Provided are a three-dimensional (3D) fibroblast cluster, a method of preparing the same, an in vitro 3D skin dermis model including a fibroblast cluster cultured from a fibroblast, and a method of screening a drug by using the in vitro 3D skin dermis model.

An enzyme-responsive peptide and a method off using such enzyme-responsive peptide are disclosed. An enzyme-responsive peptide, the peptide comprising an amino acid having an -amino group, an -carboxylic acid group and a -amine group, wherein the -amine group is covalently bonded with a first group and the -carboxylic acid is covalently bonded with a second group.

The present disclosure describes gene therapy systems, and related methods, useful for treating and/or preventing deafness caused by genetic mutation of the TMPRSS3 gene or the LOXHD1 gene. The compositions and methods disclosed herein use adeno-associated viral (AAV) vector gene delivery of TRMPSS3 or LOXHD1 into the inner ear to restore activity of the TMPRSS3 gene or the LOXHD1 gene, respectively, promote hair cell survival and restore hearing in patients suffering from hearing loss. As disclosed herein, the systems and methods may utilize a combination of gene therapy (e.g., molecular therapeutics) for hearing loss caused by a genetic mutation together with implantation of a cochlear implant.

Provided are compositions, e.g., multiplexed platforms or systems, to screen for molecules, e.g., small molecule active agents such as drugs, that inhibit enzymes such as proteases. Provided are cell-based or multiplexed platforms for monitoring or assay the activity of a protease. Provided are cell-based assays and multiplexed systems for the monitoring of enzyme, activity such as proteolytic cleavage on the cell surface, where optionally the protein, e.g., an enzyme, can be naturally expressed on the cell surface or engineered to be expressed on the cell's surface. Provided are cells and stable cell lines expressing an assay construct and an enzyme of interest, where optionally one cell or cell line expresses both the assay construct and the enzyme, or two different cells or independent cell lines are used and mixed in the assay, where one expresses the assay construct with the enzyme substrate and the second expressing the enzyme.

Provided are methods of identifying, visualizing and purifying proteases from a complex biological sample.

A system and method for creating crystals from human acetylcholinesterase. The crystals can then be analyzed using X-ray crystallography. A segment of DNA for human acetylcholinesterase is isolated that includes the codon sequence GAGGGC. A polyhistidine tag is inserted between codon GAG and codon GGC to produce a recombinant acetylcholinesterase construct. The recombinant acetylcholinesterase construct is used to transfect cells on a prepared growth medium. The growing cells secrete a portion of the recombinant acetylcholinesterase construct. The secreted portion is concentrated and the tag cleaved. The concentrate is then buffered and used to form crystals.

Aggregated Tau protein is associated with over 20 neurological disorders including Alzheimer's disease. Previous work has shown that Tau's sequence segments VQIINK and VQIVYK drive its aggregation, and that inhibitors based on the structure of the VQIVYK segment partially inhibit Tau aggregation. Here we show that the VQIINK segment is the more powerful driver of Tau aggregation. Two structures of this segment determined by the cryo EM method MicroED explain its more powerful seeding. Of practical significance, the understanding of the structures has led to the design of structure based peptide inhibitors that effectively inhibit Tau aggregation as well as the ability of exogenous Tau fibrils to seed intracellular Tau in mammalian cells into amyloid.

Compositions and methods for improving embryo development, treating idiopathic male factor infertility, and enabling infertile/sub-fertile/sterile men to father their own genetic offspring are provided. Typically, the methods include administering into a male or female gamete or fertilized embryo an effective amount of a compound that increases bioavailability of a TET protein to improve development of an embryo resulting from fertilization of the female gamete by a male gamete. The compound can be administered into the gamete or embryo before, during, or after fertilization. The compound can be administered by an injection such as intracytoplasmic injection. The compound and the male gamete can be administered in combination by intracytoplasmic sperm injection. Methods of making male gametes, and methods of modifying the genome of a male gamete or embryo using an effective amount of a gene editing composition to correct a gene mutation or anomaly in the genome thereof are also provided.

A bone delivery conjugate having a structure selected from the group consisting of: A) X-D.sub.n-Y-protein-Z; and B) Z-protein-Y-D.sub.n-X, wherein X is absent or is an amino acid sequence of at least one amino acid; Y is absent or is an amino acid sequence of at least one amino acid; Z is absent or is an amino acid sequence of at least one amino acid; and D.sub.n is a poly aspartate wherein n=10 to 16. Compositions comprising same and methods of use thereof.

The present invention relates to dual-site BACE1 inhibitors, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the present invention are useful in the therapeutic and/or prophylactic treatment of e.g. Alzheimer's disease.