Designing of potential inhibitors against Staphylococcus aureus sortase A: Combined analogue and structure based approach with in vitro validation

Staphylococcus aureus sortase A is an attractive target of Gram-positive bacteria that plays a crucial role in anchoring of surface proteins to peptidoglycan present in bacterial cell wall. Inhibiting sortase A is an elementary and essential effort in preventing the pathogenesis. In this context, in silico virtual screening of in-house database was performed using ligand based pharmacophore model as a filter. The developed pharmacophore model AAHR 11 consists of two acceptors, one hydrophobic and one ring aromatic feature. Top ranked molecule KKR1 was docked into the active site of the target. After profound analysis, it was analyzed and optimized based on the observations from its binding pose orientation. Upgraded version of KKR1 was KKR2 and has improved docking score, binding interactions and best fit in the binding pocket. KKR1 along with KKR2 were further validated using 100 ns molecular dynamic studies. Both KKR1 and KKR2 contain Indole-thiazolidine moiety and were synthesized. The disk diffusion assay has good initial results (ZI of KKR1, KKR2 were 24, 38 mm at 10 μg/mL and ZI of Ampicillin was 22 at 10 μg/mL) and calculated MICs of the molecules (KKR1 5.56 ± 0.28 μg/mL, KKR2 1.32 ± 0.12 μg/mL, Ampicillin 8 ± 1.1 μg/mL) were in good agreement with standard drug Ampicillin. KKR1 has shown IC₅₀ of 1.23 ± 0.14 μM whereas the optimized lead molecule KKR2 show IC₅₀ of 0.008 ± 0.07 μM. Results from in silico were validated by in vitro studies and proved that indole-thiazolidine molecules would be useful for future development as lead molecules against S. aureus sortase A.     

A variational multiscale method for incompressible turbulent flows: Bubble functions and fine scale fields

This paper presents a residual-based turbulence model for the incompressible Navier–Stokes equations. The method is derived employing the variational multiscale (VMS) framework. A multiscale decomposition of the continuous solution and a priori unique decomposition of the admissible spaces of functions lead to two coupled nonlinear problems termed as the coarse-scale and the fine-scale sub-problems. The fine-scale velocity field is assumed to be nonlinear and time-dependent and is modeled via the bubble functions approach applied directly to the fine-scale sub-problem. A significant contribution in this paper is a systematic and consistent derivation of the fine-scale variational operator, commonly termed as the stabilization tensor that possesses the right order in the advective and diffusive limits, and variationally projects the fine-scale solution onto the coarse-scale space. A direct treatment of the fine-scale problem via bubble functions offers several fine-scale approximation options with varying degrees of mathematical sophistication that are investigated via benchmark problems. Numerical accuracy of the proposed method is shown on a forced-isotropic turbulence problem, statistically stationary turbulent channel flow problems at Re_T = 395 and 590, and non-equilibrium turbulent flow around a cylinder at Re = 3,900.     

Regional aboveground forest biomass using airborne and spaceborne LiDAR in Québec

Aboveground dry biomass was estimated for the 1.3 M km² forested area south of the treeline in the eastern Canadian province of Québec by combining data from an airborne and spaceborne LiDAR, a Landsat ETM+ land cover map, a Shuttle Radar Topographic Mission (SRTM) digital elevation model, ground inventory plots, and vegetation zone maps. Plot-level biomass was calculated using allometric relationships between tree attributes and biomass. A small footprint portable laser profiler then flew over these inventory plots to develop a generic airborne LiDAR-based biomass equation (R² = 0.65, n = 207). The same airborne LiDAR system flew along four portions of orbits of the ICESat Geoscience Laser Altimeter System (GLAS). A square-root transformed equation was developed to predict airborne profiling LiDAR estimates of aboveground dry biomass from GLAS waveform parameters combined with an SRTM slope index (R² = 0.59, n = 1325).Using the 104,044 quality-filtered GLAS pulses obtained during autumn 2003 from 97 orbits over the study area, we then predicted aboveground dry biomass for the main vegetation areas of Québec as well as for the entire Province south of the treeline. Including cover type covariances both within and between GLAS orbits increased standard errors of the estimates by two to five times at the vegetation zone level and as much as threefold at the provincial level. Aboveground biomass for the whole study area averaged 39.0 ± 2.2 (standard error) Mg ha^? 1 and totalled 4.9 ± 0.3 Pg. Biomass distributions were 12.6% northern hardwoods, 12.6% northern mixedwood, 38.4% commercial boreal, 13% non-commercial boreal, 14.2% taiga, and 9.2% treed tundra. Non-commercial forests represented 36% of the estimated aboveground biomass, thus highlighting the importance of remote northern forests to C sequestration. This study has shown that space-based forest inventories of northern forests could be an efficient way of estimating the amount, distribution, and uncertainty of aboveground biomass and carbon stocks at large spatial scales.     

Composing Power Series Over a Finite Ring in Essentially Linear Time

Fix a finite commutative ringR. Letuandvbe power series overR, withv(0) = 0. This paper presents an algorithm that computes the firstnterms of the compositionu(v), given the firstnterms ofuandv, inn^1 + o(1)ring operations. The algorithm is very fast in practice whenRhas small characteristic.     

Small molecules with pyridine backbone modified with carbazole,fluorine and bromine for white light-emitting diode applications

Seven compounds with pyridine as the backbone modified by carbazole moiety, bromine atom and fluorine atom were synthesized. Compounds 1, 2, 3 with bromo substitution at the 2-position and carbazole modification at the 5-position of pyridine emit not only a sharp blue singlet fluorescence but also a wide banded excimer-based orange emission. The two colors coming from a single molecule can be used to fabricate a simplified white light emitting device. The electroluminescence based on 1 and 2 exhibits white-light emission with CIE coordinates of x = 0.25 and y = 0.30 for 1 and x = 0.33 and y = 0.37 for 2 at high current densities, very close to pure white emission. In addition, the role of bromo-substitution at pyridine is concluded to be essential to generate molecular interaction thus an excimer emission.     

On decidability of monadic logic of order over the naturals extended by monadic predicates

A fundamental result of Büchi states that the set of monadic second-order formulas true in the structure (Nat,  <) is decidable. A natural question is: what monadic predicates (sets) can be added to (Nat,  <) while preserving decidability? Elgot and Rabin found many interesting predicates P for which the monadic theory of 〈Nat, <,  P〉 is decidable. The Elgot and Rabin automata theoretical method has been generalized and sharpened over the years and their results were extended to a variety of unary predicates. We give a sufficient and necessary model-theoretical condition for the decidability of the monadic theory of (Nat, <, P₁, … , P_n).We reformulate this condition in an algebraic framework and show that a sufficient condition proposed previously by O. Carton and W.Thomas is actually necessary. A crucial argument in the proof is that monadic second-order logic has the selection and the uniformization properties over the extensions of (Nat, <) by monadic predicates. We provide a self-contained proof of this result.     

On identifying codes that are robust against edge changes

Assume that G = (V, E) is an undirected graph, and C ⊆ V. For every v ∈ V, denote I_r(G; v) = {u ∈ C: d(u,v) ≤ r}, where d(u,v) denotes the number of edges on any shortest path from u to v in G. If all the sets I_r(G; v) for v ∈ V are pairwise different, and none of them is the empty set, the code C is called r-identifying. The motivation for identifying codes comes, for instance, from finding faulty processors in multiprocessor systems or from location detection in emergency sensor networks. The underlying architecture is modelled by a graph. We study various types of identifying codes that are robust against six natural changes in the graph; known or unknown edge deletions, additions or both. Our focus is on the radius r = 1. We show that in the infinite square grid the optimal density of a 1-identifying code that is robust against one unknown edge deletion is 1/2 and the optimal density of a 1-identifying code that is robust against one unknown edge addition equals 3/4 in the infinite hexagonal mesh. Moreover, although it is shown that all six problems are in general different, we prove that in the binary hypercube there are cases where five of the six problems coincide.     

A study of nonlinear dispersive equations with solitary-wave solutions having compact support

With the use of Adomian decomposition method, the prototypical, genuinely nonlinear K(m,n) equation, u_t+(u^m)_x+(uⁿ)_xxx=0, which exhibits compactons — solitons with finite wavelength — is solved exactly. Two numerical illustrations, K(2,2) and K(3,3), are investigated to illustrate the pertinent features of the proposed scheme. The technique is presented in a general way so that it can be used in nonlinear dispersive equations.     

Consensus scoring model for the molecular docking study of mTOR kinase inhibitor

The discovery of mammalian target of rapamycin (mTOR) kinase inhibitors has always been a research hotspot of antitumor drugs. Consensus scoring used in the docking study of mTOR kinase inhibitors usually improves hit rate of virtual screening. Herein, we attempt to build a series of consensus scoring models based on a set of the common scoring functions. In this paper, twenty-five kinds of mTOR inhibitors (16 clinical candidate compounds and 9 promising preclinical compounds) are carefully collected, and selected for the molecular docking study used by the Glide docking programs within the standard precise (SP) mode. The predicted poses of these ligands are saved, and revaluated by twenty-six available scoring functions, respectively. Subsequently, consensus scoring models are trained based on the obtained rescoring results by the partial least squares (PLS) method, and validated by Leave-one-out (LOO) method. In addition, three kinds of ligand efficiency indices (BEI, SEI, and LLE) instead of pIC₅₀ as the activity could greatly improve the statistical quality of build models. Two best calculated models 10 and 22 using the same BEI indice have following statistical parameters, respectively: for model 10, training set R² = 0.767, Q² = 0.647, RMSE = 0.024, and for test set R² = 0.932, RMSE = 0.026; for model 22, raining set R² = 0.790, Q² = 0.627, RMSE = 0.023, and for test set R² = 0.955, RMSE = 0.020. These two consensus scoring model would be used for the docking virtual screening of novel mTOR inhibitors.     

A DFT study on the physical adsorption of cyclophosphamide derivatives on the surface of fullerene C60 nanocage

The physical sorption of a series of cyclophosphamide drug derivatives with formula

where x = 2, X = F (2), Cl (3), Br (4); x = 3, X = F (5), Cl (6), Br (7) and x = 4, X = F (8), Cl (9), Br (10) on the surface of fullerene C₆₀ was studied using density functional theory (DFT) at B3LYP and B3PW91 levels. The most negative binding energies obtained using the B3LYP approach and corrected for geometrical BSSE and dispersion energies (gCP-D3-ΔE_binding) were measured for compounds 8 (among isolated drugs) and 13 (among complexes). The dipole moments of isolated drugs were obtained close to those of their complexes with C₆₀ (∼4.0–5.5 Debye) indicating their hydrophililic nature that is an appropriate property appealing for drug delivery in biological media. The adsorption of all drugs on the surface of fullerene was endergonic with all of the ΔG_adsorption > 0. The ΔH_adsorption values at B3PW91 level were only negative for complexes 14–16 indicating their exothermic adsorption nature. The HOMO–LUMO band gaps of complexes 11–19 were about 2.7 eV and are comparable with the gap in C₆₀ but are much smaller than the gaps in isolated drugs 2–10 (6.5–8.0 eV) reflecting the increase in electrical conductivities upon complexation. The QTAIM data supported the covalent character of the C–O, C–N and N–H bonds, the intermediate character of PO, P–O and P–N bonds while the electrostatic nature of PO…C(fullerene) interactions. According to the gCP-D3-ΔE_binding binding energies and ΔH_adsorption values at B3LYP level, it seems that the complexes 12 and 13 can be the most promising prodrug + carrier delivery systems.

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A lidar-based hierarchical approach for assessing MODIS fPAR

The purpose of this study was to estimate the fraction of photosynthetically active radiation absorbed by the canopy (fPAR) from point measurements to airborne lidar for hierarchical scaling up and assessment of the Moderate Resolution Imaging Spectroradiometer (MODIS) fPAR product within a “medium-sized” (7 km × 18 km) watershed. Nine sites across Canada, containing one or more (of 11) distinct species types and age classes at varying stages of regeneration and seasonal phenology were examined using a combination of discrete pulse airborne scanning Light Detection And Ranging (lidar) and coincident analog and digital hemispherical photography (HP). Estimates of fPAR were first compared using three methods: PAR radiation sensors, HP, and airborne lidar. HP provided reasonable estimates of fPAR when compared with radiation sensors. A simplified fractional canopy cover ratio from lidar based on the number of within canopy returns to the total number of returns was then compared with fPAR estimated from HP at 486 geographically registered measurement locations. The return ratio fractional cover method from lidar compared well with HP-derived fPAR (coefficient of determination = 0.72, RMSE = 0.11), despite varying the lidar survey configurations, canopy structural characteristics, seasonal phenologies, and possible slight inaccuracies in location using handheld GPS at some sites. Lidar-derived fractional cover estimates of fPAR were ～ 10% larger than those obtained using HP (after removing wood components), indicating that lidar likely provides a more realistic estimate of fPAR than HP when compared with radiation sensors. Finally, fPAR derived from lidar fractional cover was modelled at 1 m resolution and averaged over 99 1 km areas for comparison with MODIS fPAR. The following study is one of the first to scale between plot measurements and MODIS pixels using airborne lidar.     

A finite element method with discontinuous rotations for the Mindlin–Reissner plate model

We present a continuous-discontinuous finite element method for the Mindlin–Reissner plate model based on continuous polynomials of degree k ? 2 for the transverse displacements and discontinuous polynomials of degree k ? 1 for the rotations. We prove a priori convergence estimates, uniformly in the thickness of the plate, and thus show that locking is avoided. We also derive a posteriori error estimates based on duality, together with corresponding adaptive procedures for controlling linear functionals of the error. Finally, we present some numerical results.     

Extension of a hybrid thermal LBE scheme for large-eddy simulations of turbulent convective flows

Following the work of Lallemand and Luo [Lallemand P, Luo L-S. Theory of the lattice Boltzmann method: acoustic and thermal properties in two and three dimensions. Phys Rev E 2003;68:036706] we validate, apply and extend the hybrid thermal lattice Boltzmann scheme (HTLBE) by a large-eddy approach to simulate turbulent convective flows. For the mass and momentum equations, a multiple-relaxation-time LBE scheme is used while the heat equation is solved numerically by a finite difference scheme. We extend the hybrid model by a Smagorinsky subgrid scale model for both the fluid flow and the heat flux. Validation studies are presented for laminar and turbulent natural convection in a cavity at various Rayleigh numbers up to 5 × 10¹⁰ for Pr = 0.71 using a serial code in 2D and a parallel code in 3D, respectively. Correlations of the Nusselt number are discussed and compared to benchmark data. As an application we simulated forced convection in a building with inner courtyard at Re = 50 000.     

Blue electroluminescent materials based on phenylanthracene-substituted fluorene derivatives for organic light-emitting diodes

Two phenylanthracene-substituted fluorene derivatives, 10-(9,9′-dimethyl-2-(10-phenylanthracen-9-yl)-9H-fluoren-7-yl)-phenylanthracene (1) and 2′,7′-di-(10-phenylanthracen-9-yl)-9,9′-spirobi[9H-fluorene] (2) have been designed, synthesized, and characterized. A device using compound 1 as an emitting material exhibited luminous efficiency, power efficiency, external quantum efficiency and CIE coordinates of 3.37 cd/A, 1.50 lm/W, 1.87% at 20 mA/cm² and (0.18, 0.25) at 7 V, respectively. Furthermore, by exploiting this efficient blue fluorescent material as a blue emitting material with the combination of red phosphorescent bis(2-phenylquinoline)acetylacetonate [(pq)₂Ir(acac)], an efficient white OLED (WOLED) with a external quantum efficiency of 1.70%, luminous efficiency of 1.38 cd/A, power efficiency of 0.94 lm/W at 20 mA/cm² and the color coordinates of (0.33, 0.36) at 14 V is demonstrated.     

Enhancement of an industrial finite-volume code for large-eddy-type simulation of incompressible high Reynolds number flow using near-wall modelling

We present a validation strategy for enhancement of an unstructured industrial finite-volume solver designed for steady RANS problems for large-eddy-type simulation with near-wall modelling of incompressible high Reynolds number flow. Different parts of the projection-based discretisation are investigated to ensure LES capability of the numerical method. Turbulence model parameters are calibrated by using a minimisation of least-squares functionals for first and second order statistics of the basic benchmark problems decaying homogeneous turbulence and turbulent channel flow. Then the method is applied to the flow over a backward facing step at Re_h = 37,500. Of special interest is the role of the spatial and temporal discretisation error for low order schemes. For wall-bounded flows, present results confirm existing best practice guidelines for mesh design. For free-shear layers, a sensor to quantify the resolution quality of the LES based on the resolved turbulent kinetic energy is presented and applied to the flow over a backward facing step at Re_h = 37,500.     

Broadcast in the rendezvous model

In many large, distributed or mobile networks, broadcast algorithms are used to update information stored at the nodes. In this paper, we propose a new model of communication based on rendezvous and analyze a multi-hop distributed algorithm to broadcast a message in a synchronous setting. In the rendezvous model, two neighbors u and v can communicate if and only if u calls v and v calls u simultaneously. Thus nodes u and v obtain a rendezvous at a meeting point. If m is the number of meeting points, the network can be modeled by a graph of n vertices and m edges. At each round, every vertex chooses a random neighbor and there is a rendezvous if an edge has been chosen by its two extremities. Rendezvous enable an exchange of information between the two entities. We get sharp lower and upper bounds on the time complexity in terms of number of rounds to broadcast: we show that, for any graph, the expected number of rounds is between ln n and O (n²). For these two bounds, we prove that there exist some graphs for which the expected number of rounds is either O (ln (n)) or Ω (n²). For specific topologies, additional bounds are given.     

Interpretation and topographic compensation of conifer canopy self-shadowing

The self-shadowing of conifer canopies results from the size and arrangement of trees within a stand and is a first-order term controlling radiance from forested terrain at common pixel scales of tens of meters. Although self-shadowing is a useful attribute for forest remote-sensing classification, compensation for the topographic effects of self-shadowing has proven problematic. This study used airborne canopy LiDAR measurements of 80 Pacific Northwest, USA conifer stands ranging in development stage from pre-canopy closure to old-growth in order to model canopy self-shadowing for four solar zenith angles (SZA). The shadow data were compared to physical measurements used to characterize forest stands, and were also used to test and improve terrain compensation models for remotely sensed images of forested terrain. Canopy self-shadowing on flat terrain strongly correlates with the canopy's geometric complexity as measured by the rumple index (canopy surface area/ground surface area) (R² = 0.94–0.87 depending on SZA), but is less correlated with other stand measurements: 95th percentile canopy height (R² = 0.68), mean diameter at breast height (dbh) (R² = 0.65), basal area ha^? 1 (R² = 0.18), and canopy stem count ha^? 1 (R² = 0.18). The results in this paper support interpretation of self-shadowing as a function of canopy complexity, which is an important ecological characteristic in its own right. Modeling of canopy self-shadowing was used to assess the accuracy of the Sun-Canopy-Sensor (SCS) topographic correction, and to develop a new empirical Adaptive Shade Compensation (ASC) topographic compensation model. ASC used measured shadow (as an estimate of canopy complexity) and the SCS term (to describe the illumination geometry) as independent variables in multiple regressions to determine the topographic correction. The ASC model provided more accurate radiance corrections with limited variation in results across the full range of canopy complexities and incidence angles.     

Computing Modular Invariants of p-groups

Let V be a finite dimensional representation of a p -group, G, over a field,k , of characteristic p. We show that there exists a choice of basis and monomial order for which the ring of invariants, k [ V ]^G, has a finite SAGBI basis. We describe two algorithms for constructing a generating set for k [ V ] G. We use these methods to analyse k [2V₃ ]^U₃where U₃is the p -Sylow subgroup ofGL₃ (F_p) and 2 V₃is the sum of two copies of the canonical representation. We give a generating set for k [2 V₃]^U₃forp =  3 and prove that the invariants fail to be Cohen–Macaulay forp >  2. We also give a minimal generating set for k [mV₂ ]^Z / pwere V₂is the two-dimensional indecomposable representation of the cyclic group Z / p.     

Tautomeric transformation of temozolomide,their proton affinities and chemical reactivities: A theoretical approach

The gas-phase geometry optimizations of bare, mono- and dihydrated complexes of temozolomide isomers were carried out using density functional calculation at the M06 − 2X/6 − 31 + G(d,p) level of the theory. The structures and protonation energies of protonated species of temozolomide are reported. Chemical indices of all isomers and protonated species are also reported. Energies, thermodynamic quantities, rate constants and equilibrium constants of tautomeric and rotameric transformations of all isomers I1 ↔ TZM ↔ HIa ↔ HIb ↔ I2 ↔ I3 in bare and hydrated systems were obtained.     

Modal analysis and modified cascade neural networks in identification of geometrical parameters of circular arches

A hybrid computational system, composed of the finite element method (FEM) and cascade neural network system (CNNs), is applied to the identification of three geometrical parameters of elastic arches, i.e. span l, height f and cross-sectional thickness h. FEM is used in the direct (forward) analysis, which corresponds to the mapping α = {l, f, h} → {ω_j}, where: α – vector of control parameters, ω_j – arch eigenfrequencies. The reverse analysis is related to the identification procedure in which the reverse mapping is performed {ω_j} → {α_i}. For the identification purposes a recurrent, three level CNNs of structure (D^k-H^k-1)_s was formulated, where: k – recurrence step, s = I, II, III-levels of cascade system. The Semi-Bayesian approach is introduced for the design of CNNs applying the MML Maximum Marginal Likelihood) criterion. The computation of hyperparameters is performed by means of the Bayesian procedure evidence. The numerical analysis proves a great numerical efficiency of the proposed hybrid approach for both the perfect (noiseless) values of eigenfrequencies and noisy ones simulated by an added artificial noise.