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.

The present disclosure provides genetically modified plants, plant cells and plant tissues that show reduced lignin content as compared to a control plant which was not genetically modified. In addition, the disclosure provides methods of regulating lignin content in a plant. The disclosure also provides methods of producing bioproducts using the genetically modified plants of the instant disclosure.

Isolation or in vitro assembly of the Cas9-crRNA complex of the Streptococcus thermophilus CRISPR3/Cas system and use for cleavage of DNA bearing a nucleotide sequence complementary to the crRNA and a proto-spacer adjacent motif. Methods for site-specific modification of a target DNA molecule using an RNA-guided DNA endonuclease comprising at least one RNA sequence and at least one of an RuvC active site motif and an HNH active site motif; for conversion of Cas9 polypeptide into a nickase cleaving one strand of double-stranded DNA by inactivating one of the active sites (RuvC or HNH) in the polypeptide by at least one point mutation; for assembly of active polypeptide-polyribonucleotides complex in vivo or in vitro; and for re-programming a Cas9-crRNA complex specificity in vitro or using a cassette containing a single repeat-spacer-repeat unit.

Aspects of the disclosure relate to biosynthesis of histidine in host cells. For example, host cells may comprise: a promoter; a ribosome binding site (RBS); and a nucleic acid comprising: hisG; hisD; hisC hisB; hisH; hisA; hisF; and/or hisI. Host cells may further comprise a nucleic acid encoding a ribose phosphate pyrophosphokinase (RPPK), optionally comprising one or more amino acid substitutions relative to the sequence of wildtype E. coli RPPK. Host cells of the disclosure may comprise a nucleic acid encoding a 5,10-methylene-tetrahydrofolate dehydrogenase/5,10-methylene-tetrahydrofolate cyclohydrolase (MTHFDC) enzyme. Further aspects of the disclosure relate to production of purine pathway metabolites and/or plasmid DNA in host cells.

Provided are methods for editing RNA by introducing a deaminase-recruiting RNA in a host cell for deamination of an adenosine in a target RNA, deaminase-recruiting RNAs used in the RNA editing methods, compositions and kits comprising the same.

In alternative embodiments, provided are products of manufacture and kits, and methods, for treating or ameliorating a Mycobacterium tuberculosis (TB) or a Mycobacterium africanum infection. In alternative embodiments, provided are products of manufacture and kits, and methods, that comprise or comprise use of DNA methylation inhibitory molecules for treating or ameliorating a Mycobacterium tuberculosis (TB) infection. In alternative embodiments, provided are methods and device for classifying drug-resistance phenotype, or diagnosing Multi-drug resistant Tuberculosis (MDR-TB), eXtensively Drug Resistant phenotype (XDR) tuberculosis, or for clinical decision support. In alternative embodiments, provided are kits for or treating or diagnosing drug resistance of, prognosing, or assisting in clinical decision making for a Mycobacterium tuberculosis (TB) or the Mycobacterium africanum infection.

The invention relates to a method of treating a cardiovascular disease, such as heart failure, in a subject in need comprising the step of administering an inhibitor of bZIP repressor or an activator of p38 or a combination thereof to a subject in need thereby treating the cardiovascular disease. The inhibitor to bZIP repressor is: an inhibitor of ATF3; an inhibitor of JDP2; a co-inhibitor to both ATF3 and JDP2; or a combination of an inhibitor of ATF3 and an inhibitor of JDP2.

The present disclosure relates to an inhibitor of Dynamin 2 for use in the treatment of centronuclear myopathies. The present disclosure relates to pharmaceutical compositions containing Dynamin 2 inhibitor and to their use for the treatment of centronuclear myopathies. It also deals with a method for identifying or screening molecules useful in the treatment of a centronuclear myopathy.

The present invention relates to a function of PHF20 (PHD finger protein 20) in a myogenic differentiation mechanism and, more particularly, to a use of a PHF20 gene expression inhibitor or a PHF20 protein activity inhibitor. The PHF20 gene expression inhibitor or the PHF20 protein activity inhibitor according to the present invention promotes muscle differentiation in vitro and in vivo, and thus can be utilized in various ways in the field of prevention, improvement or treatment of diseases caused by muscle loss.

The present disclosure provides methods for genetically modifying lymphocytes and methods for performing adoptive cellular therapy that include transducing T cells and/or NK cells. The methods can include inhibitory RNA molecule(s) and/or engineered signaling polypeptides that can include a lymphoproliferative element, and/or a chimeric antigen receptor (CAR), for example a microenvironment restricted biologic CAR (MRB-CAR). Additional elements of such engineered signaling polypeptides are provided herein, such as those that drive proliferation and regulatory elements therefor, as well as replication incompetent recombinant retroviral particles and packaging cell lines and methods of making the same. Numerous elements and methods for regulating transduced and/or genetically modified T cells and/or NK cells are provided, such as, for example, those including riboswitches, MRB-CARs, recognition domains, and/or pH-modulating agents.