Discovery of 5′′‐Chloro‐N‐[(5,6‐dimethoxypyridin‐2‐yl)methyl]‐2,2′:5′,3′′‐terpyridine‐3′‐carboxamide (MK‐1064): A Selective Orexin 2 Receptor Antagonist (2‐SORA) for the Treatment of Insomnia

The field of small‐molecule orexin antagonist research has evolved rapidly in the last 15 years from the discovery of the orexin peptides to clinical proof‐of‐concept for the treatment of insomnia. Clinical programs have focused on the development of antagonists that reversibly block the action of endogenous peptides at both the orexin 1 and orexin 2 receptors (OX₁R and OX₂R), termed dual orexin receptor antagonists (DORAs), affording late‐stage development candidates including Merck’s suvorexant (new drug application filed 2012). Full characterization of the pharmacology associated with antagonism of either OX₁R or OX₂R alone has been hampered by the dearth of suitable subtype‐selective, orally bioavailable ligands. Herein, we report the development of a selective orexin 2 antagonist (2‐SORA) series to afford a potent, orally bioavailable 2‐SORA ligand. Several challenging medicinal chemistry issues were identified and overcome during the development of these 2,5‐disubstituted nicotinamides, including reversible CYP inhibition, physiochemical properties, P‐glycoprotein efflux and bioactivation. This article highlights structural modifications the team utilized to drive compound design, as well as in vivo characterization of our 2‐SORA clinical candidate, 5′′‐chloro‐N‐[(5,6‐dimethoxypyridin‐2‐yl)methyl]‐2,2′:5′,3′′‐terpyridine‐3′‐carboxamide (MK‐1064), in mouse, rat, dog, and rhesus sleep models.     

Facile synthesis of luminescent TiO2 nanorods using an anionic surfactant: Their photosensitization and photocatalytic efficiency

Mixed phase (rutile/anatase) TiO₂ nanorods have been synthesized using an anionic surfactant template. Nanorod synthesis has been achieved using mild reaction conditions and without using any rod-shaped template. The shape and crystallinity of the TiO₂ nanomaterials can be modulated by careful control of the surfactant concentration. The novelty of the present work is that the anatase/rutile mixed phase nanorods were formed without using the well-known layer by layer assembly method or the hydrothermal method. These mixed phase TiO₂ nanorods are highly luminescent, can be easily sensitized by fluorescent dyes, show significant dye adsorption ability and function as efficient photocatalysts.     

Numerical investigation of fatigue characteristics of concrete pavement

In concrete pavements, fatigue is one of the major causes of distress. Repeated loads result in the formation of cracks. The propagation of these cracks cause internal progressive damage within the structure, which ultimately leads to failure of the pavement due to fatigue. This paper presents a theoretical investigation of crack propagation within concrete pavement and its fatigue characteristics under cyclic loading. A numerical fatigue performance model has been developed for this purpose. The model is based on fictitious crack approach for the propagation of cracks and stress degradation approach for estimating the bridging stress under cyclic loading. Using the numerical model, a parametric study has been performed for a typical concrete pavement to evaluate its fatigue characteristics for different foundation strengths. The method can be used for prediction of crack propagation in concrete pavement under cyclic loading and gives an estimate of the incremental damage or the entire crack history of the pavement.     

Degradation studies of transparent conducting oxide: a substrate for microcrystalline silicon thin film solar cells

Aluminium doped ZnO films have been developed by RF-magnetron sputtering at 350 °C substrate temperature on glass substrate and commercially available SnO₂-coated glass substrate. The developed ZnO and SnO₂/ZnO films can be used as the substrates of microcrystalline silicon based solar cell. The electrical, optical properties and surface morphologies of ZnO film and SnO₂/ZnO bi-layer films have been investigated and they are compared with the commercially available SnO_2-coated glass substrate. The resistivities of ZnO and SnO₂ films are comparable (10⁻⁴ Ω-cm). Surface morphologies of different transparent conducting oxide coated substrates before and after H-plasma exposure were studied by scanning electron microscopy. The optical transmission of ZnO, SnO₂/ZnO and SnO₂ films are comparable and varies from 85 to 90% in the visible region. The optical transmission reduces drastically to less than 20% in SnO₂ films and for ZnO film it remains almost unchanged after H-plasma exposure. For SnO₂/ZnO film transmission decreases slightly but remains considerably high (80%). The performance of microcrystalline silicon solar cells fabricated on different transparent conducting oxides as substrates (ZnO/glass, SnO₂/glass and ZnO/SnO₂/glass double layer) is investigated in detail.     

Dry Autoclaving for the Nanofabrication of Sulfides,Selenides, Borides,Phosphides, Nitrides,Carbides, and Oxides

This review compiles various nanostructures fabricated by a distinct “dry autoclaving” approach, where the chemical reactions are carried out without solvents; above the dissociation temperature of the chemical precursor(s) at elevated temperature in a closed reactor. The diversity to fabricate carbides (SiC, Mo₂C, WC), oxides (VOx‐C, ZnO, Eu₂O₃, Fe₃O₄, MoO₂), hexaborides (LaB₆, CeB₆, NdB₆, SmB₆, EuB₆, GdB₆), nitrides (TiN, NbN, TaN), phosphides (PtP₂, WP), sulfides (ZnS, FeS/C, SnS/C, WS₂, WS₂/C), and selenides (Zn_1‐xMn_xSe/C, Cd_1‐xMn_xSe/C), with various shapes and sizes is accounted with plausible applications. This unique single‐step, solvent‐free synthetic process opens up a new route in the growing nanomaterials science; owing to its considerable advantages on the existing approaches.     

Steady boundary layer slip flow and heat transfer over a flat porous plate embedded in a porous media

A mathematical model is presented for analyzing the boundary layer forced convective flow and heat transfer of an incompressible fluid past a porous plate embedded in a Darcy porous medium. Velocity and thermal slips are considered instead of no-slip conditions at the boundary. The similarity solutions for the problem are obtained and the reduced nonlinear ordinary differential equations are solved numerically. In case of porous plate, fluid velocity increases whereas non-dimensional temperature decreases for increasing values of suction parameter but it increases with increasing blowing parameter. Our analysis reveals that the increase of velocity slip parameter reduces the momentum boundary layer thickness and also enhances the heat transfer from the plate. On the other hand, heat transfer decreases with thermal slip parameter.     

Modeling high-viscosity,melt-phase,condensation polymer reactors with a time-scales analysis

Mathematical models for simultaneous reaction and mass transfer occurring in the manufacture of high-viscosity, condensation polymers are considered. The specific example of polycondensation of polyethylene terephthalate is examined. Reactor performance is estimated by using a kinetic expression modified by an effectiveness factor. The effectiveness factor is correlated against a ratio of two characteristic times, one identified as the time scale of mixing and the other identified as the time scale of reaction. The time scale of mixing is estimated from experimental mixing data, thereby avoiding the use of potentially inaccurate mixing assumptions. In place of reaction experiments, overall reaction rates are generated using a more detailed mixing-cell model. The effectiveness factor correlation is compared against previous models. Because the correlation is based on predicted reaction rates rather than experimentally measured reaction rates, the value of the present work lies in the demonstration of the time scales modeling technique. © 1995 John Wiley & Sons, Inc.     

Curing kinetics of medium reactive unsaturated polyester resin used for liquid composite molding process

The cure kinetics of medium reactivity unsaturated polyester resin formulated for Liquid Composite Molding process simulation was studied by Differential Scanning Calorimetry (DSC) under isothermal conditions over a specific range of temperature. For isothermal curing reactions performed at 100, 110, and 120°C, several influencing factors were evaluated using the heat evolution behavior of curing process. We propose two‐ and three‐parameter kinetic models to describe the cure kinetics of thermoset resins. Comparisons of the model solutions with our experimental data showed that the three‐parameter model was the lowest parameter model capable of capturing both the degree of cure and the curing rate qualitatively and quantitatively. The model parameters were evaluated by a non‐linear multiple regression method and the temperature dependence of the kinetic rate constants thus obtained has been determined by fitting to the Arrhenius equation. © 2009 Wiley Periodicals, Inc. J Appl Polym Sci, 2009     

Fusion Multistyle Training for Speaker Identification of Disguised Speech

Wireless Personal Communications - Determining the speaker of a given speech utterance from a group of people is referred to as speaker identification. When voice disguising is done by a person,...     

Targets (Metabolic Mediators) of Therapeutic Importance in Pancreatic Ductal Adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC), an extremely aggressive invasive cancer, is the fourth most common cause of cancer-related death in the United States. The higher mortality in PDAC is often attributed to the inability to detect it until it has reached advanced stages. The major challenge in tackling PDAC is due to its elusive pathology, minimal effectiveness, and resistance to existing therapeutics. The aggressiveness of PDAC is due to the capacity of tumor cells to alter their metabolism, utilize the diverse available fuel sources to adapt and grow in a hypoxic and harsh environment. Therapeutic resistance is due to the presence of thick stroma with poor angiogenesis, thus making drug delivery to tumor cells difficult. Investigating the metabolic mediators and enzymes involved in metabolic reprogramming may lead to the identification of novel therapeutic targets. The metabolic mediators of glucose, glutamine, lipids, nucleotides, amino acids and mitochondrial metabolism have emerged as novel therapeutic targets. Additionally, the role of autophagy, macropinocytosis, lysosomal transport, recycling, amino acid transport, lipid transport, and the role of reactive oxygen species has also been discussed. The role of various pro-inflammatory cytokines and immune cells in the pathogenesis of PDAC and the metabolites involved in the signaling pathways as therapeutic targets have been previously discussed. This review focuses on the therapeutic potential of metabolic mediators in PDAC along with stemness due to metabolic alterations and their therapeutic importance.