pre-mRNA of interest, comprising contacting the pre-mRNA with interfering oligonucleotides such as antisense, siRNA, and miRNA. The exon skipping methods are associated with methods of treating a variety of diseases and conditions, including cancer.

Abstract: The present invention provides compounds of formula I, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting kinase (e.g., GSK3 (e.g., GSK3? or GSK3?) or CK1) activity. The present invention further provides methods of using the compounds described herein for treating kinase-mediated disorders, such as neurological diseases, psychiatric disorders, metabolic disorders, and cancer.

Abstract: The invention provides for systems, methods, and compositions for targeting nucleic acids. In particular, the invention provides non-naturally occurring or engineered DNA-targeting systems comprising a novel DNA-targeting CRISPR effector protein and at least one targeting nucleic acid component like a guide RNA.

Abstract: Compounds of formula (I) processes for their production and their use as pharmaceuticals.

Abstract: The present invention provides a combination of genomic and computational technologies to provide rapid, portable sample analysis for sequencing or identifying a target sequence involving generating probes for use in analyzing a sample which may comprise a target sequence.

Abstract: It has been discovered that lung tumor growth is associated with a dysregulation of the local microbiota, including an increased total bacterial load and reduced bacterial diversity in the airway. In the lungs, commensal bacteria, which are otherwise non-pathogenic and colonize pulmonary tissue at a much lower density in healthy individuals, provoke chronic inflammation and exacerbation of lung cancer through tumor-infiltrating immune cells. Thus, targeting the lung microbiota and its responding immune pathways is useful in treating lung cancer. Disclosed are compositions and methods targeting the lung microbiota and its responding immune pathways in a subject by specific targeting of commensal bacteria in the subject. Typically, the methods involve administering an effective amount of one or more therapeutics such as an antibiotic that reduces the local bacterial load, blocks or depletes tumor-infiltrating immune cells, and/or locally inhibits one or more cytokines or chemokines.

Abstract: The present invention provides methods and tools for analyzing genetic interactions. The subject matter disclosed herein is generally directed to single cell genomics and proteomics. In one embodiment provided is a method of cell and nuclei hashing using sample barcodes. In another embodiment are method of performing genomewide CRISPR perturbation screens.

Abstract: Methods for screening for an adeno-associated virus (AAV) capsid protein that can bind to a target protein (e.g., Ly6 protein) and related compositions are provided in aspects of the disclosure.

Abstract: The invention provides for systems, methods, and compositions for manipulation of sequences and/or activities of target sequences. Provided are vectors and vector systems, some of which encode one or more components of a CRISPR complex, as well as methods for the design and use of such vectors. Also provided are methods of directing CRISPR complex formation in eukaryotic cells and methods for selecting specific cells by introducing precise mutations utilizing the CRISPR/Cas system.

Abstract: The invention provides methods and devices for determining molecular signatures in a cancer that predict response to a MARPK pathway inhibitor and methods of use of such signatures.

Abstract: Methods for single-molecule analysis of structure and sequence of linearized polynucleotides are provided.

Abstract: The present disclosure provides compounds of Formula (I), and salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. The provided compounds may be useful for inhibiting kinases, e.g., glycogen synthase kinase 3 (GSK3). The provided compounds may be able to selectively inhibit GSK3a, as compared to GSK3P and/or other kinases. The present disclosure further provides pharmaceutical compositions, kits, and methods of use, each of which involve the compounds. The compounds, pharmaceutical compositions, and kits may be useful for treating diseases associated with aberrant activity of GSK3a (e.g., Fragile X syndrome, attention deficit hyperactivity disorder (ADHD), childhood seizure, intellectual disability, diabetes, acute myeloid leukemia (AML), autism, and psychiatric disorder).

Abstract: A method for treating inflammation and/or autoimmune diseases comprises administering to a subject in need thereof, a composition comprising a CDK8 inhibitor. In another aspect, a method for increasing IL-10 production comprises administering to a subject in need thereof a CDK8 inhibitor. In another aspect, a method for enhancing Treg cell differentiation, comprising administering a composition comprising a CDK8 inhibitor. In certain example embodiments, the subject suffers from an inflammatory bowel disease. In certain other example embodiments, the subject requires immunosuppression to prevent rejection following a transplantation procedure.

Abstract: The present invention relates to macrocyclic indole derivatives of general formula (I): in which R1, R2, R3, R4, R5, R6, A and L are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds, and the use of said compounds for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases, in particular of hyperproliferative disorders, as a sole agent or in combination with other active ingredients.

Abstract: Methods of diagnosing and treating autism spectrum disorders are provided.