Constructs and methods are described for producing sparse and stochastic labeling of cells expressing one or more site-specific recombinases in a host mammal. Described is a nucleic acid construct comprising, in operable linkage, a translation start site, an optional spacer, a polycytosine mononucleotide repeat, and an open reading frame (ORF), wherein the polycytosine repeat and the ORF are out of frame with respect to the translation start site. The simple, general, and scalable solution for genetically-directed sparse cell labeling allows the visualization of the complete cellular morphology of cells. Representative examples of cells to be visualized using sparse labeling include, but are not limited to, neurons or non-neuronal cells in the central nervous system (including brain), peripheral nervous systems, and other peripheral tissues.

Methods and compositions for rapid development of reporter lines utilizing safe harbor sites in iPSCS, as well as other progenitor cells, pluripotent and multipotent stem cells and differentiated cells, and multiple Lox sites are provided.

The invention provides a genetically modified non-human animal that comprises in its genome unrearranged T cell receptor variable gene loci, as well as embryos, cells, and tissues comprising the same. Also provided are constructs for making said genetically modified non-human animal and methods of making the same. Various methods of using the genetically modified non-human animal are also provided.

Non-human animal cells and non-human animals comprising CRISPR/Cas synergistic activation mediator system components and methods of making and using such non-human animal cells and non-human animals are provided. Methods are provided for using such non-human animals to increase expression of target genes in vivo and to assess CRISPR/Cas synergistic activation mediator systems for the ability to increase expression of target genes in vivo.

The present disclosure provides dual viruses capable of producing a primary virus and a secondary virus, and dual oncolytic viruses capable of producing a primary oncolytic virus and a secondary oncolytic virus.

Transgenic mammals that express bovine-based immunoglobulins are described herein, including transgenic rodents that express bovine-based immunoglobulins for the development of bovine therapeutic antibodies.

The present disclosure provides methods and compositions for high frequency mouse transgenesis using, for example, a Bxb1 landing pad.

In alternative embodiments, provided are compositions, including products of manufacture and kits, and methods, for remotely-controlled and non-invasive manipulation of intracellular nucleic acid expression, genetic processes, function and activity in live cells, e.g., adding functions or changing or adding specificities for immune cells, for monitoring physiologic processes, for the correction of pathological processes and for control of therapeutic outcomes. In alternative embodiments, provided are ultrasound-based thermal or mechanical stimulations, and thermo- or mechano-sensitive protein, either synthetically engineered or natively (endogenously) occurring, integrated to control the production of intracellular nucleic acid and gene expression, e.g., for the expression of biological-active proteins, which can be used, in alternative embodiments, for diagnostic or therapeutic purposes. In alternative embodiments, exemplary thermo- and mechanogenetic systems provided herein allow a deep penetration of stimulation and manipulation in vivo at centimeter-level depth with high spatiotemporal precision.

Provided herein are compositions and methods for reprogramming a non-neuronal cell to a neuron. Aspects of the present disclosure relate to compositions and methods for transdifferentiating an age-restricted non-neuronal cell into a neuron. Also provided herein is a method of treating neurodegenerative disease by reprogramming region or anatomy specific non-neuronal cells into specific types of functionalized neurons.

Provided herein is a baculovirus expression vector system for the production of a desired protein. In one aspect, the desired protein is a closed-ended DNA (ceDNA) molecule comprising wild-type and/or truncated inverted terminal repeats derived from a genome of a member of the viral family Parvoviridae.