Combined use of geophysical methods and remote techniques for characterizing the fracture network of a potential unstable cliff site (the “Roche du Midi”, Vercors massif, France)

International audienceStability assessment of a cliff strongly depends on the fracture pattern and the face topography. Geological observations as well as classical geodetic measurements are difficult to perform on high nearly vertical cliffs like the ones surrounding the town of Grenoble (French Alps). In this study we combine remote and ground imaging techniques for characterizing the geometry and the fracture pattern of potential unstable cliff sites. A Dense Digital Surface Model (DDSM) of the rock face can now be obtained from laser scanning (Lidar) or photogrammetry. These techniques are safer and quicker than direct measurements. They offer the possibility to collect structural data and to sample the shape of the outcrop at a centimetric resolution. We applied these two techniques to a potential unstable site (the “Roche du Midi”, Vercors massif) for determining the main fracture families affecting the rock mass and we obtained results similar to direct measurements performed on the nearby outcrops and on the cliff face itself. The laser scanning data suffers a bias in the illumination of the site. Geophysical experiments were also conducted on the plateau and on the cliff face in order to delineate the fracture pattern inside the rock mass. ERT (Electrical Resistivity Tomography) and GPR (Ground Penetrating Radar) profiles were performed on the plateau and allowed near-vertical open fractures to be located in the vicinity of the surface. Best geophysical results in terms of penetration and resolution were however obtained from GPR profiles conducted directly on the cliff face. Laser scanning data were combined with GPR data in order to take into account the shape of the sampled profiles. The combination of vertical and short horizontal profiles allowed the strike and dip of the discontinuities to be determined. The two main families were imaged, as well as a major continuous inward dipping reflector which was not shown during the initial reconnaissance. Further investigation inside the mass effectively showed the existence of this fracture. These results highlight the power of the GPR technique in characterizing the discontinuity pattern inside rock mass for improving the model in view of hazard assessment

Involvement of the AT(2)-receptor in angiotensin II-induced facilitation of sympathetic neurotransmission

Angiotensin 11 (Ang 11) causes facilitation of sympathetic neurotransmission via prejunctionally-located AT(1)-receptors. The pithed rat is a suitable model to study the interactions between endogenously produced Ang 11 and the sympathetic nervous system at the peripheral level. Previously, we demonstrated that inhibition of the facilitatory actions of Ang 11 is a class effect of all AT(1)-receptor blockers (ARB). However, all ARBs caused less than maximal inhibition after the highest dose, thus causing a U-shaped dose-response curve with respect to sympatho-inhibition. In the present study, we investigated whether the AT(2)-receptor is involved in this 'upturn' of the dose-response relationship. Accordingly, we studied the effect of the ARB, irbesartan (1-60 mg/kg), on the sequelae of electric stimulation of the thoraco-lumbar sympathetic outflow in the presence and absence of the AT(2)-blocker, PD 123319 (0.5 mg/kg + 50 pg/kg/min). Additionally, the effect of the combined (nonselective) AT(1)/AT(2)-receptor antagonist saralasin (0.001, 0.003, 0.01 or 0.03 mg/kg/min), on stimulation-induced responses was studied. In addition, we measured PRA-levels after administration of irbesartan, in this model. The stimulation-induced increase in diastolic blood pressure (DBP) could be dose-dependently reduced by irbesartan. Co-infusion with PD 123319 increased the sympatho-inhibitory potency of irbesartan, possibly through displacement of irbesartan from plasma protein binding sites. The U-shaped dose-response relationship observed with irbesartan, which is illustrative for other ARBs in this model, was not observed when PD 123319 was co-administered with irbesartan, nor with the non-selective AT(1)/AT(2)-blocker, saralasin. PRA-levels increased from 111.0 +/- 17.8 to 198.7 +/- 22.2 ng/ml/hour after administration of irbesartan. PRA-levels did not differ when measured after the three highest doses of irbesartan. Conclusions The present findings indicate a facilitatory role for the AT(2)-receptor, which is unmasked by the highest dose of irbesartan. Different plasma Ang II-levels are unlikely to have caused the less than maximal inhibition after the highest dose of irbesarta

Class III Phosphatidylinositol 4-Kinase Alpha and Beta Are Novel Host Factor Regulators of Hepatitis C Virus Replication▿ †

Host factor pathways are known to be essential for hepatitis C virus (HCV) infection and replication in human liver cells. To search for novel host factor proteins required for HCV replication, we screened a subgenomic genotype 1b replicon cell line (Luc-1b) with a kinome and druggable collection of 20,779 siRNAs. We identified and validated several enzymes required for HCV replication, including class III phosphatidylinositol 4-kinases (PI4KA and PI4KB), carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD), and mevalonate (diphospho) decarboxylase. Knockdown of PI4KA could inhibit the replication and/or HCV RNA levels of the two subgenomic genotype 1b clones (SG-1b and Luc-1b), two subgenomic genotype 1a clones (SG-1a and Luc-1a), JFH-1 genotype 2a infectious virus (JFH1-2a), and the genomic genotype 1a (FL-1a) replicon. In contrast, PI4KB knockdown inhibited replication and/or HCV RNA levels of Luc-1b, SG-1b, and Luc-1a replicons. The small molecule inhibitor, PIK93, was found to block subgenomic genotype 1b (Luc-1b), subgenomic genotype 1a (Luc-1a), and genomic genotype 2a (JFH1-2a) infectious virus replication in the nanomolar range. PIK93 was characterized by using quantitative chemical proteomics and in vitro biochemical assays to demonstrate PIK93 is a bone fide PI4KA and PI4KB inhibitor. Our data demonstrate that genetic or pharmacological modulation of PI4KA and PI4KB inhibits multiple genotypes of HCV and represents a novel druggable class of therapeutic targets for HCV infection

Inhibitors Targeting Riboswitches and Ribozymes

Evidence accumulated over the past few decades has overshadowed the central role traditionally attributed to proteins in biological function and placed instead the RNA at the core of all fundamental biological processes. For instance, small RNA domains, such as riboswitches and ribozymes, have been shown to play important, if not essential, roles in a variety of cell functions, including regulation of gene expression. Currently, a large number of clinically relevant antibiotics target the ribosome, in particular its functional RNA component [1–4]; this indicates that, owing to its structural characteristics and complexity, the RNA is a suitable and efficient target for functional inhibition by small molecules. Similar to the interaction of proteins with small molecular ligands, the complex 3D structure of the RNA offers binding pockets and surfaces that provide hydrogen bonding, base stacking, ion pairing, and hydrophobic interactions for the specific binding of diverse compounds. In light of these premises, it is tempting to venture into novel paths in antibiotic research by exploiting small, functional RNA elements such as riboswitches and ribozymes as alternative targets for the design of novel antimicrobial compounds