Design, synthesis, and evaluation of tetrahydropyrimidinones as an example of a general approach to nonpeptide HIV protease inhibitors

Re-examination of the design of the cyclic urea class of HIV protease (HIVPR) inhibitors suggests a general approach to designing novel nonpeptide cyclic HIVPR inhibitors. This process involves the inversion of the stereochemical centers of the core transition-state isostere of the linear HIVPR inhibitors and cyclization of the resulting core using an appropriate cyclizing reagent. As an example, this process is applied to the diamino alcohol class of HIVPR inhibitors to give tetrahydropyrimidinones. Conformational analysis of the tetrahydropyrimidinones and modeling of its interaction with the active site of HIVPR suggested modifications which led to very potent inhibitors of HIVPR (24 with a Ki = 0.018 nM). The X-ray crystallographic structure of the complex of 24 with HIVPR confirms the analysis and modeling predictions. The example reported in this study and other examples that are cited indicate that this process may be generally applicable to other linear inhibitors.     

Psychophysical Test for the Independence of Perception and Action.

Research has suggested that perception and action are independent (see M. A. Goodale & A. Haffenden, 1998). The authors used the Ebbinghaus illusion to test this hypothesis in 2 experiments. Verbal reports of perceived size were compared with maximum grip aperture during grasping (Experiment 1) and manual reports of perceived size (Experiment 2). A multidimensional signal detection analysis was used to distinguish among the possible interactions between the two processes in each experiment (H. Kadlec & J. T. Townsend, 1992a, 1992b). In Experiment 1, the percepts were independent, and there were no interactions between processes for verbal and visuomotor responses. In Experiment 2, the percepts associated with verbal and manual reports were independent, but the processes interacted at the levels of the stimulus information and the decision rules used to transform each percept into a response. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Spectrokinetic Analysis of the NOx Storage Over a Pt–Ba/Al2O3 Lean NOx Trap Catalyst

In this work the kinetics of the (reactive) lean accumulation phase of the NO_x storage-reduction process is described through a detailed kinetic model, involving both the gas-phase molecules and the adsorbed species. Kinetic data have been collected following a novel approach based on simultaneous operando spectroscopic measurements and on-line pulse reactor effluent analysis. To our knowledge, this is the first time the temporal evolutions of the concentration of both the surface and the gas species are used jointly to describe the kinetic of a transient catalytic process.     

Adsorption of Cu(II) on Araucaria angustifolia wastes: determination of the optimal conditions by statistic design of experiments

Wastes of Araucaria angustifolia (named pinh?o) natural (PW) and also loaded with Congo red (CRP) were tested as low-cost adsorbents for Cu(II) removal from aqueous solutions. In order to reduce the total number of experiments to achieve the best conditions of the batch adsorption procedure, three sets of statistical designs of experiments were carried-out for each adsorbent. Initially, a full 2(4) factorial design for each adsorbent with two central points (18 experiments) were performed, to optimize the following factors: mass of adsorbent (m), pH, time of contact (t) and initial metallic ion concentration (Co). These results indicated that almost all the main factors and its interactions were significant. It was verified for both adsorbents, that a mass of 30.0mg leaded to higher Cu(II) uptake and that the best pH for Cu(II) adsorption was 5.6. In order to continue the batch adsorption optimization of the systems, a central composite surface analysis design with two factors (Co, t) containing 13 experiments, divided in to four cube points, four axial points and five centre points was carried-out for each adsorbent. By performing these two sets of statistical design of experiments, the best conditions for Cu(II) uptake using pinh?o wastes (PW) and pinh?o wastes loaded with Congo red (CRP) using batch adsorption system, where: m=30.0mg of adsorbent; pH 5.6; t=2.5h. After optimizing the batch adsorption system by statistical design of experiments, isotherms for Cu(II) uptake using PW and CRP were performed. These isotherms fitted to the linear Langmuir and Freundlich models.     

A model-based deconvolution approach to solve fiber crossing in diffusion-weighted MR imaging

A deconvolution approach is presented to solve fiber crossing in diffusion magnetic resonance imaging. In order to provide a direct physical interpretation of the signal generation process, we started from the classical multicompartment model and rewrote this in terms of a convolution process, identifying a significant scalar parameter alpha to characterize the physical system response. Deconvolution is performed by a modified version of the Richardson-Lucy algorithm. Simulations show the ability of this method to correctly separate fiber crossing, even in the presence of noisy data, with lower signal-to-noise ratio, and imprecision in the impulse response function imposed during deconvolution. The in vivo data confirms the efficacy of this method to resolve fiber crossing in real complex brain structures. These results suggest the usefulness of our approach in fiber tracking or connectivity studies.     

Effect of the charge state (z = -1, 0, +1) on the nuclear magnetic resonance of monodisperse Au25[S(CH2)2Ph]18(z) clusters

Monodisperse Au(25)L(18)(0) (L = S(CH(2))(2)Ph) and [n-Oct(4)N(+)][Au(25)L(18)(-)] clusters were synthesized in tetrahydrofuran. An original strategy was then devised to oxidize them: in the presence of bis(pentafluorobenzoyl) peroxide, the neutral or the negatively charged clusters react as efficient electron donors in a dissociative electron-transfer (ET) process, in the former case yielding [Au(25)L(18)(+)][C(6)F(5)CO(2)(-)]. As opposed to other reported redox methods, this dissociative ET approach is irreversible, easily controllable, and clean, particularly for NMR purposes, as no hydrogen atoms are introduced. By using this approach, the -1, 0, and +1 charge states of Au(25)L(18) could be fully characterized by (1)H and (13)C NMR spectroscopy, using one- and two-dimensional techniques, in various solvents, and as a function of temperature. For all charge states, the NMR results and analysis nicely match recent structural findings about the presence of two different ligand populations in the capping monolayer, each resonance of the two ligand families displaying distinct NMR patterns. The radical nature of Au(25)L(18)(0) is particularly evident in the (1)H and (13)C NMR patterns of the inner ligands. The NMR behavior of radical Au(25)L(18)(0) was also simulated by DFT calculations, and the interplay between theory and experiments revealed a fundamental paramagnetic contribution coming from Fermi contact shifts. Interestingly, the NMR patterns of Au(25)L(18)(-) and Au(25)L(18)(+) were found to be quite similar, pointing to the latter cluster form as a diamagnetic species.     

Inertial-magnetic sensors for assessing spatial cognition in infants

This letter describes a novel approach to the assessment of spatial cognition in children. In particular, we present a wireless instrumented toy embedding magneto-inertial sensors for orientation tracking, specifically developed to assess the ability to insert objects into holes. To be used in naturalistic environments (e.g., day cares), we also describe an in-field calibration procedure based on a sequence of manual rotations, not relying on accurate motions or sophisticated equipment. The final accuracy of the proposed system, after the mentioned calibration procedure, is derived by direct comparison with a gold-standard motion tracking device. In particular, both systems are subjected to a sequence of ten single-axis rotations (approximately 90°, back and forth), about three different axes. The rms of the angular error between the two measurements (gold-standard versus proposed systems) was evaluated for each trial. In particular, the average rms error is under 2°. This study indicates that a technological approach to ecological assessment of spatial cognition in infants is indeed feasible. As a consequence, prevention through screening of large number of infants is at reach.