Structural basis for selective inhibition of trypanosomatid glyceraldehyde-3-phosphate dehydrogenase: Molecular docking and 3D QSAR studies

The glycolytic enzyme glyceraldehyde-3 -phosphate dehydrogenase (GAPDH) is as an attractive target for the development of novel antitrypanosomatid agents. In the present work, comparative molecular field analysis and comparative molecular similarity index analysis were conducted on a large series of selective inhibitors of trypanosomatid GAPDH. Four statistically significant models were obtained (r(2) > 0.90 and q(2) > 0.70), indicating their predictive ability for untested compounds. The models were then used to predict the potency of an external test set, and the predicted values were in good agreement with the experimental results. Molecular modeling studies provided further insight into the structural basis for selective inhibition of trypanosomatid GAPDH.

Comparative molecular field analysis of a series of inhibitors of HIV-1 protease

Several protease inhibitors have reached the world market in the last fifteen years, dramatically improving the quality of life and life expectancy of millions of HIV-infected patients. In spite of the tremendous research efforts in this area, resistant HIV-1 variants are constantly decreasing the ability of the drugs to efficiently inhibit the enzyme. As a consequence, inhibitors with novel frameworks are necessary to circumvent resistance to chemotherapy. In the present work, we have created 3D QSAR models for a series of 82 HIV-1 protease inhibitors employing the comparative molecular field analysis (CoMFA) method. Significant correlation coefficients were obtained (q(2) = 0.82 and r(2) = 0.97), indicating the internal consistency of the best model, which was then used to evaluate an external test set containing 17 compounds. The predicted values were in good agreement with the experimental results, showing the robustness of the model and its substantial predictive power for untested compounds. The final QSAR model and the information gathered from the CoMFA contour maps should be useful for the design of novel anti-HIV agents with improved potency.

Pharmacophore-based 3D QSAR studies on a series of high affinity 5-HT(1A) receptor ligands

5-HT(1A) receptor antagonists have been employed to treat depression, but the lack of structural information on this receptor hampers the design of specific and selective ligands. In this study, we have performed CoMFA studies on a training set of arylpiperazines (high affinity 5-HT(1A) receptor ligands) and to produce an effective alignment of the data set, a pharmacophore model was produced using Galahad. A statistically significant model was obtained, indicating a good internal consistency and predictive ability for untested compounds. The information gathered from our receptor-independent pharmacophore hypothesis is in good agreement with results from independent studies using different approaches. Therefore, this work provides important insights on the chemical and structural basis involved in the molecular recognition of these compounds. (C) 2010 Elsevier Masson SAS. All rights reserved.

Structural requirement for PPAR gamma binding revealed by a meta analysis of holo-crystal structures

PPAR gamma is a ligand regulated transcriptional factor that modulates the transcription of several genes involved in fat and sugar metabolism. Due to its easy bacterial expression and crystallization, several crystal structures of holo-PPAR gamma have been reported and deposited in the Protein Data Bank. Here, we investigated the three-dimensional electrostatic properties of 55 PPAR gamma ligands and used this information for clustering them through principal component analysis. We found out that, according to their electrostatic potential, these ligands can be separated in three groups, with different binding features. We also observed that non-selective and selective ligands show different 3D electrostatic properties and are separated in different clusters. The relevance of this analysis for the development of new binders is discussed. (C) 2010 Elsevier Masson SAS. All rights reserved.

Two- and three-dimensional shape fabric analysis by the intercept method in grey levels

The count intercept is a robust method for the numerical analysis of fabrics Launeau and Robin (1996). It counts the number of intersections between a set of parallel scan lines and a mineral phase, which must be identified on a digital image. However, the method is only sensitive to boundaries and therefore supposes the user has some knowledge about their significance. The aim of this paper is to show that a proper grey level detection of boundaries along scan lines is sufficient to calculate the two-dimensional anisotropy of grain or crystal distributions without any particular image processing. Populations of grains and crystals usually display elliptical anisotropies in rocks. When confirmed by the intercept analysis, a combination of a minimum of 3 mean length intercept roses, taken on 3 more or less perpendicular sections, allows the calculation of 3-dimensional ellipsoids and the determination of their standard deviation with direction and intensity in 3 dimensions as well. The feasibility of this quick method is attested by numerous examples on theoretical objects deformed by active and passive deformation, on BSE images of synthetic magma flow, on drawing or direct analysis of thin section pictures of sandstones and on digital images of granites directly taken and measured in the field. (C) 2010 Elsevier B.V. All rights reserved.

Deformation and geochronology of syntectonic granitoids emplaced in the Major Gercino Shear Zone, southeastern South America

The Major Gercino Shear Zone is one of the NE-SW lineaments that separate the Neoproterozoic Dom Feliciano Belt, of Brazil and Uruguay, into two different domains: a northwestern supracrustal domain from a southeastern granitoid domain. The shear zone, striking NE, is composed of protomylonites to ultramylonites with mainly dextral kinematic indicators. In Santa Catarina State, southern Brazil, the shear zone is composed of two mylonite belts. The mylonites have mineral orientations produced under greenschist fades conditions at a high strain rate. Strong flattening and coaxial deformation indicate the transpressive character, while the role of pure shear is emphasized by the orientation of the mylonite belts in relation to the inferred stress field component. The quartz microstructures point out that different dynamic recrystallization regimes and crystal plasticity were the dominant mechanisms of deformation during the mylonitization process. Additionally, the fabrics suggest that the glide systems are activated for deformation conditions compatible with the metamorphism in the middle greenschist facies. Elongated granitoid intrusions belonging to two petrographically, geochemically and isotopically distinct rock associations occur between the two mylonite belts. The structures observed in the granites result from a deformation range from magmatic to solid-state conditions points to a continuum of magma straining during and just after its crystallization. Conventional U-Pb analysis of multi-crystal zircon fractions yielded essentially identical ages of 609 +/- 16 Ma and 614 +/- 2 Ma for the two granitic associations, and constrain the transpressive phase of the shear zone. K-Ar ages of biotites between 585 and 560 Ma record the slow cooling and uplift of the intrusions. Some K-Ar ages of micas in regional mylonites are similar, suggesting that thermo-tectonic activity was intense up to this time, probably related to the agglutination of the granite belt to the supracrustal belt NW of the MGSZ. (C) 2009 International Association for Gondwana Research. Published by Elsevier B.V. All rights reserved.

Magnetic fabric and zircon U-Pb geochronology of the Itaoca pluton: Implications for the Brasiliano deformation of the southern Ribeira Belt (SE Brazil)

The Itaoca pluton consists of porphyritic monzogranite that intruded the upper crust into low-grade metasedimentary rocks of the Apiai Dornain (Ribeira Belt). Anisotropy of magnetic susceptibility and zircon U-Pb (Shrimp) geochronology were combined to determine pluton emplacement mechanisms and its chronology relative to the collision structures of the Paranapiacaba (Brasiliano II) orogenic system. Magnetic susceptibility ranges between 4 and 38 x 10(-3) SI, and thermomagnetic measurements indicate multidomain magnetite is the main carrier of anisotropy. The pluton shows an ""onion-skin"" structure roughly elongated to the northeast with its hinge zone including kilometer-wide roof-pendants. Magnetic lineations are variable in orientation in consistency with the dominant oblate symmetry of the magnetic fabric. A distinct NE-trending point-maxima, however, indicates the mean lineation is parallel to the stretching direction of the transpressive deformation that affected the regional host rocks. Prismatic zircon from the monzogranite, both in the core and in the finely-zoned margins, yielded an age of 623 +/- 10 Ma. These results suggest the magmatic fabric recorded the earlier strain increments of the regional shear deformation. It may correspond to the transition from continental arc to collision tectonics of the southern Ribeira Belt. (C) 2008 Elsevier Ltd. All rights reserved.

Structural analysis of the Itapucumi Group in the Vallemi region, northern Paraguay: Evidence of a new Brasiliano/Pan-African mobile belt

The Neoproterozoic (Ediacaran) Itapucumi Group in northern Paraguay is composed of carbonate and siliciclastic rocks, including ooid grainstones, marls, shales and sandstones, containing Cloudina fossils in the eastern region. It is almost undeformed over the Rio Apa Cratonic Block but shows a strong deformational pattern at its western edge. A detailed structural analysis of the Itapucumi Group was conducted in the Vallemi Mine, along with a regional survey in other outcrops downstream in the Paraguay River and in the San Alfredo, Cerro Paiva and Sargent Jose E. Lopez regions. In the main Vallemi quarry, the structural style is characterized by an axial-plane slaty cleavage in open to isoclinal folds, sometimes overturned, associated with N-S trending thrust faults and shear zones of E-vergence and with a low-grade chlorite zone metamorphism. The structural data presented here are compatible with the hypothesis of a newly recognized mobile belt on the western side of the Rio Apa Cratonic Block, with opposite vergence to that of the Paraguay Mobile Belt in Brazil. Both belts are related to the Late Brasiliano/Pan-African tectonic cycle with a Lower Cambrian deformation and metamorphism age. The deformation could be due to the late collision of the Amazonian Craton with the remainder of Western Gondwana or to the western active plate boundary related to the Pampean Belt. The structural and lithologic differences between the western Itapucumi Group in the Vallemi and Paraguay River region and the eastern region, near San Alfredo and Cerro Paiva, suggest that this group could be divided into two lithostratigraphic units, but more stratigraphic and geochronological analyses are required to confirm this possibility. (C) 2010 Elsevier Ltd. All rights reserved.

3D face computational photography using PCA spaces

In this paper, we present a 3D face photography system based on a facial expression training dataset, composed of both facial range images (3D geometry) and facial texture (2D photography). The proposed system allows one to obtain a 3D geometry representation of a given face provided as a 2D photography, which undergoes a series of transformations through the texture and geometry spaces estimated. In the training phase of the system, the facial landmarks are obtained by an active shape model (ASM) extracted from the 2D gray-level photography. Principal components analysis (PCA) is then used to represent the face dataset, thus defining an orthonormal basis of texture and another of geometry. In the reconstruction phase, an input is given by a face image to which the ASM is matched. The extracted facial landmarks and the face image are fed to the PCA basis transform, and a 3D version of the 2D input image is built. Experimental tests using a new dataset of 70 facial expressions belonging to ten subjects as training set show rapid reconstructed 3D faces which maintain spatial coherence similar to the human perception, thus corroborating the efficiency and the applicability of the proposed system.

Digital subtraction radiographic analysis of the combination of bioabsorbable membrane and bovine morphogenetic protein pool in human periodontal infrabony defects

OBJECTIVES: This study assessed the bone density gain and its relationship with the periodontal clinical parameters in a case series of a regenerative therapy procedure. MATERIAL AND METHODS: Using a split-mouth study design, 10 pairs of infrabony defects from 15 patients were treated with a pool of bovine bone morphogenetic proteins associated with collagen membrane (test sites) or collagen membrane only (control sites). The periodontal healing was clinically and radiographically monitored for six months. Standardized pre-surgical and 6-month postoperative radiographs were digitized for digital subtraction analysis, which showed relative bone density gain in both groups of 0.034 ± 0.423 and 0.105 ± 0.423 in the test and control group, respectively (p>0.05). RESULTS: As regards the area size of bone density change, the influence of the therapy was detected in 2.5 mm² in the test group and 2 mm² in the control group (p>0.05). Additionally, no correlation was observed between the favorable clinical results and the bone density gain measured by digital subtraction radiography (p>0.05). CONCLUSIONS: The findings of this study suggest that the clinical benefit of the regenerative therapy observed did not come with significant bone density gains. Long-term evaluation may lead to a different conclusions.

Isolation of Pseudomonas aeruginosa strains from dental office environments and units in Barretos, state of São Paulo, Brazil, and analysis of their susceptibility to antimicrobial drugs

A wide variety of opportunistic pathogens has been detected in the tubing supplying water to odontological equipment, in special in the biofilm lining of these tubes. Among these pathogens, Pseudomonas aeruginosa, one of the leading causes of nosocomial infections, is frequently found in water lines supplying dental units. In the present work, 160 samples of water, and 200 fomite samples from forty dental units were collected in the city of Barretos, State of São Paulo, Brazil and evaluated between January and July, 2005. Seventy-six P. aeruginosa strains, isolated from the dental environment (5 strains) and water system (71 strains), were tested for susceptibility to six antimicrobial drugs most frequently used against P. aeruginosa infections. Susceptibility to ciprofloxacin, followed by meropenem was the predominant profile. The need for effective means of reducing the microbial burden within dental unit water lines is emphasized, and the risk of exposure and cross-infection in dental practice, in special when caused by opportunistic pathogens like P. aeruginosa, are highlighted.

Analysis of TMJ vibration sounds before and after use of two types of occlusal splints

Temporomandibular joint (TMJ) sounds are important and common physical signs of temporomandibular disorders (TMD). The aim of this study was to evaluate the influence of the effect of the use of occlusal bite splints (stabilizing and repositioning) on the sounds produced in the TMJ, by means of the electrovibratography (EVG). Thirty-one patients with TMD from the Dental School of Ribeirão Preto, University of São Paulo, Brazil were selected for this study. Group 1 (n=23) wore stabilizing bite splints and Group 2 (n=8) used anterior repositioning splints. Before and after treatment with occlusal splints both groups were analyzed using the SonoPAK Q/S recording system (BioResearch System, Inc.). The treatments with stabilizing bite splints were satisfactory, since they reduced the total amount of the sound energies (p<0.05), but the use of anterior repositioning splints for no more than 4 weeks produced significantly better results (p<0.01). The total amount of vibration energy involved in the vibrating movements of the TMJ showed significant improvement using anterior repositioning splints.

Adhesion of an endodontic sealer to dentin and gutta-percha: shear and push-out bond strength measurements and SEM analysis

The use of an adequate method for evaluation of the adhesion of root canal filling materials provides more reliable results to allow comparison of the materials and substantiate their clinical choice. The aims of this study were to compare the shear bond strength (SBS) test and push-out test for evaluation of the adhesion of an epoxy-based endodontic sealer (AH Plus) to dentin and gutta-percha, and to assess the failure modes on the debonded surfaces by means of scanning electron microscopy (SEM). Three groups were established (n=7): in group 1, root cylinders obtained from human canines were embedded in acrylic resin and had their canals prepared and filled with sealer; in group 2, longitudinal sections of dentin cylinders were embedded in resin with the canal surface smoothed and turned upwards; in group 3, gutta-percha cylinders were embedded in resin. Polyethylene tubes filled with sealer were positioned on the polished surface of the specimens (groups 2 and 3). The push-out test (group 1) and the SBS test (groups 2 and 3) were performed in an Instron universal testing machine running at crosshead speed of 1 mm/min. Means (±SD) in MPa were: G1 (8.8±1.13), G2 (5.9±1.05) and G3 (3.8±0.55). Statistical analysis by ANOVA and Student's t-test (a=0.05) revealed statistically significant differences (p<0.01) among the groups. SEM analysis showed a predominance of adhesive and mixed failures of AH Plus sealer. The tested surface affected significantly the results with the sealer reaching higher bond strength to dentin than to gutta-percha with the SBS test. The comparison of the employed methodologies showed that the SBS test produced significantly lower bond strength values than the push-out test, was skilful in determining the adhesion of AH Plus sealer to dentin and gutta-percha, and required specimens that could be easily prepared for SEM, presenting as a viable alternative for further experiments.

Morphological analysis of glass, carbon and glass/carbon fiber posts and bonding to self or dual-cured resin luting agents

OBJECTIVE: The aim of this study was to evaluate the morphology of glass (GF), carbon (CF) and glass/carbon (G/CF) fiber posts and their bond strength to self or dual-cured resin luting agents. MATERIAL AND METHODS: Morphological analysis of each post type was conducted under scanning electron microscopy (SEM). Bond strength was evaluated by microtensile test after bisecting the posts and re-bonding the two halves with the luting agents. Data were subjected to two-way ANOVA and Tukey's test (α=0.05). Failure modes were evaluated under optical microscopy and SEM. RESULTS: GF presented wider fibers and higher amount of matrix than CF, and G/CF presented carbon fibers surrounded by glass fibers, and both involved by matrix. For CF and GF, the dual-cured material presented significantly higher (p<0.05) bond strength than the self-cured agent. For the dual agent, CF presented similar bond strength to GF (p>0.05), but higher than that of G/CF (p<0.05). For the self-cured agent, no significant differences (p>0.05) were detected, irrespective of the post type. For GF and G/CF, all failures were considered mixed, while a predominance of adhesive failures was detected for CF. CONCLUSION: The bonding between fiber posts and luting agents was affected by the type of fibers and polymerization mode of the cement. When no surface treatment of the post is performed, the bonding between glass fiber post and dual-cured agent seems to be more reliable.

Influence of cervical preflaring on determinationof apical file size in mandibular molars: SEM analysis

This study investigated the influence of cervical preflaring with different rotary instruments on determination of the initial apical file (IAF) in mesiobuccal roots of mandibular molars. Fifty human mandibular molars whose mesial roots presented two clearly separated apical foramens (mesiobuccal and mesiolingual) were used. After standard access opening and removal of pulp tissue, the working length (WL) was determined at 1 mm short of the root apex. Five groups (n=10) were formed at random, according to the type of instrument used for cervical preflaring. In group 1, the size of the IAF was determined without preflaring of the cervical and middle root canal thirds. In groups 2 to 5, preflaring was performed with Gates-Glidden drills, ProTaper instruments, EndoFlare instruments and LA Axxes burs, respectively. Canals were sized manually with K-files, starting with size 08 K-files, inserted passively up to the WL. File sizes were increased until a binding sensation was felt at the WL and the size of the file was recorded. The instrument corresponding to the IAF was fixed into the canal at the WL with methylcyanoacrylate. The teeth were then sectioned transversally 1 mm short of the apex, with the IAF in position. Cross-sections of the WL region were examined under scanning electron microscopy and the discrepancies between canal diameter and the diameter of IAF were calculated using the tool "rule" (FEG) of the microscope's proprietary software. The measurements (µm) were analyzed statistically by Kruskal-Wallis and Dunn's tests at 5% significance level. There were statistically significant differences among the groups (p<0.05). The non-flared group had the greatest discrepancy (125.30 ± 51.54) and differed significantly from all flared groups (p<0.05). Cervical preflaring with LA Axxess burs produced the least discrepancies (55.10 ± 48.31), followed by EndoFlare instruments (68.20 ± 42.44), Gattes Glidden drills (68.90 ± 42.46) and ProTaper files (77.40 ± 73.19). However, no significant differences (p>0.05) were found among the rotary instruments. In conclusion, cervical preflaring improved IAF fitting to the canals at the WL in mesiobuccal roots of maxillary first molars. The rotary instruments evaluated in this study did not differ from each other regarding the discrepancies produced between the IAF size and canal diameter at the WL.