Singularities in the determination of the situation of a robot effector from the perspective view of 3 points

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Mechanical Mixtures of Me (Ni, Pd) Ce Oxides and Silica-Supported Heteropolyacids: Role and Optimal Concentration of Each Active Species in n-Hexane Isomerization

Catalytic properties of silica-supported heteropolyacids (HPA) in a mechanical mixture with reduced Me–Ce oxides (Me = Ni, Pd) in n-hexane isomerization are studied. The role of each component of the mixed oxides (Ce and, typically, Ni and Pd) and their optimum content has been illuminated: cerium is not only beneficial for eliminating or preventing coke deposition but is also effective for maintaining the Keggin structure of the highly-organized HPA during the reaction and probably allows a better dispersion of the second metal species. Nickel and palladium, present as Ni0 and Pd0, reinforce the activation of the alkane, which is difficult to obtain by means of a direct attack by an acid, and, thus, enhance noticeably the activity of the catalyst. The best mechanical mixtures are obtained with 30–70 wt % NiCeO–HPW/SiO2 and 50–50 wt %Pd0.1CeO–PW/SiO2. These mixtures have the highest efficiency for a Ni/(Ni + W) atomic ratio of 0.66 and a Pd/(Pd + W) ratio of 0.40, respectively. Finally, the conversion of n-hexane is in the order HPW > HSiW >HBW, which seems to be consistent with the order of their acid strength as per the literature, but the isomerization selectivity appears to be slightly higher on HSiW

Prediction of the Water Content in Protein Binding Sites

An efficient molecular simulation methodology has been developed to determine the positioning of water molecules in the binding site of a protein or protein-ligand complex. Occupancies and absolute binding free energies of water molecules are computed using a statistical thermodynamics approach. The methodology, referred to as JAWS, features “θ-water” molecules that can appear and disappear on a binding-site grid. Key approximations render the technique far more efficient than conventional free energy simulations. Testing of JAWS on five diverse examples (neuraminidase, scytalone dehydratase, major urinary protein 1, β-lactoglobulin, and COX-2) demonstrates its accuracy in locating hydration sites in comparison to results from high-resolution crystal structures. Possible applications include aid in refinement of protein crystal structures, drug lead optimization, setup of docking calculations and simulations of protein-ligand complexes

Dose to organ at risk and dose prescription in liver SBRT

Stereotactic body radiation therapy (SBRT) is delivered in a curative intent to many primary and secondary tumors.Concerning liver metastasis, SBRT can be safely delivered using one to five fractions. An excellent local control is obtained with doses from 20 to 60[[ce:hsp sp="0.25"/]]Gy. For primary hepatic tumors, results are also good, but the risk of hepatic toxicity related to liver pre-existent pathology must be taken into account. Radiation induced liver disease (RILD) is not frequent in its classical presentation, but modifications of liver enzymes are often observed. Other toxicities of SBRT on the duodenum, small bowel and biliary tract are also described. With respect to contraindications and dose limitations on surrounding structures, SBRT is well tolerated and takes place among curative treatment of liver tumors, as surgery, radiofrequency and embolization

The field high-amplitude SX Phe variable BL Cam: results from a multisite photometric campaign. II. Evidence of a binary - possibly triple - system

Short-period high-amplitude pulsating stars of Population I ($\delta$ Sct stars) and II (SX Phe variables) exist in the lower part of the classical (Cepheid) instability strip. Most of them have very simple pulsational behaviours, only one or two radial modes being excited. Nevertheless, BL Cam is a unique object among them, being an extreme metal-deficient field high-amplitude SX Phe variable with a large number of frequencies. Based on a frequency analysis, a pulsational interpretation was previously given. aims heading (mandatory) We attempt to interpret the long-term behaviour of the residuals that were not taken into account in the previous Observed-Calculated (O-C) short-term analyses. methods heading (mandatory) An investigation of the O-C times has been carried out, using a data set based on the previous published times of light maxima, largely enriched by those obtained during an intensive multisite photometric campaign of BL Cam lasting several months. results heading (mandatory) In addition to a positive (161 $\pm$ 3) x 10$^{-9}$ yr$^{-1}$ secular relative increase in the main pulsation period of BL Cam, we detected in the O-C data short- (144.2 d) and long-term ($\sim$ 3400 d) variations, both incompatible with a scenario of stellar evolution. conclusions heading (mandatory) Interpreted as a light travel-time effect, the short-term O-C variation is indicative of a massive stellar component (0.46 to 1 M_{\sun}) with a short period orbit (144.2 d), within a distance of 0.7 AU from the primary. More observations are needed to confirm the long-term O-C variations: if they were also to be caused by a light travel-time effect, they could be interpreted in terms of a third component, in this case probably a brown dwarf star ($\geq$ 0.03 \ M_{\sun}), orbiting in $\sim$ 3400 d at a distance of 4.5 AU from the primary.Comment: 7 pages, 5 figures, accepted for publication in A&

Phase II randomised trial of chemoradiotherapy with FOLFOX4 or cisplatin plus fluorouracil in oesophageal cancer

International audienceBackground: Concurrent chemoradiotherapy is a valuable treatment option for localised oesophageal cancer (EC), but improvement is still needed. A randomised phase II trial was initiated to assess the feasibility and efficacy in terms of the endoscopic complete response rate (ECRR) of radiotherapy with oxaliplatin, leucovorin and fluorouracil (FOLFOX4) or cisplatin/fluorouracil. Methods: Patients with unresectable EC (any T, any N, M0 or M1a), or medically unfit for surgery, were randomly assigned to receive either six cycles (three concomitant and three post-radiotherapy) of FOLFOX4 (arm A) or four cycles (two concomitant and two post-radiotherapy) of cisplatin/fluorouracil (arm B) along with radiotherapy 50 Gy in both arms. Responses were reviewed by independent experts. Results: A total of 97 patients were randomised (arm A/B, 53/44) and 95 were assessable. The majority had squamous cell carcinoma (82%; arm A/B, 42/38). Chemoradiotherapy was completed in 74 and 66%. The ECRR was 45 and 29% in arms A and B, respectively. Median times to progression were 15.2 and 9.2 months and the median overall survival was 22.7 and 15.1 months in arms A and B, respectively. Conclusion: Chemoradiotherapy with FOLFOX4, a well-tolerated and convenient combination with promising efficacy, is now being tested in a phase III trial

Current and emerging opportunities for molecular simulations in structure-based drug design

An overview of the current capabilities and limitations of molecular simulation of biomolecular complexes in the context of computer-aided drug design is provided. Steady improvements in computer hardware coupled with more refined representations of energetics are leading to a new appreciation of the driving forces of molecular recognition. Molecular simulations are poised to more frequently guide the interpretation of biophysical measurements of biomolecular complexes. Ligand design strategies emerge from detailed analyses of computed structural ensembles. The feasibility of routine applications to ligand optimization problems hinges upon successful extensive large scale validation studies and the development of protocols to intelligently automate computations

Complementarity Between a Docking and a High-Throughput Screen in Discovering New Cruzain Inhibitors†

Virtual and high-throughput screens (HTS) should have complementary strengths and weaknesses, but studies that prospectively and comprehensively compare them are rare. We undertook a parallel docking and HTS screen of 197861 compounds against cruzain, a thiol protease target for Chagas disease, looking for reversible, competitive inhibitors. On workup, 99 % of the hits were eliminated as false positives, yielding 146 well-behaved, competitive ligands. These fell into five chemotypes: two were prioritized by scoring among the top 0.1 % of the docking-ranked library, two were prioritized by behavior in the HTS and by clustering, and one chemotype was prioritized by both approaches. Determination of an inhibitor/cruzain crystal structure and comparison of the high-scoring docking hits to experiment illuminated the origins of docking false-negatives and false-positives. Prioritizing molecules that are both predicted by docking and are HTS-active yields well-behaved molecules, relatively unobscured by the false-positives to which both techniques are individually prone

Quantifying Water-Mediated Protein–Ligand Interactions in a Glutamate Receptor: A DFT Study

It is becoming increasingly clear that careful treatment of water molecules in ligand–protein interactions is required in many cases if the correct binding pose is to be identified in molecular docking. Water can form complex bridging networks and can play a critical role in dictating the binding mode of ligands. A particularly striking example of this can be found in the ionotropic glutamate receptors. Despite possessing similar chemical moieties, crystal structures of glutamate and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) in complex with the ligand-binding core of the GluA2 ionotropic glutamate receptor revealed, contrary to all expectation, two distinct modes of binding. The difference appears to be related to the position of water molecules within the binding pocket. However, it is unclear exactly what governs the preference for water molecules to occupy a particular site in any one binding mode. In this work we use density functional theory (DFT) calculations to investigate the interaction energies and polarization effects of the various components of the binding pocket. Our results show (i) the energetics of a key water molecule are more favorable for the site found in the glutamate-bound mode compared to the alternative site observed in the AMPA-bound mode, (ii) polarization effects are important for glutamate but less so for AMPA, (iii) ligand–system interaction energies alone can predict the correct binding mode for glutamate, but for AMPA alternative modes of binding have similar interaction energies, and (iv) the internal energy is a significant factor for AMPA but not for glutamate. We discuss the results within the broader context of rational drug-design