Molecular quantum similarity in QSAR: applications in computer-aided molecular design

La present tesi està centrada en l'ús de la Teoria de Semblança Quàntica per a calcular descriptors moleculars. Aquests descriptors s'utilitzen com a paràmetres estructurals per a derivar correlacions entre l'estructura i la funció o activitat experimental per a un conjunt de compostos. Els estudis de Relacions Quantitatives Estructura-Activitat són d'especial interès per al disseny racional de molècules assistit per ordinador i, en particular, per al disseny de fàrmacs. Aquesta memòria consta de quatre parts diferenciades. En els dos primers blocs es revisen els fonaments de la teoria de semblança quàntica, així com l'aproximació topològica basada en la teoria de grafs. Ambdues teories es fan servir per a calcular els descriptors moleculars. En el segon bloc, s'ha de remarcar la programació i implementació de programari per a calcular els anomenats índexs topològics de semblança quàntica. La tercera secció detalla les bases de les Relacions Quantitatives Estructura-Activitat i, finalment, el darrer apartat recull els resultats d'aplicació obtinguts per a diferents sistemes biològics.

How well do regional or national Breeding Bird Survey data predict songbird population trends at an intact boreal site?

A study to monitor boreal songbird trends was initiated in 1998 in a relatively undisturbed and remote part of the boreal forest in the Northwest Territories, Canada. Eight years of point count data were collected over the 14 years of the study, 1998-2011. Trends were estimated for 50 bird species using generalized linear mixed-effects models, with random effects to account for temporal (repeat sampling within years) and spatial (stations within stands) autocorrelation and variability associated with multiple observers. We tested whether regional and national Breeding Bird Survey (BBS) trends could, on average, predict trends in our study area. Significant increases in our study area outnumbered decreases by 12 species to 6, an opposite pattern compared to Alberta (6 versus 15, respectively) and Canada (9 versus 20). Twenty-two species with relatively precise trend estimates (precision to detect > 30% decline in 10 years; observed SE ≤ 3.7%/year) showed nonsignificant trends, similar to Alberta (24) and Canada (20). Precision-weighted trends for a sample of 19 species with both reliable trends at our site and small portions of their range covered by BBS in Canada were, on average, more negative for Alberta (1.34% per year lower) and for Canada (1.15% per year lower) relative to Fort Liard, though 95% credible intervals still contained zero. We suggest that part of the differences could be attributable to local resource pulses (insect outbreak). However, we also suggest that the tendency for BBS route coverage to disproportionately sample more southerly, developed areas in the boreal forest could result in BBS trends that are not representative of range-wide trends for species whose range is centred farther north.

PECAM-1 expression and activity negatively regulate multiple platelet signaling pathways

Platelet endothelial cell adhesion molecule-1 (PECAM-1) inhibits platelet response to collagen and may also inhibit two other major platelet agonists ADP and thrombin although this has been less well explored. We hypothesized that the combined effect of inhibiting these three platelet activating pathways may act to significantly inhibit thrombus formation. We demonstrate a negative relationship between PECAM-1 surface expression and platelet response to cross-linked collagen related peptide (CRP-XL) and ADP, and an inhibitory effect of PECAM-1 clustering on platelet response to CRP-XL, ADP and thrombin. This combined inhibition of multiple signaling pathways results in a marked reduction in thrombus formation. (C) 2009 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.

Ordering on multiple lengthscales in a series of side group liquid crystal block copolymers containing a cholesteryl-based mesogen

Hierarchical ordering in a side group liquid crystal block copolymer is investigated by differential scanning calorimetry, polarized optical microscopy, small-angle X-ray and neutron scattering (SAXS and SANS) and transmission electron microscopy (TEM). A series of block copolymers with a range of compositions was prepared by atom transfer radical polymerization, comprising a polystyrene block and a poly(methyl methacrylate) block bearing chiral cholesteryl mesogens. Smectic ordering is observed as well as microphase separation of the block copolymer. Lamellar structures were observed for far larger volume fractions than for coil-coil copolymers (up to a volume fraction of liquid crystal block, f(LC) = 0.8). A sample with f(LC) = 0.86 exhibited a hexagonal-packed cylinder morphology, as confirmed by SAXS and TEM. The matrix comprised the liquid crystal block, with the mesogens forming smectic layers. For the liquid crystal homopolymer and samples with high f(LC), a smectic-smectic phase transition was observed below the clearing point. At low temperature, the smectic phase comprises coexisting domains with monolayer S-A,S-1 coexisting with interdigitated S-A,S-d domains. At high temperature a SA,1 phase is observed. This is the only structure observed for samples with lower f(LC). These unprecedented results point to the influence of block copolymer microphase separation on the smectic ordering.

Multiple morphologies of gold nano-plates by high-temperature polyol syntheses

High-temperature polyol methods were used to fabricate micro- or nano-sized gold plates. 1,2propanediol served as both medium and reducing agent. Triangular plates and polygonal plate shapes derived from triangular prisms as well as pentagonal structured gold particles have been synthesized. Poly(vinylpyrrolidone) (PVP) plays an important role, but is not necessary, for the formation of these structures. These gold plates may have applications in the characterisation of adsorbed proteins or peptides. (C) 2008 Elsevier B. V. All rights reserved.

Full-dimensional quantum calculations of ground-state tunneling splitting of malonaldehyde using an accurate ab initio potential energy surface

Quantum calculations of the ground vibrational state tunneling splitting of H-atom and D-atom transfer in malonaldehyde are performed on a full-dimensional ab initio potential energy surface (PES). The PES is a fit to 11 147 near basis-set-limit frozen-core CCSD(T) electronic energies. This surface properly describes the invariance of the potential with respect to all permutations of identical atoms. The saddle-point barrier for the H-atom transfer on the PES is 4.1 kcal/mol, in excellent agreement with the reported ab initio value. Model one-dimensional and "exact" full-dimensional calculations of the splitting for H- and D-atom transfer are done using this PES. The tunneling splittings in full dimensionality are calculated using the unbiased "fixed-node" diffusion Monte Carlo (DMC) method in Cartesian and saddle-point normal coordinates. The ground-state tunneling splitting is found to be 21.6 cm(-1) in Cartesian coordinates and 22.6 cm(-1) in normal coordinates, with an uncertainty of 2-3 cm(-1). This splitting is also calculated based on a model which makes use of the exact single-well zero-point energy (ZPE) obtained with the MULTIMODE code and DMC ZPE and this calculation gives a tunneling splitting of 21-22 cm(-1). The corresponding computed splittings for the D-atom transfer are 3.0, 3.1, and 2-3 cm(-1). These calculated tunneling splittings agree with each other to within less than the standard uncertainties obtained with the DMC method used, which are between 2 and 3 cm(-1), and agree well with the experimental values of 21.6 and 2.9 cm(-1) for the H and D transfer, respectively. (C) 2008 American Institute of Physics.

Quercetin inhibits collagen-stimulated platelet activation through inhibition of multiple components of the glycoprotein VI signaling pathway

Background: The regulation of platelet function by pharmacological agents that modulate platelet signaling haspharmacolo proven a successful approach to the prevention of thrombosis. A variety of molecules present in the diet have been shown to inhibit platelet activation, including the antioxidant quercetin. Objectives: In this report we investigate the molecular mechanisms through which quercetin inhibits collagen-stimulated platelet aggregation. Methods: The effect of quercetin on platelet aggregation, intracellular calcium release, whole cell tyrosine phosphorylation and intracellular signaling events including tyrosine phosphorylation and kinase activity of proteins involved in the collagen-stimulated glycoprotein (GP) signaling pathway were investigated. Results: We report that quercetin inhibits collagen-stimulated whole cell protein tyrosine phosphorylation and intracellular mobilization of calcium, in a concentration-dependent manner. Quercetin was also found to inhibit various events in signaling generated by the collagen receptor GPVI. This includes collagen-stimulated tyrosine phosphorylation of the Fc receptor gamma-chain, Syk, LAT and phospholipase Cgamma2. Inhibition of phosphorylation of the Fc receptor gamma-chain suggests that quercetin inhibits early signaling events following stimulation of platelets with collagen. The activity of the kinases that phosphorylate the Fc receptor gamma-chain, Fyn and Lyn, as well as the tyrosine kinase Syk and phosphoinositide 3-kinase was also inhibited by quercetin in a concentration-dependent manner, both in whole cells and in isolation. Conclusions: The present results provide a molecular basis for the inhibition by quercetin of collagen-stimulated platelet activation, through inhibition of multiple components of the GPVI signaling pathway, and may begin to explain the proposed health benefits of high quercetin intake.

3D path planning with novel multiple 2D layered approach for complex human-robot interaction

Navigating cluttered indoor environments is a difficult problem in indoor service robotics. The Acroboter concept, a novel approach to indoor locomotion, represents unique opportunity to avoid obstacles in indoor environments by navigating the ceiling plane. This mode of locomotion requires the ability to accurately detect obstacles, and plan 3D trajectories through the environment. This paper presents the development of a resilient object tracking system, as well as a novel approach to generating 3D paths suitable for such robot configurations. Distributed human-machine interfacing allowing simulation previewing of actions is also considered in the developed system architecture.

Multiple-model fault tolerant control of terminal unites of HVAC Systems

In this work, a fault-tolerant control scheme is applied to a air handling unit of a heating, ventilation and air-conditioning system. Using the multiple-model approach it is possible to identify faults and to control the system under faulty and normal conditions in an effective way. Using well known techniques to model and control the process, this work focuses on the importance of the cost function in the fault detection and its influence on the reconfigurable controller. Experimental results show how the control of the terminal unit is affected in the presence a fault, and how the recuperation and reconfiguration of the control action is able to deal with the effects of faults.

Gas-phase kinetics of chlorosilylene reactions II. ClSiH + C2H4: absolute rate measurements and quantum chemical and RRKM calculations for the prototype pi addition reaction

Time-resolved studies of chlorosilylene, ClSiH, generated by the 193 nm laser flash photolysis of 1-chloro-1-silacyclopent-3-ene, are carried out to obtain rate constants for its bimolecular reaction with ethene, C2H4, in the gas-phase. The reaction is studied over the pressure range 0.13-13.3 kPa (with added SF6) at five temperatures in the range 296-562 K. The second order rate constants, obtained by extrapolation to the high pressure limits at each temperature, fitted the Arrhenius equation: log(k(infinity)/cm(3) molecule(-1) s(-1))=(-10.55 +/- 0.10) + (3.86 +/- 0.70) kJ mol(-1)/RT ln10. The Arrhenius parameters correspond to a loose transition state and the rate constant at room temperature is 43% of that for SiH2 + C2H4, showing that the deactivating effect of Cl-for-H substitution in the silylene is not large. Quantum chemical calculations of the potential energy surface for this reaction at the G3MP2//B3LYP level show that, as well as 1-chlorosilirane, ethylchlorosilylene is a viable product. The calculations reveal how the added effect of the Cl atom on the divalent state stabilisation of ClSiH influences the course of this reaction. RRKM calculations of the reaction pressure dependence suggest that ethylchlorosilylene should be the main product. The results are compared and contrasted with those of SiH2 and SiCl2 with C2H4.

Gravity well visibility in haptic interfaces for motion-impaired

Haptic computer interfaces provide users with feedback through the sense of touch, thereby allowing users to feel a graphical user interface. Force feedback gravity wells, i.e. attractive basins that can pull the cursor toward a target, are one type of haptic effect that have been shown to provide improvements in "point and click" tasks. For motion-impaired users, gravity wells could improve times by as much as 50%. It has been reported that the presentation of information to multiple sensory modalities, e.g. haptics and vision, can provide performance benefits. However, previous studies investigating the use of force feedback gravity wells have generally not provided visual representations of the haptic effect. Where force fields extend beyond clickable targets, the addition of visual cues may affect performance. This paper investigates how the performance of motion-impaired computer users is affected by having visual representations of force feedback gravity wells presented on-screen. Results indicate that the visual representation does not affect times and errors in a "point and click" task involving multiple targets.

The effect of multiple haptic distractors on the performance of motion-impaired users

The effect of multiple haptic distractors on target selection performance was examined in terms of times to select the target and the associated cursor movement patterns. Two experiments examined: a) The effect of multiple haptic distractors around a single target and b) the effect of inter-item spacing in a linear selection task. It was found that certain target-distractor arrangements hindered performance and that this could be associated with specific, explanatory cursor patterns. In particular, it was found that the presence of distractors along the task axis in front of the target was detrimental to performance, and that there was evidence to suggest that this could sometimes be associated with consequent cursor oscillation between distractors adjacent to a desired target. A further experiment examined the effect of target-distractor spacing in two orientations on a user’s ability to select a target when caught in the gravity well of a distractor. Times for movements in the vertical direction were found to be faster than those in the horizontal direction. In addition, although times for the vertical direction appeared equivalent across five target-distractor distances, times for the horizontal direction exhibited peaks at certain distances. The implications of these results for the design and implementation of haptically enhanced interfaces using the force feedback mouse are discussed.

Determination of the density of the multiple access interference of a CDMA system from its moments

A standard CDMA system is considered and an extension of Pearson's results is used to determine the density function of the interference. The method is shown to work well in some cases, but not so in others. However this approach can be useful in further determining the probability of error of the system with minimal computational requirements.

Diversity of strains of Salmonella enterica serotype Enteritidis from English poultry farms assessed by multiple genetic fingerprinting

Reliable and sufficiently discriminative methods are needed for differentiating individual strains of Salmonella enterica serotype Enteritidis beyond the phenotypic level; however, a consensus has not been reached as to which molecular method is best suited for this purpose. In addition, data are lacking on the molecular fingerprinting of serotype Enteritidis from poultry environments in the United Kingdom. This study evaluated the combined use of classical methods (phage typing) with three well-established molecular methods (ribotyping, macrorestriction analysis of genomic DNA, and plasmid profiling) in the assessment of diversity within 104 isolates of serotype Enteritidis from eight unaffiliated poultry farms in England. The most sensitive technique for identifying polymorphism was PstI-SphII ribotyping, distinguishing a total of 22 patterns, 10 of which were found among phage type 4 isolates. Pulsed-field gel electrophoresis of XhaI-digested genomic DNA segregated the isolates into only six types with minor differences between them. In addition, 14 plasmid profiles were found among this population. When all of the typing methods were combined, 54 types of strains were differentiated, and most of the poultry farms presented a variety of strains, which suggests that serotype Enteritidis organisms representing different genomic groups are circulating in England. In conclusion, geographical and animal origins of Salmonella serotype Enteritidis isolates may have a considerable influence on selecting the best typing strategy for individual programs, and a single method cannot be relied on for discriminating between strains.

A parallel quantum histogram architecture

A parallel formulation of an algorithm for the histogram computation of n data items using an on-the-fly data decomposition and a novel quantum-like representation (QR) is developed. The QR transformation separates multiple data read operations from multiple bin update operations thereby making it easier to bind data items into their corresponding histogram bins. Under this model the steps required to compute the histogram is n/s + t steps, where s is a speedup factor and t is associated with pipeline latency. Here, we show that an overall speedup factor, s, is available for up to an eightfold acceleration. Our evaluation also shows that each one of these cells requires less area/time complexity compared to similar proposals found in the literature.