We apply the general protocol of parameter optimization (Lee, J.; Ripoll, D. R.; Czaplewski, C.; Pillardy, J.; Wedemeyer, W. J.; Scheraga, H. A. J. Phys. Chem. B 2001, 105, 7291) to the UNRES potential. In contrast to earlier works where only the relative weights of various interaction terms were optimized, we optimize all linear parameters of the potential. The method exploits the high efficiency of the conformal space annealing method in finding distinct low-energy conformations. For a given training set of proteins, the parameters are modified to make the nativelike conformations energetically more favorable than the non-native ones. Linear approximation is used to estimate the energy change due to the parameter modification. The parameter change is followed by local energy reminimization and new conformational searches to find the energies of nativelike and non-native local minima of the energy function with new parameters. These steps are repeated until the potential predicts a nativelike conformation as one of the low-energy conformations for each protein in the training set. We consider a training set of crambin (PDB ID 1ejg), 1fsd, and the 10-55 residue fragment of staphylococcal protein A (PDB ID 1bdd). As the first check for the feasibility of our protocol, we optimize the parameters separately for these proteins and find an optimal set of parameters for each of them. Next, we apply the method simultaneously to these three proteins. By refining all linear parameters, we obtain an optimal set of parameters from which the nativelike conformations of the all three proteins are retrieved as the global minima, without introducing additional multibody energy terms.

An application of spectral domain optical coherence tomography (SD-OCT) was demonstrated for a fast industrial inspection of an optical thin film panel. An optical thin film sample similar to a liquid crystal display (LCD) panel was examined. Two identical SD-OCT systems were utilized for parallel scanning of a complete sample in half time. Dual OCT inspection heads were utilized for transverse (fast) scanning, while a stable linear motorized translational stage was used for lateral (slow) scanning. The cross-sectional and volumetric images of an optical thin film sample were acquired to detect the defects in glass and other layers that are difficult to observe using visual inspection methods. The rapid inspection enabled by this setup led to the early detection of product defects on the manufacturing line, resulting in a significant improvement in the quality assurance of industrial products.

Imatinib is the first molecularly targeted compound for chronic myeloid leukemia (CML) capable to inhibit BCR-ABL kinase activity. However, recent clinical evidence indicates that a substantial proportion of CML patients exhibit BCR-ABL-dependent or independent resistance to imatinib. Despite the importance of imatinib resistance in CML, the underlying molecular mechanisms of this resistance are largely unknown. Here, we identified GCA (grancalcin) as a critical regulator of imatinib resistance in chronic phase CML via activation of autophagy. Mechanistically, we demonstrated that GCA activates TRAF6 ubiquitin ligase activity to induce Lys63 ubiquitination of ULK1, a crucial regulator of autophagy, resulting in its stabilization and activation. We also highlighted the role of GCA-TRAF6-ULK1 autophagy regulatory axis in imatinib resistance. Our findings represent the basis for novel therapeutic strategies against CML.

The initial detection of dental caries is an essential biomedical requirement to barricade the progression of caries and tooth demineralization. The objective of this study is to introduce an optical frequency-domain imaging technique based quantitative evaluation method to calculate the volume and thickness of enamel residual, and a quantification method was developed to evaluate the total intensity fluctuation in depth direction owing to carious lesions, which can be favorable to identify the progression of dental caries in advance. The cross-sectional images of the ex vivo tooth samples were acquired using 1.3 μm spectral domain optical coherence tomography system (SD-OCT). Moreover, the advantages of the proposed method over the conventional dental inspection methods were compared to highlight the potential capability of OCT. As a consequence, the threshold parameters obtained through the developed method can be used as an efficient investigating technique for the initial detection of demineralization.

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We have demonstrated the application of optical coherence tomography (OCT) in diagnosis of growth and spread of the gray leaf spot disease in Capsicum annuum leaf caused by the fungus Stemphylium lycopersici. Using 2D cross-sectional and 3D volumetric images of OCT, in vivo study of layer differences between fungus infected leaves and healthy leaves was observed with distinctive features. We observed that the internal layers of the disease-affected parts of the leaf seem to merge forming a single thick layer. The obtained OCT results verify the noninvasive diagnosis ability of fungal growth and spread in Capsicum annuum leaves and the applicability of this methodology for other plant diseases.

We analyzed several energy functions for predicting the native state of proteins from an energy minimization procedure. We derived the parameters of a given energy function by imposing the basic requirement that the energy of the native conformation of a protein is lower than that of any conformation chosen from a set of decoys. Our work is motivated by a recent result which proved that the simple pairwise contact approximation of the energy is insufficient to satisfy simultaneously such a basic requirement for all the proteins in a database. Here, we investigate the reasons of such negative results and show how to improve the predictive power of methods based on energy minimization. We generated decoys by gapless threading, and we derive energy parameters by perceptron learning. We first considered hydrophobic contributions to the energy, defined in several ways, and showed that the additional hydrophobic terms enlarge slightly the number of proteins that can be stabilized together. Next, we performed various modifications of the pairwise energy term. We introduced (1) a distinction between inter-residue contacts on the surface and in the core of a protein and (2) a simple distance-dependent pairwise interaction in which a two-tier definition of contact replaces the original (single-tier) one. Our results suggest that a detailed treatment of the pairwise potential is likely to be more relevant than the consideration of other forces.

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