The present invention belongs to the technical field of protein and genetic engineering, and specifically discloses use of an erythropoietin human hepatocyte receptor B4 as a target in screening and preparing a biological formulation or medicament for increasing sensitivity to insulin. Also disclosed is use of an erythropoietin human hepatocyte receptor B4 in preparing an insulin-sensitized mouse model. On the basis of insulin signal regulation, a protein EphB4 capable of interacting with an insulin receptor (InsR) is found. The protein can interact with InsR, and insulin stimulation can promote the interaction between the two, which provides a basis for insulin resistance in the case of hyperinsulinaemia. Over-expression of EphB4 can promote degradation of InsR. Inhibition of EphB4 can enhance the sensitivity to insulin and improve insulin resistance.

Pre-conditioning a vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumor antigen-specific DC vaccines. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumor growth in a manner dependent on the chemokines CCL3 and CCL21 and Td-activated CD4.sup.+ T cells. Interference with any component of this axis markedly reduced Td-mediated DC migration and antitumor responses. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen represents a viable strategy to increase DC homing to lymph nodes and improve antitumor immunotherapy.

Non-human animals, and methods and compositions for making and using the same, are provided, wherein the non-human animals comprise a humanization of a Programmed cell death 1 (Pdcd1) gene. The non-human animals, in some embodiments, comprise a genetic modification to an endogenous Pdcd1 gene so that the non-human animals express a PD-1 polypeptide that includes a human portion and an endogenous portion (e.g., a non-human portion).

Provided herein are methods for creating an animal model for the study of dry eye and methods of using such animal models to test candidate treatments for ocular conditions and determine the efficacy of such treatments.

Methods and compositions for drug discovery, analysis and treatment of a proliferative disorder characterized by abnormal cells in a mammalian subject are provided according to aspects of the present invention which include administering a pharmaceutically effective amount of a combination of: a cytotoxic agent, a SET agonist and a SET ribosome antagonist. Methods and compositions according aspect of the present invention incorporate agents effective to regulate and/or affect selective translation in a cell characterized by abnormal proliferation, such as a cancer cell, thereby promoting death of the cell.

The present invention encompasses the recognition that identification of alternative means to block RAS oncogenic signaling may be required for developing novel cancer therapies. Among other things, the present invention encompasses the recognition that targeting RAS palmitoylation can achieve effective therapy for RAS-related cancers. Furthermore, the present invention encompasses the recognition that reduction of ZDHHC9 level and/or activity can significantly reduce palmitoylation level of Ras protein. Among other things, the present invention encompasses the recognition that identification of agents that modulate expression and/or activity of ZDHHC9 can reduce palmitoylation level of Ras protein. In some embodiments, the present invention provides methods of treating a subject suffering from cancer by administering ZDHHC9 inhibition therapy.

Methods for treatment and diagnosis of neurological disorders such as autism and autism spectrum disorder are disclosed. Also disclosed are modulators of alternative splicing regulators SRRM4 and/or SRRM3 for treating neurological disorders. Further disclosed are agents that modulate the expression of at least one splice variant for treating neurological disorders. Mouse models of neurological disorders having increased or decreased expression of SRRM4 and/or SRRM3 are also disclosed.

The invention provides in vivo methods for identifying cancer-associated immunotherapy targets.

The present invention relates to methods and compositions for high content drug screening in Caenorhabditis elegans which may be used to identify compounds that treat disorders associated with protein aggregation. It is based, at least in part, on the discovery that Caenorhabditis elegans, genetically modified to create a model system for disorders of protein aggregation, could be used, in a high throughput screening system, to identify agents that reduce the amount of aggregated protein.

In one aspect, the invention provides a transgenic non-human animal model having germ cells and somatic cells containing an endogenous MMTV-SV40-Spy1A gene sequence introduced into said animal model or an ancestor of said animal model at an embryonic stage, wherein said gene sequence comprises a mouse mammary tumor virus gene (MMTV), a functionally disrupted SV40 gene (SV40) and a human Spy1A gene. In another aspect, the present invention provides a transgenic non-human animal model whose germ cells and somatic cells contain an endogenous Spy1A-pTRE-Tight gene sequence introduced into said animal model or an ancestor of said animal model at an embryonic stage. Preferably, the Spy1A-pTRE-Tight animal model expresses the Spy1A gene and develop cancer, preferably breast cancer, when administered with tetracycline, preferably doxycycline.