Disclosed herein is a recombinant adenovirus genome, said adenovirus genome comprising a heterologous nucleic acid inserted into a cloning site of said genome, said heterologous nucleic acid comprising: (a) a first nucleic acid sequence comprising an adenovirus tripartite sequence (e.g., SEQ ID NO:1) operably linked to a second nucleic acid sequence encoding an interferon (e.g., SEQ ID NO:2); (b) a third nucleic acid sequence comprising a bovine growth hormone polyA termination sequence operably linked to said second nucleic acid sequence (e.g., SEQ ID NO:3); (c) a fourth nucleic acid sequence comprising a porcine elongation factor 1-alpha (EF1α) promoter (e.g., SEQ ID NO:4); (d) a fifth nucleic acid sequence operably linked to said fourth nucleic acid sequence, said fifth nucleic acid sequence encoding a suppressor of cytokine signaling 1 (SOCS1) protein (e.g., SEQ ID NO:5). Furthermore, there is disclosed a method of producing interferon in an animal (e.g., swine).

Provided is an invention that is based on the novel function of a transcription factor RP58 in cells of the central nervous system. The present invention relates to: a transgenic non-human animal capable of increasing or decreasing the expression of the transcription factor RP58 in cells of the central nervous system of a non-human animal in the nascent stage and/or during and after the developmental stage; and a pharmaceutical composition for use in the treatment or prevention of brain dysfunction, or behavioral disorder, or a disease related thereto, wherein the pharmaceutical composition comprises a transcription factor RP58 protein, or a gene encoding the transcription factor RP58; etc.

Methods and compositions are provided for expanding coronary artery networks in an adult mammal in vivo, by increasing activity or expression of the transcription factor DACH1 in capillary endothelial cells. Compositions and kits for practicing the methods and/or for use with the systems of the disclosure are also provided.

The present invention provides a method of lowering blood pressure in a subject, comprising genetically modifying a myosin phosphatase target subunit (Mypt1) gene in a vascular smooth muscle cell of the subject, whereby the genetic modification of Mypt1 results in a deletion or inactivation of exon 24. The invention further provides vectors, host cells, and compositions useful for carrying out the methods of the invention.

The present invention provides a kidney production method including a step of tissue-specifically removing a metanephric mesenchyme of a metanephros of a non-human animal; a step of transplanting a human kidney precursor cell into the metanephros; and a step of advancing development of the metanephros, which is a step in which the transplanted human kidney precursor cell is differentiated and matured to form a part of the kidney.

Endothelial dysfunction is a hallmark of peripheral arterial disease which is defined as vascular occlusion below the level of the inguinal ligament, and which is one of the most severe complications of diabetes and inflammatory conditions such as sepsis. Evidences accumulated within the past decades, identified Hedgehog (Hh) signaling as a new regulator of micro-vessel integrity. The purpose of the inventors was to investigate whether Hh co-receptors Gas1 and Cdon may be used as therapeutic targets to modulate Dhh signaling in ECs. The inventors demonstrated that both Gas1 and Cdon are expressed in adult ECs and relied on either siRNAs or EC specific conditional KO mice to investigate their role. They found that Gas1 deficiency mainly photocopies Dhh deficiency especially by inducing VCAM-1 and ICAM-1 overexpression while Cdon deficiency has opposite effects by promoting endothelial junction integrity. At a molecular level, Cdon prevents Dhh binding to Ptch1 and thus acts a decoy receptor for Dhh, while Gas1 promotes Dhh binding to Smo and as a result potentiates Dhh effects. Since Cdon is overexpressed in ECs treated by inflammatory cytokines including TNFα and Il1β, the inventors then tested whether Cdon inhibition would promote endothelium integrity in acute inflammatory conditions and found that both fibrinogen and IgG extravasation were decreased in association with an increased Cdh5 expression in the brain cortex of EC specific Cdon KO mice administered locally with Il1β. Altogether these results demonstrate that Cdon is a negative regulator and justify that Cdon blocking molecules may be used to promote endothelium integrity at least in inflammatory conditions.

An object of the present invention is to provide a method of conveniently producing a genetically modified non-human mammal with high efficiency using a CRISPR-Cas9 system and particularly a production method whereby gene knock-in can be achieved with high efficiency regardless of the gene size. The method of producing a genetically modified non-human mammal comprises introducing a Cas9 protein, a crRNA fragment comprising a nucleotide sequence complementary to a target DNA region, and a tracrRNA fragment into a non-human mammalian oocyte to genetically modify the target DNA.

The present invention provides methods and compositions for treating atherosclerosis in a subject comprising the use of therapeutic compounds to reduce Reelin in the circulation of the subject, thereby reducing the adhesion of leukocytes to the vascular wall. The invention also provides methods and compositions for reducing leukocyte adhesion to the vascular wall in a subject.

The present disclosure is directed to a method of treating neurological disorder comprising peripheral administration to a patient in need thereof a DN-TNF polypeptide that inhibits the activity of soluble TNF- but not transmembrane TNF-α.

The present invention provides methods and compositions for treating atherosclerosis in a subject comprising the use of therapeutic compounds to reduce Reelin in the circulation of the subject, thereby reducing the adhesion of leukocytes to the vascular wall. The invention also provides methods and compositions for reducing leukocyte adhesion to the vascular wall in a subject.