Provided herein are methods for identifying pairs of protein binding partners, mutations of which may inform the discovery of pharmaceutically useful small molecules. The methods disclosed herein may allow for the adaptation of the native protein degradation system to modulate specific disease targets at the protein level, in particular, for targets that have long been considered undruggable.

The invention pertains to a method to identify an effective combination of a transmembrane E3 ubiquitin ligase and a membrane-bound protein, wherein the combination is effective when the transmembrane E3 ubiquitin ligase is capable of decreasing the surface level of the membrane-bound protein upon forced dimerization, preferably by ubiquitination of the membrane-bound protein. The method of the invention comprises a step of exposing a cell to a heterobifunctional molecule, wherein the heterobifunctional molecule comprises a first binding domain capable of specific binding to an extracellular portion of the transmembrane E3 ubiquitin ligase, and a second binding domain capable of specific binding to an extracellular portion of the membrane-bound protein. The method further comprises a step of determining the decrease in surface level of the membrane-bound protein. The invention additionally pertains to a heterobifunctional molecule targeting an effective combination of a transmembrane E3 ubiquitin ligase and a membrane-bound protein.

Transgenic plants exhibiting phytochelatin-based heavy metal tolerance and methods of use thereof for bioremediation are disclosed.

The present invention provides compounds, compositions thereof, and methods of using the same.

The present disclosure relates generally to the field of immunotherapy. In particular, the present disclosure describes to 20 single nucleotide variants (SNVs) within the A20 coding sequence that can differentially impact the immune system. Differential expression of the identified A20 SNVs can be used to “tune” the immune system of a subject e.g., tune up or tune down the sensitivity and/or strength of the immune system of a subject in response to a treatment or a pathogen. On the basis, the present disclosure provides methods for modulating the immune system of a subject by modulating the A20 SNV expression profile in the subject, thereby “tuning” the immune system. The present disclosure also describes reagents for use in such methods. The methods and reagents may have application in the treatment and/or management of diseases/conditions such as, for example, cancer, autoimmune disease, pathogenic infection, complement deficiency, and transplant rejection, where the strength of a subject's immune system plays an important role. The present disclosure also describes methods in which the A20 SNVs are used as biomarkers to stratify subjects according to the strength of their immune system e.g., strong or poor immune response relative to a reference A20 genotype, and the use of such methods in personalised medicine.

This disclosure relates to modified viruses, e.g., oncolytic vaccinia viruses, which have been modified to contain an exogenous nucleic acid that expresses a protein that modulates STAT3 activity. It is based, at least in part, on the discovery that vaccinia viruses modified to contain nucleic acid encoding PIAS3 and that express PIAS3 or a fragment thereof can inhibit STAT3 activity and enhance the anti-cancer activity of the vaccinia virus. Accordingly, this disclosure provides for oncolytic vaccinia viruses and methods of using them in the treatment of cancers.

The present invention is related to a polypeptide comprising an amino acid sequence, whereby the amino acid sequence of the polypeptide is at least 80% identical to a stretch of consecutive amino acids of the region of HPGGT comprising an amino acid sequence corresponding to SEQ.ID.No. 1, whereby such region is defined by (a) amino acid positions 150 to 200 of the amino acid sequence according to SEQ.ID.No.1, or (b) amino acid positions 410 to 480 of the amino acid sequence according to SEQ.ID.No.1, and
whereby the polypeptide is suitable to elicit an immune response which is capable of inhibiting the catalytic activity of HPGGT.

Angelman syndrome is a genetic neurological disorder with characteristics including delayed development, intellectual disability, severe speech impairment, and problems with movement and balance. Provided herein are polynucleotides, vectors, polypeptides, cells, compositions, kits and methods to treat Angelman syndrome.

The present disclosure provides, inter alia, nanobodies targeting a Ca.sub.Vβ auxiliary subunit and compositions thereof. Methods for blocking a High-Voltage Activated Calcium Channel (HVACC) using such compositions, methods for selectively targeting a population of cells in a subject, and methods for treating or ameliorating the effects of a disease in a subject are also provided.

Methods and compositions disclosed herein generally relate to compositions and methods for suppressing hematopoietic stem and progenitor cells (HSPCs) and the treatment of diseases or disorders involving UBE2N, such as cancers, including disorders such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) and chronic inflammatory disorders. Particular aspects relate to treating, e.g. acute myelomonocytic leukemia (AML-M4) and acute monocytic leukemia (AML-M5). Particular aspects of the invention relate to determining an individual in need of treatment who can be treated with a UBE2N inhibitor, such as an individual having AML-M4 and/or AML-M5. The invention further relates to using a UBE2N inhibitor to treat a disease or disorder characterized by malignant hematopoietic cells, as well as other cancers, and chronic inflammatory disorders, and as immune checkpoint regulators.