Provided herein are glucagon superfamily peptides conjugated with NHR ligands that are capable of acting at a nuclear hormone receptor. Also provided herein are pharmaceutical compositions and kits of the conjugates of the invention. Further provided herein are methods of treating a disease, e.g., a metabolic disorder, such as diabetes and obesity, comprising administering the conjugates of the invention.

Provided herein are methods for the repopulation of organs and tissues, such as the liver, using modified cells that express a transcription coactivation factor-ligand binding domain fusion protein, such as a YAP-ERT2 fusion protein. Also provided are compositions, including nucleic acid molecules that encode a YAP-ERT2 fusion protein, YAP-ERT2 fusion polypeptides, and cells containing nucleic acid molecules that encode a YAP-ERT2 fusion protein.

The present invention provides methods and compositions useful in the diagnosis and management of autoimmune diseases. In particular, the present invention provides improved methods and compositions for the diagnosis and management of Graves' disease. The methods of the present invention not only avoids the need for radioactivity and are much simpler, economical, and rapid than methods traditionally used for the diagnosis of Graves' disease, but also improve upon the sensitivity and detection abilities of previous luciferase-based autoantibody detection assays.

GPCR-fusion partner proteins comprising G protein coupled receptors (GPCRs) of GPCRs and fusion partners such as rubredoxin, cytochrome b562 RIL (Bril, bRIL, BRIL), T4 lysozyme C-terminal fragment (C-term-T4L), flavodoxin, or xylanase either substituted for some or all of the third intracellular loop of the GPCR between the fifth and sixth helix of the GPCR are described or attached to an terminus or C terminus of the GPCR. GPCR-fusion partner proteins in crystalline form, optionally of a quality suitable for x-ray crystallographic structure determination of the GPCR, are described. Methods of using fusion partners in GPCR-fusion partner proteins to support crystallization of GPCR-fusion partner proteins for x-ray crystallographic structure determination of the GPCR, are described. Methods of identifying other suitable fusion partners through screening of protein data banks are also described.

The present invention relates to peptides, proteins, nucleic acids and cells for use in immunotherapeutic methods. In particular, the present invention relates to the immunotherapy of cancer. The present invention furthermore relates to tumor-associated T-cell peptide epitopes, alone or in combination with other tumor-associated peptides that can for example serve as active pharmaceutical ingredients of vaccine compositions that stimulate anti-tumor immune responses, or to stimulate T cells ex vivo and transfer into patients. Peptides bound to molecules of the major histocompatibility complex (MHC), or peptides as such, can also be targets of antibodies, soluble T-cell receptors, and other binding molecules.

Some aspects of this disclosure provide compositions, methods, systems, and kits for controlling the activity of RNA-programmable endonucleases, such as Cas9, or for controlling the activity of proteins comprising a Cas9 variant fused to a functional effector domain, such as a nuclease, nickase, recombinase, deaminase, transcriptional activator, transcriptional repressor, or epigenetic modifying domain. For example, the inventive proteins provided comprise a ligand-dependent intein, the presence of which inhibits one or more activities of the protein (e.g., gRNA binding, enzymatic activity, target DNA binding). The binding of a ligand to the intein results in self-excision of the intein, restoring the activity of the protein.

Provided herein are methods for preventing or treating post-traumatic stress disorder (PTSD) in a subject, the methods including: administering an agent which inhibits formation of a glucocorticoid receptor (GR)-FK506 Binding Protein 51 (FKBP51) complex (GR-FKBP51 complex), or which disrupts already formed GR-FKBP51 complex, to the subject; thereby reducing a level of GR-FKBP51 complex in the subject and preventing or treating the PTSD. Also provided are methods for diagnosing a subject as having, or being at risk of developing, a PTSD, the methods including steps of: measuring a level of a GR-FKBP51 complex in the subject; comparing the measured level to a reference level of a non-PTSD condition; and identifying the subject as having, or being at risk of developing, PTSD where the measured level is elevated relative to the reference level. Agents, compositions, and/or kits for the diagnosis and/or treatment of PTSD are also described.

Methods and compositions are provided for reversibly localizing proteins to the exterior part of the cell surface. Compositions provided herein can include nucleic acids that encode polypeptides of interest and the ligand binding domain (LBD) of a nuclear hormone receptor. Medical applications are provided, including controlling the toxicity of CAR T cells.

Certain aspects of the present invention relate to methods and reagents for the treatment of prostate cancer. Also included in the present invention is an enzymatic nucleic acid molecule (“DNAzyme”) comprising a catalytic core and two specific binding arms complementary to a nucleic acid sequence comprised in an Androgen Receptor mRNA molecule. Also included are compositions comprising the enzymatic nucleic acid molecules and methods of treating disorders such as prostate cancer comprising use of such nucleic acid molecules.

Disclosed herein are improved methods for treatment of brain cancer (such as glioma/glioblastoma) via ligand-inducible gene-switch controlled in vivo expression of an immunomodulator (i.e., IL-12) in combination with one or more other immunomodulators (i.e., an immune cell check point inhibitor; e.g., such as a PD-1 inhibitor or a PD-1 binder.