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

Abstract: The subject matter disclosed herein is generally directed to treating cancers sensitive to phosphate dysregulation with inhibitors of inositol pyrophosphate (PP-InsP) synthesis, in particular, inhibitors of inositol hexakisphosphate kinases IP6Ks.

Abstract: The present disclosure provides compositions, reagents, and methods for producing capped, circular RNA molecules, circularized RNA molecules, and in particular, circularized mRNA molecules encoding a polypeptide such as a therapeutic protein.

Abstract: Some aspects of this disclosure provide strategies, systems, reagents, methods, and kits that are useful for the targeted editing of nucleic acids or the modification of nucleic acids or proteins, including editing a single site within the genome of a cell or subject, e.g., within the human genome. In some embodiments, fusion proteins of nucleic acid programmable DNA binding proteins e.g., GeoCas9 or variants thereof, and effector domains, e.g., deaminase domains, are provided. In some embodiments, methods for targeted nucleic acid editing or protein modification are provided. In some embodiments, reagents and kits for the generation of targeted nucleic acid editing proteins, e.g., fusion proteins of a GeoCas9 and effector domains, are provided.

Abstract: Compositions and methods are provided herein for conducting prime editing of a target DNA molecule (e.g., a genome) that enables the incorporation of a nucleotide change and/or targeted mutagenesis. The compositions include fusion proteins comprising nucleic acid programmable DNA binding proteins (napDNAbp) and a polymerase (e.g., reverse transcriptase), which is guided to a specific DNA sequence by a modified guide RNA, named an PEgRNA. The PEgRNA has been altered (relative to a standard guide RNA) to comprise an extended portion that provides a DNA synthesis template sequence which encodes a single strand DNA flap which is synthesized by the polymerase of the fusion protein and which becomes incorporated into the target DNA molecule.

Abstract: Echocardiography deep learning and cardiovascular outcomes are described. An echocardiogram analysis module may include a deep learning model to generate a video output for an input echocardiogram video, the deep learning model comprising a convolutional neural network and at least one dense layer. The echocardiogram analysis module may further include a cardiac prediction generator to generate a cardiac prediction based on video outputs generated for a plurality of input echocardiogram videos of an echocardiogram study, the cardiac prediction comprising a measurement prediction or a classification prediction.

Abstract: Compositions and methods are provided herein for conducting prime editing of a target DNA molecule (e.g., a genome) that enables the incorporation of a nucleotide change and/or targeted mutagenesis. The compositions include fusion proteins comprising nucleic acid programmable DNA binding proteins (napDNAbp) and a polymerase (e.g., reverse transcriptase), which is guided to a specific DNA sequence by a modified guide RNA, named an PEgRNA. The PEgRNA has been altered (relative to a standard guide RNA) to comprise an extended portion that provides a DNA synthesis template sequence which encodes a single strand DNA flap which is synthesized by the polymerase of the fusion protein and which becomes incorporated into the target DNA molecule.

Abstract: Provided herein are compounds of Formula (I-A), (I-B), or (I-C), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically enriched forms, prodrugs, or mixtures thereof, and compositions thereof. Also provided are methods and kits involving the inventive compounds or compositions for treating and/or preventing diseases and/or conditions (e.g., neurological disease (e.g., Alzheimer's disease, multiple sclerosis, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis), metabolic disorder (e.g., obesity, diabetes, X-linked adrenoleukodystrophy (X-ALD)), proliferative disease (e.g., cancers), hepatic disease (e.g., liver cirrhosis), conditions associated with autophagy (e.g., neurodegenerative disease, infection, cancer, conditions associated with aging, heart disease), conditions associated with aging, conditions associated with modulating the mPTP, cardiovascular conditions (e.g.

Abstract: Aspects of the disclosure relate to compositions and methods for targeted protein degradation. In some embodiments, the disclosure relates to methods of evolving protein degrons to interact with certain small molecule inducers (e.g., VS-777, PT-179, or PK-1016). In some embodiments, the disclosure relates to compositions (e.g., peptides, nucleic acids encoding the protein degrons, etc.) used for targeted protein degradation. In some embodiments, the disclosure relates to methods of degrading a target polypeptide in a cell.

Abstract: Described herein are methods and uses thereof for in vivo evaluating functions of multiple genes in parallel by combining in utero genetic perturbation of progenitor cells and single-cell transcriptomic profiling of progeny cells in animals. These methods can be used, among other things, to reveal in vivo gene functions in a cell type-specific manner.

Abstract: The present disclosure provides Cas protein variants comprising one or more amino acid substitutions relative to wild-type Cas14a1. Fusion proteins comprising the Cas protein variants described herein are also provided by the present disclosure. Further provided herein are methods for modifying a target nucleic acid using the Cas proteins and fusion proteins provided herein. The present disclosure also provides guide RNAs, complexes, polynucleotides, systems, cells, kits, and pharmaceutical compositions.

Abstract: The invention provides for delivery, engineering and optimization of systems, methods, and compositions for manipulation of sequences and/or activities of target sequences. Provided are delivery systems and tissues of organ which are targeted as sites for delivery. Also 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 provide dare methods of directing CRISPR complex formation in eukaryotic cells to ensure enhanced specificity for target recognition and avoidance of toxicity and to edit or modify a target site in a genomic locus of interest to alter or improve the status of a disease or a condition.

Abstract: Described in various embodiments herein are tiled amplification nucleic acid detection systems and uses thereof. In some embodiments, the nucleic acids amplified and detected are cell free DNA (cfDNA).

Abstract: The present invention provides dihydrooxydiazinone compounds of general formula (I): in which R1, R2, R3, and R4, 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 diseases, as a sole agent or in combination with other active ingredients.

Abstract: The disclosure features compositions, systems, and methods for preparation and use of efficient RNA nuclear export of ribozyme-assisted circular RNA molecules (racRNAs). In embodiments, the methods involve characterizing a cell or tissue using racRNAs.

Abstract: The present disclosure provides zinc finger domain-containing proteins comprising optimized ?-, ?-, and linker motifs, and fusion proteins comprising said zinc finger domain-containing proteins fused to an effector domain. The present disclosure also provides double-stranded DNA deaminase A (DddA) variants and fusion proteins comprising said DddA variants fused to a programmable DNA binding protein (e.g., any of the zinc finger domain-containing proteins disclosed herein, a TALE protein, or a CRISPR/Cas9 protein). Methods for editing DNA (including genomic DNA and mitochondrial DNA) using the fusion proteins described herein are also provided by the present disclosure. The present disclosure further provides polynucleotides, vectors, cells, kits, and pharmaceutical compositions comprising the zinc finger domain-containing proteins, DddA variants, and fusion proteins described herein.

Abstract: The present disclosure provides methods and compositions for determining the antigen specificity of T cells and in a scalable, high-throughput approach. The disclosure provides methods for producing RNA-barcoded pMHC multimers that can be decoded using single-cell RNA sequencing methods. Among these, disclosed herein are multivalent virus-like-particles bound with pMHC in E. coli cells that encapsulate an RNA barcode encoding the peptide identity.

Abstract: Disclosed herein are compositions, methods, kits, and systems relating to efficient delivery of cargos (e.g., therapeutic cargos) into cells, for instance, for in vivo delivery. The present disclosure provides lipid-containing particles (e.g., virus-like particles) for delivering therapeutic cargos. The present disclosure also provides polynucleotides encoding the lipid-containing particles provided herein, which may be useful for producing said lipid-containing particles. Also provided are methods for editing nucleic acid molecules in cells using the lipid-containing particles provided herein, as well as cells and kits comprising the lipid-containing particles.

Abstract: The invention features compositions and methods that are useful for characterizing a complex biological sample.

Abstract: Disclosed herein are compositions, methods, kits, and systems relating to efficient delivery of cargos (e.g., therapeutic cargos) into cells, for instance, for in vivo delivery. The present disclosure provides lipid-containing particles (e.g., virus-like particles) for delivering therapeutic cargos. The present disclosure also provides polynucleotides encoding the lipid-containing particles provided herein, which may be useful for producing said lipid-containing particles. Also provided are methods for editing nucleic acid molecules in cells using the lipid-containing particles provided herein, as well as cells and kits comprising the lipid-containing particles.