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Drug discovery and development are among the most important translational science activities that contribute to human health and wellbeing. However, the development of a new drug is a very complex, expensive, and long process which typically costs 2.6 billion USD and takes 12 years on average. How to decrease the costs and speed up new drug discovery has become a challenging and urgent question in industry. Artificial intelligence (AI) combined with new experimental technologies is expected to make the hunt for new pharmaceuticals quicker, cheaper, and more effective. We discuss here emerging applications of AI to improve the drug discovery process. AI has enormous potential to revolutionize drug discovery. Computational prediction of atomic and molecular properties is the foundation of most de novo design strategies. Machine learning, a branch of AI, can now predict the physical and chemical properties of small molecules at quantum mechanics-level accuracy with much lower time-cost. AI is also able to search for correlations between molecular representations and biological and toxicological activities. AI-based algorithms are also being developed to efficiently probe the pathways of synthesis of novel drug candidates. In combination with robotic platforms, the chemical space for novel reactions can be explored by learning from automated analysis of reaction feasibility. [ABSTRACT FROM AUTHOR]

Abstract Increasing land developments, unreasonable utilization of land, earthquakes, typhoons, and torrential rain often cause hillside disasters. Soil depth is a crucial parameter influencing the scale of shallow landslides and sustainable land use in hillside areas. This paper presents a statistical model, integrated with environmental factors, for estimating soil depth in a catchment area with complex topography. The study area selected was upstream of the Houlong River in Taiwan. The model was developed using multinomial logistic regression and environmental factors such as hill slope, hill aspect, elevation, topographical curvature, and the normalized difference vegetation index. The results were then compared with those obtained from previous models applying Ordinary Kriging, Regression Kriging, and topographical wetness index methods. A classification error matrix and the Kappa index were then employed to assess the various models. The results showed that, for the data set used for model establishment, the overall accuracy and Kappa index were 76.6% and 0.65, respectively, whereas for the data set used for verification, they were 70.5% and 0.57, respectively. By contrast, the Ordinary Kriging method yielded an overall accuracy and a Kappa index of 45.7% and 0.15, respectively; the Regression Kriging method yielded results of 46.7% and 0.16, respectively; and the topographical wetness index method yielded results of 30.5% and −0.05, respectively. The proposed model was therefore determined to be superior to the others in terms of soil depth estimation accuracy. The proposed model can predict soil depth on a regional scale and serve as a reliable tool that provides reference data for future research on land use and shallow landslides. Graphical abstract Unlabelled Image Highlights • Soil depth was modelled in a regional scale with complex topography. • Predictive performance of four statistical techniques was compared. • Multinomial logistic regression proved in soil depth estimation. • Soil depth conditioned by the topographical and geomorphological characteristics. [ABSTRACT FROM AUTHOR]

Many central biological events rely on protein–ligand interactions. The identification and characterization of protein-binding sites for ligands are crucial for the understanding of functions of both endogenous ligands and synthetic drug molecules. G protein-coupled receptors (GPCRs) typically detect extracellular signal molecules on the cell surface and transfer these chemical signals across the membrane, inducing downstream cellular responses via G proteins or β-arrestin. GPCRs mediate many central physiological processes, making them important targets for modern drug discovery. Here, we focus on the most recent breakthroughs in finding new binding sites and binding modes of GPCRs and their potentials for the development of new medicines. Highlights G protein-coupled receptors (GPCRs) mediate numerous physiological activities in the body. Recently resolved crystal structures reveal an increasing number of allosteric ligands. In this review, we systematically cluster the locations of these binding sites from the extracellular, the transmembrane, to the intracellular regions. We also analyze the protein–ligand interactions between these allosteric ligands and their corresponding GPCRs. Whether the intriguing binding modes of these ligands can be rationalized for designing new drug molecules remains an open question. Allosteric sites offer new opportunities to improve ligand selectivity. However, generalizing the application of allosteric binding can be difficult. Certain binding sites, such as that in the intracellular regions, may overlap with the G protein-binding sites. This might reduce ligand specificity and unexpected side effects in clinical applications. Nevertheless, a number of allosteric ligands bind to the receptor–lipid interface. Despite the shallow topology in such region for successful structure-based drug design, these locations appear to have a pivotal role in receptor activation and should not be neglected. More importantly, designing allosteric ligands that target orthosteric and the D2.50×50 allosteric sites simultaneously is a more robust strategy for applying rational drug design. Yet, we expect more allosteric sites to be discovered to open more options for developing new medicines. [ABSTRACT FROM AUTHOR]

Pain is both a major clinical and economic problem, affecting more people than diabetes, heart disease, and cancer combined. While a variety of prescribed or over-the-counter (OTC) medications are available for pain management, opioid medications, especially those acting on the μ-opioid receptor (μOR) and related pathways, have proven to be the most effective, despite some serious side effects including respiration depression, pruritus, dependence, and constipation. It is therefore imperative that both academia and industry develop novel μOR analgesics which retain their opioid analgesic properties but with fewer or no adverse effects. In this review we outline recent progress towards the discovery of safer opioid analgesics. [ABSTRACT FROM AUTHOR]

Web browsers have long been recognized as potential platforms for remote macromolecule visualization. However, the difficulty in transferring large-scale data to clients and the lack of native support for hardware-accelerated applications in the local browser undermine the feasibility of such utilities. With the introduction of WebGL and HTML5 technologies in recent years, it is now possible to exploit the power of a graphics-processing unit (GPU) from a browser without any third-party plugin. Many new tools have been developed for biological molecule visualization and modern drug discovery. In contrast to traditional offline tools, real-time computing, interactive data analysis, and cross-platform analyses feature WebGL- and HTML5-based tools, facilitating biological research in a more efficient and user-friendly way. [ABSTRACT FROM AUTHOR]

Abstract: This paper presents the findings of an experimental study on the turbulent flow field in the vicinity of structures mounted on the bottom of a rectangular open channel. Three model structures used in this study have geometric porosities () of 0%, 34.9% and 47.5%. Detailed measurements of the time-averaged velocity components, turbulent intensity components, turbulent kinetic energy and Reynolds stress were taken by the acoustic Doppler velocimeter (ADV) at different locations around the structures. Measurements obtained with the electro-magnetic micro-velocimeter were used to observe the velocity distributions within the porous structures. As the structure porosity increases, the turbulence intensity, turbulent kinetic energy and Reynolds shear stress over the structure all decrease. Among the structures used in this study, the porous structures show the elongating of the recirculation region in the downstream direction due to bleed flow passing through the gaps of the structures. Significant maximum streamwise turbulent intensity of the porous structure with decreases by about 37% compared to that of the solid structure (). The data presented in this paper would be useful to develop and verify mathematical models for flow both over and within a porous structure. [Copyright &y& Elsevier]

Abstract: This study numerically investigates effects of cutting riparian vegetation on flow characteristics by using a two-dimensional numerical model. The numerical model is based on depth-averaging the time- and volume-averaged Navier–Stokes equation with turbulent effects determined by the standard k–ε turbulence model. Drag forces exerted by the flow on vegetation are considered by adding source terms into momentum equations. In a rectangular channel and compound channel with vegetation along one side, numerical predictions show are in good agreement with those of previous studies. Five cutting scenarios, including the original, cutting along the main channel side, cutting along the bank side, alternative cutting, and reducing vegetative density, are analyzed in this study. The influences of the cutting scenarios on hydrodynamic behaviors are evaluated via numerical simulations. Simulation results suggest that cutting along the main channel side is the most effective scenario for reducing water depth and flow velocities. [Copyright &y& Elsevier]

Abstract: Turbulent flow over a porous medium has been one of the most critical subjects in numerous environmental and engineering studies. The characteristics associated with the hybrid domain, involving both a porous region and a clear fluid region, are not fully understood primarily due to a lack of proper mathematical treatments of different regions and the fluid/porous interface. The objective of this study is to present a numerical implementation for examining such a hybrid domain. The governing equations were solved by a control volume method and the k–ε turbulent model in an attempt to predict the turbulent stresses. The present model treated the hybrid domain problem with a single domain approach by adopting the classical continuity interface conditions. Our numerical results were compared with the experimental data available in the literature for two cases. The effects of the porous medium on the flow properties, including porosity and permeability, were further investigated. Moreover, the calculated flow features were examined for three different Reynolds numbers. Results indicated that the penetration extent of turbulence was Darcy number- and porosity-dependent. [Copyright &y& Elsevier]

Presents a study which investigated the continuous Warren truss resting on equidistant roller supports under static loading. Technique applied to static analysis of bioperiodic structures; Example of a bioperiodic structure; Computation of a Warren truss with six substrates and four supports.

Carbamazepine (CBZ), a Biopharmaceutics Classification System (BCS) class II drug, is widely-used as a first line antiepileptic drug. Numbers of cocrystals have reported to regulate its poor solubility. However, the solubility behaviors are rarely discussed on theoretical calculations and phase solubility diagrams. In this study, two new drug-drug cocrystals (DDC) of CBZ with emodin (EMO , 1: 1) and paeonol (PAE , 1: 1) as conformers, which offer the advantages of synergetic therapy and patient compliance are reported for the first time. The solubilities in water and in pH = 1.2, 6.8 buffer solutions, demonstrating that the rank order is as follows: CBZ-PAE > CBZ > CBZ-EMO. CBZ-PAE presents the biggest solubility at 0.563 ± 0.003 mmoL/L of in water among all the investigated samples. The solubilities of all the starting materials and cocrystals in six pure organic solvents such as methanol, ethanol, 2-propanol, acetone, acetonitrile, ethyl acetate were investigated to discuss the phase solubility diagrams. The results indicate that experimental solubilities are consistent with the theoretical solubilities on consideration of solubility product (K sp) and solution binding constant (K 11) together. The enthalpy differences between cocrystal and its coformer are calculated through the Perdew-Burke-Ernzerhof (PBE) functional with the projector augmented wave (PAW) pseudopotentials. CBZ-EMO presents the lowest enthalpy (−0.38 kcal/mol) with a highly unfavorable solvation energy (2.42 kcal/mol), resulting in unfavorable in an aqueous environment. Overall, the phase solubility diagrams and theoretical calculations support the solubility regulations on DDCs of CBZ. [Display omitted] • Drug-Drug cocrystals of carbamazepine with emodin, paeonol as coformers are firstly reported. • The experimental solubilities of both cocrystals are in good agreement with the theoretical solubilities. • The theoretical calculations based on universal solvation model support the solubility changes. [ABSTRACT FROM AUTHOR]

Presents information on a study which considers static and natural vibration analyses of bi-periodic structures. Uncoupling of governing equation for rotationally bi-periodic structures; Static analysis of continuous beams with two kinds of periodic supports; Conclusions.

Examines the localized modes in periodic systems with nonlinear disorders by use of the Lindstedt-Poincare (l-P) method. Details on the derivation of nonlinear algebraic equations with infinite numbers; Information on the use of the U-tranformation technique for solving equations; Discussion on the existing localized modes.

Studies the purinergic regulation of anion secretion across cystic fibrosis pancreatic ductal epithelium by extracellular adenosine triphosphatase (ATP) with short-circuit current technique. Formation of polarized monolayers; Apical application of ATP in concentration-dependent manner; Effect of different adenosine nucleosides and nucleotides.

Characterizes swelling-induced chloride (Cl(-)) conductance of electrolytes in cultured rat epididymal cells. Use of cell patch-clamp techniques; Anion selectivity sequence of the swelling-induced Cl(-) conductance; Inhibition of the swelling-induced Cl(-) conductance by anion channel blockers; Role of calcium and adenosine 3',5'-cyclic monophosphate.

Studies the regulation of anion secretion across cystic fibrosis pancreatic ductal epithelium by extracellular ATP with the short-circuit current technique. Formation of polarized monolayers with junctional complexes; Cultivation of polarized cultures on permeable supports; Ca2+ dependence of ATP response.

Investigates the penetration and spreading of a round jet into an ambient counterflow using the planar laser-induced fluorescence technique. Concentration field of the penetrating jet effluent; Large-scale wandering of jet penetration; Mean penetration distance predicted by considering the decay of centerline jet velocity.

Shuguang Yuan is no longer associated with Institute of Chemical Science and Engineering (ISIC), Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland. His current affiliations are: Research Center for Computer-Aided Drug Discovery, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China and AlphaMol Science Ltd, CH-4123 Allschwil, Switzerland. The authors also wish to include the following Disclaimer Statement: H.C.S.C., T.D., H.V., and S.Y. are the cofounders of AlphaMol Science Ltd. [Extracted from the article]

The frequency bands of perfect bi-periodic mass–spring systems and the localized modes in the same systems with one disordered subsystem are exactly analyzed using the U-transformation method.The linear bi-periodic system with an infinite number of subsystems may be considered as an equivalent cyclic bi-periodic system having infinite subsystems. The governing equation for such an equivalent system with cyclic bi-periodicity can be uncoupled by applying the U-transformation twice to form a set of single-degree-of-freedom equations. These equations can be used to analyze the pass bands and localized modes corresponding to the considered system with and without disorder, respectively.Some specific systems are taken as examples to demonstrate how to apply the formulas obtained in this paper and to find the localized modes and frequencies. [Copyright &y& Elsevier]

[Display omitted] Herein, we reported a new bergenin: 4-aminobenzamide (BGN-4AM) cocrystal with significantly enhanced solubility and low hygroscopicity probed from two aspects such as phase solubility diagrams and theoretical calculations. Compared with anhydrous BGN , BGN-4AM solubilities in water and different buffer solutions (pH = 1.2, 4.5, 6.8) increase significantly. It is noted that BGN-4AM solubility in pH = 6.8 buffer solution presents 32.7 times higher than anhydrous BGN. Interestingly, BGN-4AM (0.31 ± 0.07%) showcases lower hygroscopicity than anhydrous BGN (9.31 ± 0.16%). The predicted and experimental solubilities agree with each other when considering solubility product (K sp) and solution binding constant (K 11) in phase solubility diagrams, indicating the solution complexes formation occurs. Further crystal surface-water interactions and Bravais, Friedel, Donnay-Harker (BFDH) analyses based on Density Functional Theory with dispersion correction (DFT- d) methods support the enhanced solubility. The water probe demonstrates an average interaction energy of −6.48 kcal/mol on the 002 plane of BGN-4AM , and only −5.47 kcal/mol on the 011 plane of BGN monohydrate. The lower lattice energy of BGN-4AM guarantees its lower hygroscopicity than BGN monohydrate. BGN-4AM with enhanced solubility and low hygroscopicity can be a potential candidate for further formulation development. [ABSTRACT FROM AUTHOR]

Examines the leakage current and reliability of thin oxide nitride film capacitors grown on as-deposited rugged polycrystalline silicon layers. Capacitance improvement of the devices with slight leakage current increase; Measurement of the field acceleration coefficient of the capacitance.

Abstract: This paper presents a boundary treatment method for 2D elliptic mesh generation in complex geometries. Corresponding to Neumann–Dirichlet boundary conditions (sliding boundary conditions), the proposed method aims at achieving orthogonal and smooth nodal distribution along irregular boundaries. In this method, a three-lined auxiliary mesh is constructed which is composed of the boundary line, an auxiliary line generated on its inner side, and the reflection line of this auxiliary line. The movements of the boundary nodes are determined by solving this auxiliary mesh. The boundary nodes are further corrected and adjusted by a second-order parabolic interpolation method and a weighting parameter depending on the curvature of the boundary. The proposed method was demonstrated through examples, and applied to field cases with complex geometries. It has been shown that this method is stable and effective in producing high quality meshes. [Copyright &y& Elsevier]

Two dye-sensitized semiconductor titanium dioxide films containing copper(II) phthalocyaninechloride (CuPcCl14–15) and copper(II) phthalocyaninetetrasulfonic acid (CuPcTs) TiO2 films were prepared. Their bactericidal effects under visible light irradiation were measured. Experimental results indicate that these films inhibit the growth of Escherichia coli under visible light irradiation, and the bactericidal efficiency is related to the coverage of the TiO2 films. A possible mechanism was proposed. [Copyright &y& Elsevier]

The present study investigated bactericidal and photocatalytic activities of transparent anatase TiO2 thin films on soda-lime glass prepared by using reverse micelle and sol–gel methods. Both films exhibited significant bactericidal activity towards three strains of Escherichia coli, namely DH5α, JM109 and XL1 Blue MRF’. The TiO2 films were characterized by X-ray photoelectron spectroscopy (XPS), atomic force microscopy (AFM), X-ray diffraction (XRD), and UV-Vis spectrometry. Results of photocatalytic activity measurements suggest that the TiO2 film prepared by the reverse micelle method is a better photocatalyst than that prepared by sol–gel method in gaseous phase oxidation but their activities in aqueous phase are about the same. [Copyright &y& Elsevier]

Demonstrates oxide-nitride storage dielectrics on smooth and rough polycrystalline silicon layers. Capacitance of the textured devices; Use of higher oxidation rate in the texturing process; Increase of storage capacitance without changing dielectric thickness.

Reports on a surgical audit of appendectomy in Hong Kong, China from March 2000 to June 2000. Level of negative appendicectomy rate in the department; Expectation that the use of unenhanced computerized tomography can not further decrease the negative appendicitis rate.