Compositions and methods are provided for modifying a genomic locus of interest in a eukaryotic cell, a mammalian cell, a human cell or a non-human mammalian cell using a large targeting vector (LTVEC) comprising various endogenous or exogenous nucleic acid sequences as described herein. Further methods combine the use of the LTVEC with a CRISPR/Cas system. Compositions and methods for generating a genetically modified non-human animal comprising one or more targeted genetic modifications in their germline are also provided.

The application relates to methods for determining a parameter such as toxicity and pharmacokinetic behavior for a pharmaceutical compound against a disease or disorder. The test animals being used are non-human animals not suffering from or is not showing symptoms or signs of the disorder and which do not provoke an immune response against said pharmaceutical compound. These animals are obtainable by administration of a peptide comprising an oxidoreductase motif further comprising an NKT peptide epitope or an MHC class II T cell epitope of said pharmaceutical compound, wherein said motif and said epitope are separated by a linker of between 0 and 4 amino acids.

The present invention includes compositions and methods for treating diseases or disorders associated with pathological calcification or pathological ossification. In certain embodiments, the diseases or disorders are selected from the group consisting of Generalized Arterial Calcification of Infancy (GACI), Idiopathic Infantile Arterial Calcification (IIAC), Ossification of the Posterior Longitudinal Ligament (OPLL), hypophosphatemic rickets, osteoarthritis, calcification of atherosclerotic plaques, PXE, hereditary and non-hereditary forms of osteoarthritis, ankylosing spondylitis, hardening of the arteries occurring with aging, calciphylaxis resulting from end stage renal disease and progeria.

Generation of chimeric non-human animals hosting bat donor cells involves chimeric mice having bat cells that may be stably tolerated to provide a new platform technology in the general field of biology, and having application in the field of immunology related to virus-host interaction, cancer biology, autoimmunity, and the development of new drugs.

Disclosed herein is a composition comprising a nucleic acid sequence encoding a Mayaro Virus antigen that elicits an immune response in a mammal. Also disclosed herein is a nucleic acid sequence encoding an anti-Mayaro Virus antibody, a fragment thereof, a variant thereof. Also disclosed herein is a method of generating a synthetic antibody in a subject by administering the composition to the subject. The disclosure also provides a method of preventing and/or treating a Mayaro virus infection in a subject using said composition and method of generation.

The present invention relates generally to genetically modified non-human animals and immunodeficient non-human animals characterized by restored complement-dependent cytotoxicity, as well as methods and compositions for assessment of therapeutic antibodies in the genetically modified immunodeficient non-human animals. In specific aspects, the present invention relates to immunodeficient non-obese diabetic (NOD), A/J, A/He, AKR, DBA/2, NZB/BIN, B10.D2/oSn and other mouse strains genetically modified to restore complement-dependent cytotoxicity which is lacking in the unmodified immunodeficient mice. In further specific aspects, the present invention relates to NOD.Cg-Prkdc.sup.scid IL2rg.sup.tm1Wjl/SzJ (NSG), NOD.Cg-Rag1.sup.tm1Mom IL2rg.sup.tm1Wjl/SzJ (NRG) and NOD.Cg-Prkdc.sup.scid IL2rg.sup.tm1Sug/JicTAc (NOG) mice genetically modified to restore complement-dependent cytotoxicity which is lacking in unmodified NSG, NRG and NOG mice. Methods for assessment of therapeutic antibodies or putative therapeutic antibodies in the genetically modified immunodeficient mice characterized by an intact complement system are provided according to specific aspects of the present invention.

Genetically modified non-human animals and methods and compositions for making and using the same are provided, wherein the genetic modification comprises a humanization of an endogenous signal-regulatory protein gene, in particular a humanization of a SIRP gene. Genetically modified mice are described, including mice that express a human or humanized SIRP protein from an endogenous SIRP locus.

The present invention relates to an in vitro immune synapse system and a method of in vitro evaluating immune response using the same. The in vitro immune synapse system includes antigen-presenting cells (APCs) and at least one cell type of several specific T cell subtypes isolated from peripheral blood mononuclear cells (PBMCs), all of which is from a same individual of pigs. When a test sample is co-cultured in the in vitro immune synapse system for a given period, it can be determined that the test sample is immunogenic, immunostimulatory or not according to the immunization-related changes of these cells, thereby potentially replacing some kinds of animal experimentation.

Genetically modified non-human animals comprising a humanized interleukin-15 (IL-15) gene. Cells, embryos, and non-human animals comprising a human IL-15 gene. Rodents that express humanized or human IL-15 protein.

Provided herein are engineered TSC2 polypeptides, and nucleic acid sequences encoding them, in which the ability of a serine residue to be phosphorylated is altered. In some aspects, the TSC2 serine residue cannot be phosphorylated (e.g., by substituting the serine residue with an alanine residue). In some aspects, the TSC2 serine acts as if it is constitutively phosphorylated (e.g., by substituting the serine residue with a glutamic acid residue). Also provided herein are engineered immune cells comprising altered TSC2 polypeptides or nucleic acid sequences encoding them, and methods of making and using such engineered immune cells.