First universal pharmacophore model for hERG1 K+ channel activators: acthER

The intra-cavitary drug blockade of hERG1 channel has been extensively studied, both experimentally and theoretically. Structurally diverse ligands inadvertently block the hERG1 K⁺ channel currents lead to drug induced Long QT Syndrome (LQTS). Accordingly, designing either hERG1 channel openers or current activators, with the potential to target other binding pockets of the channel, has been introduced as a viable approach in modern anti-arrhythmia drug development. However, reports and investigations on the molecular mechanisms underlying activators binding to the hERG1 channel remain sparse and the overall molecular design principles are largely unknown. Most of the hERG1 activators were discovered during mandatory screening for hERG1 blockade. To fill this apparent deficit, the first universal pharmacophore model for hERG1 K⁺ channel activators was developed using PHASE. 3D structures of 18 hERG1 K⁺ channel activators and their corresponding measured binding affinity values were used in the development of pharmacophore models. These compounds spanned a range of structurally different chemotypes with moderate variation in binding affinity. A five sites AAHRR (A, hydrogen-bond accepting, H, hydrophobic, R, aromatic) pharmacophore model has shown reasonable high statistical results compared to the other developed more than 1000 hypotheses. This model was used to construct steric and electrostatic contour maps. The predictive power of the model was tested with 3 external test set compounds as true unknowns. Finally, the pharmacophore model was combined with the previously developed receptor-based model of hERG1 K⁺ channel to develop and screen novel activators. The results are quite striking and it suggests a greater future role for pharmacophore modeling and virtual drug screening simulations in deciphering complex patterns of molecular mechanisms of hERG1 channel openers at the target sites. The developed model is available upon request and it may serve as basis for the synthesis of novel therapeutic hERG1 activators.     

Red emitting MTiO3 (M = Ca or Sr) phosphors doped with Eu3+ or Pr3+ with some cations as co-dopants

Ca (or Sr)TiO₃:Eu³⁺, M (Li⁺ or Na⁺ or K⁺) and CaTiO₃:Pr³⁺, M (Li⁺ or Na⁺ or Ag⁺ or K⁺ or Gd³⁺ or La³⁺) powders were prepared by combustion synthesis method and the samples were further heated to ～1000 °C to improve the crystallinity. The structure and morphology of materials were examined by X-ray diffraction (XRD) and a scanning electron microscopy (SEM). The morphologies of SrTiO₃:Eu³⁺, CaTiO₃:Eu³⁺ or CaTiO₃:Pr³⁺ powders co-doped with other metal ions were very similar. Small and coagulated particles of nearly cubical shapes with small size distribution having smooth and regular surface were formed. Photo-luminescence spectra of CaTiO₃:Pr³⁺ and co-doped either with Li⁺, Na⁺, K⁺, Ag⁺, La³⁺ or Gd³⁺ ions showed red emissions at 613 nm due to the ¹D₂ → ³H₄ transition of Pr³⁺. The variation of intensity of emission peak with different co-doping follows the order: K⁺ > Ag⁺ > Na⁺ > Li⁺ > La³⁺ > Gd³⁺. The characteristic emissions of CaTiO₃:Eu³⁺ lattices had strong emission at 614 and 620 nm for ⁵D₀ → ⁷F₂ with other weak transitions observed at 580, 592, 654, 705 nm for ⁵D₀ → ⁷F_n transitions where n = 0, 1, 3, 4 respectively in all host lattices. Photoluminescence intensity in SrTiO₃:Eu³⁺ is more than CaTiO₃:Eu³⁺ lattices. A remarkable increase of photoluminescence intensity (in ⁵D₀ → ⁷F₂ transition) was observed if co-doped with Li⁺ ions in CaTiO₃:Eu³⁺ and SrTiO3:Eu³⁺.     

CaMoO4:RE3+,Yb3+,M+ phosphor with controlled morphology and color tunable upconversion

CaMoO₄:RE³⁺,Yb³⁺ (RE = Er, Ho, Tm) phosphors were successfully synthesized by a facile hydrothermal method. XRD patterns confirmed tetragonal structure under different RE³⁺ and M⁺ ions doping conditions. Particles shapes and sizes were confirmed by SEM and TEM analyses. Particles shape and size were well tuned by control of solution pH; spherical balls consisting of nano-grains at low pH of ∼2, rice grain shapes at moderate pH of ∼6, and thin flakes at higher pH of ∼12, were observed. Fine tunability of upconversion (UC) emission color was achieved by doping multiple RE³⁺ ions within a single CaMoO₄ host. Blue, green and orange upconverted emission were observed by doping Tm³⁺, Er³⁺ and Ho³⁺ in the CaMoO₄, respectively. Further, the emission colors were well tuned by the combination of Tm, Er and Ho ions and their concentrations. CaMoO₄:Tm³⁺,Ho³⁺,Yb³⁺ exhibited perfect white emission with well tunability from cool white to warm white colors. Substitution of part of Ca ions by M⁺ (M = Li, Na, K, Rb) ions affected the crystal field symmetry around RE³⁺ ions and hence changed the transition probabilities between their f–f transition levels, consequently intensified the UC intensities. The blue (Tm³⁺), green (Er³⁺), and orange (Ho³⁺) upconversion intensities of CaMoO₄:RE³⁺,Yb³⁺,0.10 K⁺ phosphors increased by 60, 50 and 40 folds compared to the unsubstituted analogues, respectively. The K substituted CaMoO₄:RE³⁺,Yb³⁺,K⁺ phosphors exhibited intense UC emissions visible by naked eye even pumped by less than 1 mW laser power and can have potential application in displays and variety of other applications.     

Cationic P⋯N interaction in XH3P+⋯NCY complexes (X = H,F, CN,NH2, OH; Y = H,Li, F,Cl) and its cooperativity with hydrogen/lithium/halogen bond

The geometries, interaction energies and bonding properties of cationic pnicogen bond (CPB) interactions are studied in binary XH₃P⁺⋯NCY (X = H, F, CN, NH₂, OH; Y = H, Li, F, Cl) complexes by means of MP2/aug-cc-pVTZ calculations. Interaction energies of these binary complexes span a large range, from −16.36 kcal/mol in (NH₂)H₃P⁺⋯NCF to −71.36 kcal/mol in FH₃P⁺⋯NCLi complex. The spin–spin coupling constant across P⋯N interaction depends considerably on the nature of X and Y substituents. The characteristic of CPB interactions is analyzed in terms of parameters derived from quantum theory of atoms in molecules (QTAIM) and natural bond orbital (NBO) analyses. The charge transfer from the nitrogen base to the cationic acid stabilizes these pnicogen–bonded complexes. For a given XH₃P⁺, the net charge transfer value increases as the interaction energy of the complex becomes more negative, i.e., NCLi > NCCl > NCH > NCF. Moreover, mutual influence between the CPB and hydrogen/halogen/lithium bond is studied in the ternary XH₃P⁺⋯NCY⋯NCH complexes. The results indicate that the formation of a Y⋯N interaction tends to strengthen CPB in the ternary systems.     

A molecular dynamic study on the dissociation mechanism of SI methane hydrate in inorganic salt aqueous solutions

Gas hydrate is not only a potential energy resource, but also almost the biggest challenge in oil/gas flow assurance. Inorganic salts such as NaCl, KCl and CaCl₂ are widely used as the thermodynamic inhibitor to reduce the risk caused by hydrate formation. However, the inhibition mechanism is still unclear. Therefore, molecular dynamic (MD) simulation was performed to study the dissociation of structure I (SI) methane hydrate in existence of inorganic salt aqueous solution on a micro-scale. The simulation results showed that, the dissociation became stagnant due to the presence of liquid film formed by the decomposed water molecules, and more inorganic ions could shorten the stagnation-time. The diffusion coefficients of ions and water molecules were the largest in KCl system. The structures of ion/H₂O and H₂O/H₂O were the most compact in hydrate/NaCl system. The ionic ability to decompose hydrate cells followed the sequence of: Ca²⁺ > 2K⁺ > 2Cl⁻ > 2Na⁺.     

Evolution of structure,stability, and nonlinear optical properties of the heterodinuclear CNLin (n = 1–10) clusters

The lowest-energy structures and stabilities of the heterodinuclear clusters, CNLi_n (n = 1–10) and relevant CNLi_n⁺ (n = 1–10) cations, are studied using the density functional theory with the 6-311 + G(3df) basis set. The CNLi₆ and CNLi₅⁺ clusters are the first three-dimensional ones in the CNLi_n^0/+ series, respectively, and the CN group always caps the Li_n^0/+ moiety in the CNLi_n^0/+ (n = 1–9) configurations. The CN triple bond is found to be completely cleaved in the CNLi₁₀^0/+ clusters where the C and N atoms are bridged by two Li atoms. The CNLi_n (n = 2–10) clusters are hyperlithiated molecules with delocalized valence electrons and consequently possess low VIP values of 3.780–5.674 eV. Especially, the CNLi₈ and CNLi₁₀ molecules exhibit lower VIPs than that of Cs atom and can be regarded as heterobinuclear superalkali species. Furthermore, these two superalkali clusters show extraordinarily large first hyperpolarizabilities of 19,423 and 42,658 au, respectively. For the CNLi_n⁺ cationic species, the evolution of the energetic and electronic properties with the cluster size shows a special stability for CNLi₂⁺.     

Mechanistic and kinetic study on the reaction of methylperoxy radical with atomic iodine

Singlet and triplet potential energy surfaces for the CH₃O₂ with I reaction have been investigated computationally to propose the reaction mechanisms and possible products. Multichannel RRKM theory and transition-state theory have been used to compute the overall and individual rate constants at 200–3000 K and 10⁻¹⁴–10¹⁴ Torr. On the singlet PES, addition-elimination, substitution and H-abstraction mechanisms are located, and the addition-elimination mechanism is dominant. At 70 Torr with N₂ as bath gas, IM1(CH₃OOI) formed by collisional stabilization is dominated at 200–300 K, whereas CH₂O and HIO are the major products at the temperatures between 350 and 3000 K; The title reaction exhibits the typical falloff behavior. The results show that temperature and pressure affect the yield of products.Furthermore, the predicted rate constants at 298 K 70 Torr of N₂ agree well with the available experimental values. On the triplet PES, the most favorable product should be CH₃I + O₂(³Σ) at atmospheric condition. Other two pathways on the triplet PES will not compete with the pathways on the singlet PES in kinetically and thermodynamically.     

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.     

Prediction of cutting temperature in orthogonal machining of AISI 316L using artificial neural network

In this study, an approach based on artificial neural network (ANN) was proposed to predict the experimental cutting temperatures generated in orthogonal turning of AISI 316L stainless steel. Experimental and numerical analyses of the cutting forces were carried out to numerically obtain the cutting temperature. For this purpose, cutting tests were conducted using coated (TiCN + Al₂O₃ + TiN and Al₂O₃) and uncoated cemented carbide inserts. The Deform-2D programme was used for numerical modelling and the Johnson–Cook (J–C) material model was used. The numerical cutting forces for the coated and uncoated tools were compared with the experimental results. On the other hand, the cutting temperature value for each cutting tool was numerically obtained. The artificial neural network model was used to predict numerical cutting temperatures by means of the numerical cutting forces. The best results in predicting the cutting temperature were obtained using the network architecture with a hidden layer which has seven neurons and LM learning algorithm. Finally, the experimental cutting temperatures were predicted by entering the experimental cutting forces into a formula obtained from the artificial neural networks. Statistical results (R², RMSE, MEP) were quite satisfactory. This demonstrates that the established ANN model is a powerful one for predicting the experimental cutting temperatures.     

Calibration and validation of hyperspectral indices for the estimation of broadleaved forest leaf chlorophyll content,leaf mass per area,leaf area index and leaf canopy biomass

This article aims at finding efficient hyperspectral indices for the estimation of forest sun leaf chlorophyll content (CHL, µg cm_leaf^? 2), sun leaf mass per area (LMA, g_{dry matter} m_leaf^? 2), canopy leaf area index (LAI, m²_leaf m_soil^? 2) and leaf canopy biomass (B_leaf, g_{dry matter} m_soil^? 2). These parameters are useful inputs for forest ecosystem simulations at landscape scale. The method is based on the determination of the best vegetation indices (index form and wavelengths) using the radiative transfer model PROSAIL (formed by the newly-calibrated leaf reflectance model PROSPECT coupled with the multi-layer version of the canopy radiative transfer model SAIL). The results are tested on experimental measurements at both leaf and canopy scales. At the leaf scale, it is possible to estimate CHL with high precision using a two wavelength vegetation index after a simulation based calibration. At the leaf scale, the LMA is more difficult to estimate with indices. At the canopy scale, efficient indices were determined on a generic simulated database to estimate CHL, LMA, LAI and Bleaf in a general way. These indices were then applied to two Hyperion images (50 plots) on the Fontainebleau and Fougères forests and portable spectroradiometer measurements. They showed good results with an RMSE of 8.2 µg cm^? 2 for CHL, 9.1 g m^? 2 for LMA, 1.7 m² m^? 2 for LAI and 50.6 g m^? 2 for Bleaf. However, at the canopy scale, even if the wavelengths of the calibrated indices were accurately determined with the simulated database, the regressions between the indices and the biophysical characteristics still had to be calibrated on measurements. At the canopy scale, the best indices were: for leaf chlorophyll content: ND_chl = (ρ₉₂₅ ? ρ₇₁₀)/(ρ₉₂₅ + ρ₇₁₀), for leaf mass per area: ND_LMA = (ρ₂₂₆₀ ? ρ₁₄₉₀)/(ρ₂₂₆₀ + ρ₁₄₉₀), for leaf area index: D_LAI = ρ₁₇₂₅ ? ρ₉₇₀, and for canopy leaf biomass: ND_Bleaf = (ρ₂₁₆₀ ? ρ₁₅₄₀)/(ρ₂₁₆₀ + ρ₁₅₄₀).     

Some Applications of Magma in Designs and Codes: Oval Designs,Hermitian Unitals and Generalized Reed–Muller Codes

We describe three applications of Magma to problems in the area of designs and the associated codes:  •  Steiner systems, Hadamard designs and symmetric designs arising from an oval in an even-order plane, leading in the classical case to bent functions and difference-set designs;  •  the Hermitian unital as a 2-(q³ +  1, q +  1, 1) design, and the code overF_p where p divides q +  1;  •  a basis of minimum-weight vectors for the code over F_pof the design of points and hyperplanes of the affine geometry AG_d(F_p), where p is a prime.     

Bounds for the Roots of Lacunary Polynomials

A polynomial P(X)  = X^d + a_d − 1X^d − 1 + ⋯ is called lacunary when a_d − 1 =  0. We give bounds for the roots of such polynomials with complex coefficients. These bounds are much smaller than for general polynomials.     

Influence of initial and boundary conditions for ozone modeling in very complex terrains: A case study in the northeastern Iberian Peninsula

Initial (IC) and boundary conditions (BC) are required in order to solve the set of stiff differential equations included in air quality models. In this work, the influences of IC–BC are analyzed in the northeastern Iberian Peninsula (NEIP) by applying MM5–EMICAT2000–CMAQ. A multiscale-nested configuration has been used to generate the IC–BC. The wider domain (D1) covers an area of 1392 × 1104 km² centered in the Iberian Peninsula. Domain 2 (D2) covers an area of 272 × 272 km² in the NEIP (D2) with high spatial and temporal resolution. The information related to BC has been supplied to D2 through one-way nesting. Different scenarios were considered (base case, increments of +50% in ozone (O₃) IC, +50% in O₃ BC, +50% in O₃ precursors IC, +50% in O₃ precursors BC and clean BC). The impacts of the IC on a site decrease with simulation time. Focusing on the conditions within the PBL, a 48-h spin-up time is sufficient to reduce the impact factor of IC to 10% or less for O₃ since the influence of pervasive local emissions. The influences of BC are more important for areas near domain boundaries, especially in areas where the contribution of O₃ precursors is due to a short-medium range transport.     

3D-SDAR modeling of hERG potassium channel affinity: A case study in model design and toxicophore identification

A dataset of 237 human Ether-à-go-go Related Gene (hERG) potassium channel inhibitors (180 of which were used for model building and validation, whereas 57 constituted the “true” external prediction set) collected from 22 literature sources was modeled by 3D-SDAR. To produce reliable and reproducible classification models for hERG blocking, the initial set of 180 chemicals was split into two subsets: a balanced modeling set consisting of 118 compounds and an unbalanced validation set comprised of 62 compounds. A PLS bagging-like algorithm written in Matlab was used to process the data and assign each compound to one of the two (hERG+ or hERG-) activity classes. The best predictive model evaluated on the basis of a fully randomized hold-out test set (comprising 20% of the modeling set) used 4 latent variables and a grid of 6 ppm × 6 ppm × 1 Å in the C-C region, 6 ppm × 30 ppm × 1 Å in the C-N region, and 30 ppm × 30 ppm × 1 Å in the N-N region. An overall accuracy of 0.84 was obtained for both the hold-out test set and the validation set. Further, an external prediction set consisting of 57 drugs and drug derivatives was used to estimate the true predictive power of the reported 3D-SDAR model – a slight reduction of the overall accuracy down to 0.77 was observed. 3D-SDAR map of the most frequently occurring bins and their projection on the standard coordinate space of the chemical structures allowed identification of a three-center toxicophore composed of two aromatic rings and an amino group. A U test along the distance axis of the most frequently occurring 3D-SDAR bins was used to set the distance limits of the toxicophore. This toxicophore was found to be similar to an earlier reported phospholipidosis (PLD) toxicophore.     

Facile synthesis of lanthanide vanadates and their luminescent properties

GdVO₄:Eu³⁺, Bi³⁺ with tetragonal phase has been successfully synthesized by employing efficient irradiations. The assembly of composites with fine grains based on acoustic energy and microwave radiation requires low temperature (90 °C) and short reaction time (60 min). All the compounds exhibited red emissions and they can be sensitized through the doped Bi³⁺ ions. The dependence of pH changes and doping concentration on the fluorescence features has been discussed. The photoluminescence measurements show that the optical properties achieved the best results at pH = 9 for GdVO₄:Eu³⁺(5 mol%), Bi³⁺(1 mol%) or pH = 7 for GdVO₄:Eu³⁺.