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Cyclopamine, a natural alkaloid, can act as an agonist when it binds to the Cysteine-Rich Domain (CRD) of Smoothened receptor and as an antagonist when it binds to the Transmembrane Domain (TMD). To study the effect of cyclopamine binding to each site experimentally, mutations in the other site are required. Hence, simulations are critical for understanding the WT activity due to binding at different sites. Using multi-milliseconds long aggregate MD simulations combined with Markov state models and machine learning, we explore the dynamic behavior of cyclopamine's interactions with different domains of WT SMO. A higher population of the active state at equilibrium, a lower free energy barrier of ~2 kcal/mol, and expansion of hydrophobic tunnel to facilitate cholesterol transport agrees with cyclopamine's agonistic behavior when bound to CRD. A higher population of the inactive state at equilibrium, a higher free energy barrier of ~4 kcal/mol and restricted hydrophobic tunnel shows cyclopamine's antagonistic behavior when bound to TMD. With cyclopamine bound to both sites, there is a slightly larger inactive population at equilibrium and an increased free energy barrier (~3.5 kcal/mol) exhibiting an overall weak antagonistic effect. These findings show cyclopamine's domain-specific modulation of SMO regulates Hedgehog signaling and cholesterol transport. Millisecond scale MD simulations explain how cyclopamine modulates human Smoothened receptor activity based on different binding positions. [ABSTRACT FROM AUTHOR]

In this study, a high-load expansion strategy was investigated by varying the effective compression ratio (CR) using the variable valve duration (VVD) method during combustion in a gasoline/diesel dual-fuel premixed compression ignition engine. The effective CR was varied from 15.0 to 10.6 via the retardation of the intake valve closing timing (IVC) at 1,500 rpm. With respect to optimization, the diesel injection timing, fuel ratio, and exhaust gas recirculation (EGR) rate were adjusted for each optimized condition. The limitations were the maximum pressure rise rate (below 10 bar/deg) and in-cylinder pressure (below 150 bar) with NOx < 40 ppm and soot < 0.2 FSN. The results emphasized that when the effective CR was 12.7, the maximum load increased by 10.5 % (gIMEP from 13.3 to 14.7 bar) compared with that at a CR of 15.0. Although the decrease in CR resulted in a gross thermal efficiency loss, the difference was negligible (from 45.9 to 45.5 %). The main reason for high-load expansion was the increase in intake air volume under the same intake pressure upon lowering the CR and the margin for the maximum in-cylinder pressure. From this result, it can be concluded that the Miller cycle is useful for the expansion of high load ranges in premixed combustion systems. [ABSTRACT FROM AUTHOR]

In-cylinder flow motion is important for enhancing combustion in internal combustion engines. There are two major flow motions: tumble and swirl. Tumble enhances the flame propagation speed to spread throughout the entire cylinder. Swirl affects the behavior of diesel spray; an enhanced swirl ratio has been widely used in conventional diesel engines. Because dual-fueled combustion has the characteristics of premixed combustion from background fuels and mixing-controlled combustion from directly injected fuels such as diesel, understanding the effect of in-cylinder flow motion on combustion characteristics in dual-fuel combustion is critical. In this research, the effect of swirl in gasoline and diesel dual-fuel combustion was evaluated with different diesel injection timing conditions. As the dual-fuel combustion engine used in this research was driven by diesel spray, swirl was selected as the main flow motion rather than tumble. The effect of swirl with different diesel injection timings was investigated under low-speed and low-load conditions. The results demonstrate that increasing swirl intensity provokes fast-burning caused by the enhanced air-fuel mixture, decreasing the diesel fraction and allowing more exhaust gas recirculation (EGR) to be used for the reduction of engine-out nitrogen oxides (NOx) and smoke emissions, without reducing thermal efficiency. [ABSTRACT FROM AUTHOR]

Natural fractures have a significant effect on fluid flow and heat transfer in naturally fractured geothermal reservoirs. However, most previous studies have assumed that reservoir systems are either a single continuum or dual continuum model, while some studies have just considered a pipeline model. In this study, we developed a discrete fracture network (DFN) geothermal reservoir simulator. The DFN model developed was validated for synthetic fracture systems using a Tetrad; a comparison of the results revealed good agreement between two models. However, developed model is only a fracture model and cannot simulate fluid flow and heat transfer in the matrix. A matrix flow model will be added in the future. [ABSTRACT FROM AUTHOR]

Coal solvent extraction is a clean coal technology that involves the extraction of organic matter from coal using solvents. In this study, the effects of various coal and solvent properties on extraction yield were studied and their correlations were observed. Solvent extraction was performed for fifteen coal samples of different ranks with eight solvents under mild conditions. Statistical analyses were then conducted to find correlations between the extraction yields and the coal and solvent characteristics. The extraction yield was strongly correlated with the atomic H/C ratio or volatile matter content. Among the solvent properties, the correlation between the electron donor, acceptor number (DN-AN) and yield was confirmed to be high. The results of multiple regression showed that positive correlations were found with the content of volatile matter of coal and polar force, DN-AN of solvent. Whereas negative correlations were found with the Ca/Mg content of coal and dispersion force, hydrogen bonding force of solvent. The regressionequation- calculated value was similar to the experimental value. [ABSTRACT FROM AUTHOR]

Mig6 is a feedback inhibitor that directly binds, inhibits and drives internalization of ErbB-family receptors. Mig6 selectively targets activated receptors. Here we found that the epidermal growth factor receptor (EGFR) phosphorylates Mig6 on Y394 and that this phosphorylation is primed by prior phosphorylation of an adjacent residue, Y395, by Src. Crystal structures of human EGFR-Mig6 complexes reveal the structural basis for enhanced phosphorylation of primed Mig6 and show how Mig6 rearranges after phosphorylation by EGFR to effectively irreversibly inhibit the same receptor that catalyzed its phosphorylation. This dual phosphorylation site allows Mig6 to inactivate EGFR in a manner that requires activation of the target receptor and that can be modulated by Src. Loss of Mig6 is a driving event in human cancer; analysis of 1,057 gliomas reveals frequent focal deletions of ERRFI1, the gene that encodes Mig6, in EGFR-amplified glioblastomas. [ABSTRACT FROM AUTHOR]

We investigate theoretically the nature of the states and the localization properties in a one-dimensional Anderson model with long-range correlated disorder and weak nonlinearity. Using the stationary discrete nonlinear Schrödinger equation, we calculate the disorder-averaged logarithm of the transmittance and the localization length in the fixed input case in a numerically exact manner. Unlike in many previous studies, we strictly fix the intensity of the incident wave and calculate the localization length as a function of other parameters. We also calculate the wave functions in a given disorder configuration. In the linear case, flat phased localized states appear near the bottom of the band and staggered localized states appear near the top of the band, while a continuum of extended states appears near the band center. We find that the focusing Kerr-type nonlinearity enhances the Anderson localization of flat phased states and suppresses that of staggered states. We observe that there exists a perfect symmetry relationship for the localization length between focusing and defocusing nonlinearities. Above a critical value of the strength of nonlinearity, delocalization due to the long-range correlations of disorder is destroyed and all states become localized. [ABSTRACT FROM AUTHOR]

promising strategy for the selective growth of ZnO nanorods on SiO/Si substrates using a graphene buffer layer in a low temperature solution process is described. High densities of ZnO nanorods were grown over a large area and most ZnO nanorods were vertically well-aligned on graphene. Furthermore, selective growth of ZnO nanorods on graphene was realized by applying a simple mechanical treatment, since ZnO nanorods formed on graphene are mechanically stable on an atomic level. These results were confirmed by first principles calculations which showed that the ZnO-graphene binding has a low destabilization energy. In addition, it was found that ZnO nanorods grown on SiO/Si with a graphene buffer layer have better optical properties than ZnO nanorods grown on bare SiO/Si. The nanostructured ZnO-graphene materials have promising applications in future flexible electronic and optical devices. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

An amendment to this paper has been published and can be accessed via a link at the top of the paper. [ABSTRACT FROM AUTHOR]