(E)-3,5-Dimethyl-1-p-tolyl-4-(p-tolyl­diazen­yl)-1H-pyrazole

There are two independent mol­ecules, A and B, in the asymmetric unit of the title compound, C19H20N4, in each of which the N=N double bond has an E conformation. The dihedral angles between the pyrazole ring and the p-tolyl rings in the 1- and 4-positions are 22.54 (8) and 35.73 (7)°, respectively, in mol­ecule A. The corresponding dihedral angles in mol­ecule B are 28.13 (8) and 22.18 (8)°. In the crystal, the A and B mol­ecules are linked by weak C—H⋯π inter­actions, leading to inversion dimers in each case

New experimental approach to study host tissue response to surgical mesh materials in vivo

Implantation of surgical meshes is a common procedure to increase abdominal wall stability in hernia repair. To improve biocompatibility of the implants, sophisticated in vivo animal models are needed to study inflammation and incorporation of biomaterials. Herein, we have established a new model that allows for the quantitative analysis of host tissue response and vascular ingrowth into surgical mesh materials in vivo. Ultrapro meshes were implanted into dorsal skinfold chambers of Syrian golden hamsters. Angiogenesis, microhemodynamics, microvascular permeability, and leukocyte-endothelial cell interaction of the host tissue were analyzed in response to material implantation over a 2-week period using intravital fluorescence microscopy. Mesh implantation resulted in a short-term activation of leukocytes, reflected by leukocyte accumulation and adherence in postcapillary venules. This cellular inflammatory response was accompanied by an increase of mac-romolecular leakage, indicating loss of integrity of venular endothelial cells. Angiogenesis started at day 3 after implantation by protrusion of capillary sprouts, originating from the host microvasculature. Until day 10, these sprouts interconnected with each other to form a new microvascular network. At day 14, the inflammatory response had disappeared and the vascular ingrowth was completed. Histology confirmed the formation of granulation tissue with adequate incorporation of the mesh filaments within the host tissue. We conclude that this novel model of surgical mesh implantation is a useful experimental approach to analyze host tissue response and vascular ingrowth of newly devised materials for hernia repair

TGF-β coordinately activates TAK1/MEK/AKT/NFkB and SMAD pathways to promote osteoclast survival

To better understand the roles of TGF-β in bone metabolism, we investigated osteoclast survival in response TGF-β and found that TGF-β inhibited apoptosis. We examined the receptors involved in promotion of osteoclast survival and found that the canonical TGF-β receptor complex is involved in the survival response. The upstream MEK kinase TAK1 was rapidly activated following TGF-β treatment. Since osteoclast survival involves MEK, AKT, and NFkappaB activation, we examined TGF-β effects on activation of these pathways and observed rapid phosphorylation of MEK, AKT, IKK, IkappaB, and NFkappaB. The timing of activation coincided with SMAD activation and dominant negative SMAD expression did not inhibit NFkappaB activation, indicating that kinase pathway activation is independent of SMAD signaling. Inhibition of TAK1, MEK, AKT, NIK, IKK, or NFkappaB repressed TGF-β-mediated osteoclast survival. Adenoviral-mediated TAK1 or MEK inhibition eliminated TGF-β-mediated kinase pathway activation and constitutively active AKT expression overcame apoptosis induction following MEK inhibition. TAK1/MEK activation induces pro-survival BclX(L) expression and TAK1/MEK and SMAD pathway activation induces pro-survival Mcl-1 expression. These data show that TGF-β-induced NFkappaB activation is through TAK1/MEK-mediated AKT activation, which is essential for TGF-β to support of osteoclast survival