Connective tissue growth factor (CTGF/CCN2) is a cysteine rich, extracellular matrix protein that acts as an anabolic growth factor to regulate osteoblast differentiation and function. In osteoblasts, CTGF is induced by TGF-beta1 where it acts as a downstream mediator of TGF-beta1 induced matrix production. The molecular mechanisms that control CTGF induction by TGF-beta1 in osteoblasts are not known. To assess the role of individual Smads in mediating the induction of CTGF by TGF-beta1, we used specific Smad siRNAs to block Smad expression. These studies demonstrated that Smads 3 and 4, but not Smad 2, are required for TGF-beta1 induced CTGF promoter activity and expression in osteoblasts. Since the activation of MAPKs (Erk, Jnk and p38) by TGF-beta1 is cell type specific, we were interested in determining the role of individual MAPKs in TGF-beta1 induction of CTGF promoter activity and expression. Using dominant negative (DN) mutants for Erk, Jnk and p38, we demonstrated that the expression of DN-Erk caused a significant inhibition of TGF-beta1 induced CTGF promoter activity. In contrast, the expression of DN-p38 or DN-Jnk failed to inhibit activation of CTGF promoter activity. To confirm the vital role of Erk, we used the Erk inhibitor (PD98059) to block its activation, demonstrating that it prevented TGF-beta1 activation of the CTGF promoter and up-regulation of CTGF expression in osteoblasts. Since Src can also act as a downstream signaling effector for TGF-beta in some cell types, we determined its role in TGF-beta1 induction of CTGF in osteoblasts. Treatment of osteoblasts with a Src family kinase inhibitor, PP2, or the expression of two independent kinase-dead Src mutant constructs caused significant inhibition of TGF-beta1 induced CTGF promoter activity and expression. Additionally, blocking Src activation prevented Erk activation by TGF-beta1 demonstrating a role for Src as an upstream mediator of Erk in regulating CTGF expression in osteoblasts. To investigate the involvement of the TGF-beta1 response element (TRE) and the SMAD binding element (SBE) in CTGF induction, we cloned the rat CTGF proximal promoter (-787 to +1) containing the TRE and SBE motifs into a pGL3-Luciferase reporter construct. Using a combination of CTGF promoter deletion constructs and site-directed mutants, we demonstrated the unique requirement of both the TRE and SBE for CTGF induction by TGF-beta1 in osteoblasts. Electro-mobility shift assays using specific probes containing the TRE, SBE or both showed TGF-beta1 inducible complexes that can be ablated by mutation of the respective motif, confirming their requirement for TGF-beta1 induced CTGF promoter activity. In conclusion, these studies demonstrate that CTGF induction by TGF-beta1 in osteoblasts involves Smads 3 and 4, the Erk and Src signaling pathways, and requires both the TRE and SBE motifs in the CTGF proximal promoter.

Hypoxia Inducible Factor-1 (HIF-1) is considered the major coordinator of the cellular adaptive response to hypoxia. Over recent years, its activity in the context of wound healing has been the object of increasing investigation. On the molecular level, HIF-1 transcriptional target products have been shown to regulate the process of endothelial cell survival, migration and proliferation (VEGF, ANGPT-1, ANGPT-2, ANGPT-4, FGF-2, PlGF, PDGF-B, RGC-32), vascular smooth muscle cell migration and proliferation (FGF-2, EGF, PDGF, thrombospondin) and mobilization of Circulating Angiogenic Cells to the periphery (SFD-1/CXCR4). Studies on the effect of HIF-1 on the expression and activity of extracellular cell matrix modifying enzymes, such as MMPs and prolidase, have been conducted in the context of tumor angiogenesis and metastasis, and have resulted in controversial findings. A growing body of evidence suggests that HIF-1 also affects reepithelialization of the wound bed, through increasing keratinocyte migration, but decreasing their proliferation. Diminished HIF-1 levels and activity have been documented in conditions of impaired wound healing, such as wound healing in aged and in diabetic mice. The increasing number of studies on the role of HIF-1 in wound healing, apart from answering certain questions, has also raised an equal number, if not more. Clarifying the topics that still remain unclear could introduce a new era of HIF-1 targeted management of a wide range of problematic wounds.

We present scanning tunneling microscopy and spectroscopy measurements of the charge-density wave state in 1T -TiSe2, Cu0.05TiSe2 and Cu0.06TiSe2 single crystals. Topography images at 4.2 K reveal that the charge density waves are present in all samples studied, although the amplitude of the charge modulation decreases with the Cu-doping. Moreover, the chiral phase of the charge density wave is preserved also in Cu-doped samples. Tunneling spectroscopy shows that there is only a partial gap in the pure compound, with bands crossing the Fermi surface. In the Cu-doped samples the system becomes more metallic due to the increase of the chemical potential.PACS numbers: 71.45. Lr, 74.55.+v, 72.80.Ga, 73.22.Gk INTRODUCTIONTransition metal dichalcogenides are quasi-twodimensional, highly anisotropic compounds that often show instabilities to charge density wave (CDW) formation at low temperature. The chalcogenide atoms form two parallel layers with the atoms in a hexagonal arrangement. The transition metal atoms exist in between these two layers. In the 1T -type crystal structure the transition metal atoms are octahedrally coordinated. In particular, 1T -TiSe 2 undergoes a CDW phase transition below 200 K with a formation of a commensurate (2a 0 × 2a 0 × 2c 0 ) superlattice [1] that involves a small ionic displacement( 0.08Å), and it is accompanied by a phonon softening [2]. ARPES measurements revealed the band structure, with some of the details that still remain controversial. In the normal state, above the CDW state, TiSe 2 is either a semimetal [3,4] or a semiconductor [5,6] with a small indirect gap. The Se 4p valence band is at the Brillouin zone center Γ while the Ti 3d conduction band forms pockets at the Brillouin zone boundary L. In the CDW state the Se 4p bands become backfolded. The origin of the CDW state remains still a matter of controversy up to date. The CDW transition is not likely to originate from nesting since parallel sheets of the Fermi surface were not detected by ARPES measurements. The proposed scenarios are an indirect Jahn-Teller effect [7], an exciton insulator mechanism [8] or an exciton-phonon driven CDW [9]. Being a material with bands very close to the Fermi level, TiSe 2 is a unique candidate for the excitonic mechanism. Unlike many semiconductors, TiSe 2 has a large number of states close to E F that makes it favorable for collective phenomena to take place. On the other hand, the small total number of carriers yields to a poorly screened Coulomb interaction, so the system is unstable to formation of excitons. However, the softening of the L − 1 mode has been observed in x-ray experiments and it might have some relevance to the CDW formation as well [2]. The discovery of superconductivity upon intercalation of Cu has further attracted the attention to this material [10]. With Cu doping it was found that the CDW transition temperature drops and the superconductivity sets in at a doping x = 0.04 with a highest superconducting transition temperature of 4.15 K occurring at x = 0.08. With ...

A variety of improvements in FBP implementation (geometric calibration, truncation and saturation effects, and isotropic apodization) offer the potential for improved image quality and reduced radiation dose on the O-arm system. Further gains are possible with MBIR, including improved soft-tissue visualization, low-dose imaging protocols, and extension to methods that naturally incorporate prior information of patient anatomy and/or surgical instrumentation.

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