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We conducted large‐scale screening test on drugs that were already approved for other diseases to find pigmentation‐modulating agents. Among drugs with potential for pigmentation control, we selected sorafenib and further investigated the effect on pigmentation using HM3KO melanoma cells. As a result of treating melanoma cells with sorafenib, pigmentation was promoted in terms of melanin content and tyrosinase activity. Sorafenib increased mRNA and protein levels of pigmentation‐related genes such as MITF, tyrosinase and TRP1. To uncover the action mechanism, we investigated the effect of sorafenib on the intracellular signalling pathways. Sorafenib reduced phosphorylation of AKT and ERK, suggesting that sorafenib induces pigmentation through inhibition of the AKT and ERK pathways. In addition, sorafenib significantly increased the level of active β‐catenin, together with activation of β‐catenin signalling. Mechanistic study revealed that sorafenib decreased phosphorylation of serine 9 (S9) of GSK3β, while it increased phosphorylation of tyrosine 216 (Y216) of GSK3β. These results suggest that sorafenib activates the β‐catenin signalling through the regulation of GSK3β phosphorylation, thereby affecting the pigmentation process. [ABSTRACT FROM AUTHOR]

Abstract Skin color is determined by the melanin pigments that are produced in melanocytes then transferred to surrounding keratinocytes. Despite the growing number of commercial products claiming the pigmentation-regulatory effects, there is still a demand for the development of new materials that are safe and more efficacious. We tried to screen the pigmentation-regulatory materials using a commercially available drugs, and found that nilotinib could induce pigmentation in melanoma cells. When HM3KO melanoma cells were treated with nilotinib, melanin content was increased together with increase of tyrosinase activity. Nilotinib increased the expression of pigmentation-related genes such as MITF, tyrosinase and TRP1. Consistent with these results, the protein level for MITF, tyrosinase, and TRP1 was significantly increased by nilotinib. To delineate the action mechanism of nilotinib, we investigated the effects of nilotinib on intracellular signaling. As a result, nilotinib decreased the phosphorylation of AKT, while increased the phosphorylation of CREB. The pretreatment of PKA inhibitor H89 markedly blocked the nilotinib-induced phosphorylation of CREB. In accordance with, pretreatment of H89 significantly inhibited the nilotinib-induced pigmentation, indicating that nilotinib induces pigmentation via the activation of PKA signaling. Together, our data suggest that nilotinib can be developed for the treatment of hypopigmentary disorder such as vitiligo. Highlights • The nilotinib induced the pigmentation of HM3KO melanoma cells. • The nilotinib decreased the phosphorylation of AKT, while increased the phosphorylation of CREB. • The inhibition of PKA signaling abrogated nilotinib-induced pigmentation. [ABSTRACT FROM AUTHOR]

Melanin pigments are the primary contributors for the skin color. They are produced in melanocytes and then transferred to keratinocytes, eventually giving various colors on skin surface. Although many depigmenting and/or skin-lightening agents have been developed, there is still a growing demand on materials for reducing pigmentation. We attempted to find materials for depigmentation and/or skin-lightening using the small molecule compounds commercially available, and found that 5-iodotubercidin had inhibitory potential on pigmentation. When HM3KO melanoma cells were treated with 5-iodotubercidin, pigmentation was dramatically reduced. The 5-iodotubercidin decreased the protein level for pigmentation-related molecules such as MITF, tyrosinase, and TRP1. In addition, 5-iodotubercidin decreased the phosphorylation of CREB, while increased the phosphorylation of AKT and ERK. These data suggest that 5-iodotubercidin inhibits melanogenesis via the regulation of intracellular signaling related with pigmentation. Finally, 5-iodotubercidin markedly inhibited the melanogenesis of zebrafish embryos, an in vivo evaluation model for pigmentation. Together, these data suggest that 5-iodotubercidin can be developed as a depigmenting and/or skin-lightening agent. [ABSTRACT FROM AUTHOR]

Background Wnt/β-catenin signaling is important in development and differentiation of melanocytes. Objective The object of this study was to evaluate the effects of several Wnt/β-catenin signaling inhibitors on pigmentation using melanoma cells. Methods Melanoma cells were treated with Wnt/β-catenin signaling inhibitors, and then melanin content and tyrosinase activity were checked. Results Although some inhibitors showed slight inhibition of pigmentation, we failed to observe potential inhibitory effect of those chemicals on pigmentation of HM3KO melanoma cells. Rather, one of powerful Wnt/β-catenin signaling inhibitors, ICG-001, increased the pigmentation of HM3KO melanoma cells. Pigmentation-enhancing effect of ICG-001 was reproducible in other melanoma cell line MNT-1. Consistent with these results. ICG-001 increased the expression of pigmentation-related genes, such as MITF, tyrosinase and TRP1. When ICG-001 was treated, the phosphorylation of CREB was significantly increased. In addition, ICG-001 treatment led to quick increase of intracellular cAMP level, suggesting that ICG-001 activated PKA signaling. The blockage of PKA signaling with pharmaceutical inhibitor H89 inhibited the ICG-001-induced pigmentation significantly. Conclusions These results suggest that PKA signaling is pivotal in pigmentation process itself, while the importance of Wnt/β-catenin signaling should be emphasized in the context of development and differentiation. [ABSTRACT FROM AUTHOR]

Voice over Internet Protocol (VoIP) is an emerging communication service that has advanced in ubiquitous computing environments. Although VoIP is inexpensive and offers additional services, there has been little provision for attacks at the weak points. With the advances of Wireless Sensor Network (WSN) technologies, the risk is increasing. Due to the resource constraints of WSN, attacks have become easier, making protection of the network more difficult. In this work, we attempt to distinguish fraud call attacks as outliers from normal calls on the basis of call detail records. We adopted and applied a Local Outlier Factor (LOF) method on real call data, which include actual fraud call attacks. Our results show the outlier detection method can be effective in detecting fraud calls. Moreover, introducing two additional attributes related to fraud call characteristics enhanced the detection performance. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine the influence of cocultured adipose-derived stromal cells (ASCs) in enhancing the osteogenic differentiation and angiogenesis of bone marrow stromal cells (BMSCs) as well as the underlying mechanism and the optimal ratio. Two in vitro coculture models, segregated cocultures using transwell and mixed cocultures, were employed to assess the indirect and direct effects of coculture respectively. Coculture was carried out for 14 days using 1 × 105 BMSCs and ASCs of variable number. BMSCs, ASCs, or both were seeded in PLGA scaffold and implanted in the subcutaneous tissue of 25 nude mice for in vivo analysis of angiogenesis. To evaluate the orthotopic bone formation, critical size calvarial defects were created on 20 mice, and implanted with hydroxyapatite/β-tricalcium phosphate granules plus BMSCs, ASCs, or both. From both transwell and mixed coculture model, 1 × 105 BMSCs cocultured with 0.5 × 105 ASCs showed significantly greater osteogenic differentiation and mineralization than BMSCs alone. The mixed ASC/BMSC coculture at or above a ratio of 0.5/1 showed increased secretion of vascular endothelial growth factor (VEGF), and induced effective tube formation from human umbilical vein endothelial cells, which were comparable to ASCs. Cytokine profiling assay and gene expression study showed elevated levels of angiogenic factors VEGF and CXCL1, osteogenic factor Wnt5a as well as transforming growth factor (TGF)-βR1 and SMAD3 from BMSCs when cocultured with ASCs. After 5 weeks of implantation, polylactic-co-glycolic acid (PLGA)-ASCs-BMSCs had a number of vascular structures comparable to PLGA-ASCs and significantly greater than PLGA-BMSCs. Calvarial defects treated with ceramic/BMSCs/ASCs had greater area of repair and better reconstitution of osseous structure than the defects treated with ceramic/ASCs or ceramic/BMSCs after 10 weeks. In conclusion, ASCs added to BMSCs promoted osteogenesis and angiogenesis at the optimal ASC/BMSC ratio of 0.5/1. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this study was to investigate the chondrogenic features of human induced pluripotent stem cells (hiPSCs) and examine the differences in the chondrogenesis between hiPSCs and human bone marrow-derived MSCs (hBMMSCs). Embryoid bodies (EBs) were formed from undifferentiated hiPSCs. After EBs were dissociated into single cells, chondrogenic culture was performed in pellets and alginate hydrogel. Chondro-induced hiPSCs were implanted in osteochondral defects created on the patellar groove of immunosuppressed rats and evaluated after 12 weeks. The ESC markers NANOG, SSEA4 and OCT3/4 disappeared while the mesodermal marker BMP-4 appeared in chondro-induced hiPSCs. After 21 days of culture, greater glycosaminoglycan contents and better chondrocytic features including lacuna and abundant matrix formation were observed from chondro-induced hiPSCs compared to chondro-induced hBMMSCs. The expression of chondrogenic markers including SOX-9, type II collagen, and aggrecan in chondro-induced hiPSCs was comparable to or greater than chondro-induced hBMMSCs. A remarkably low level of hypertrophic and osteogenic markers including type X collagen, type I collagen and Runx-2 was noted in chondro-induced hiPSCs compared to chondro-induced hBMMSCs. hiPSCs had significantly greater methylation of several CpG sites in COL10A1 promoter than hBMMSCs in either undifferentiated or chondro-induced state, suggesting an epigenetic cause of the difference in hypertrophy. The defects implanted with chondro-induced hiPSCs showed a significantly better quality of cartilage repair than the control defects, and the majority of cells in the regenerated cartilage consisted of implanted hiPSCs. [Copyright &y& Elsevier]

Supercritical CO2 (ScCO2) can dissolve organic materials easily just by changing temperature and pressure. This property of ScCO2 can be applied to extract some ScCO2-philic organic molecules from matrix material. The ScCO2 was used to generate the meso/macro double porous structure of polyimide/polysilsesquioxane (PI/PSSQ) hybrid film. The morphology of the porous structure was measured by scanning electron microscope (SEM). Here, we demonstrate that the ScCO2 could penetrate into the hybrid thin film and take away the small molecules, which are the by-product (CO2) from the imidization reaction of the PI segment and the solvent remained in the PSSQ segment by sol-gel process. [ABSTRACT FROM AUTHOR]

A novel synthetic process for multi-porous polyimide(PI)/poly(methyl silsesquioxane)(PMSSQ)hybrid material has been studied via supercritical CO 2 technology. The end groups of PI precursors were modified by coupling agent to be hybridized with alkoxysilanes and became PMSSQ precursors. PI/PMSSQ hybrid precursor solution was spun on a silicon wafer substrate for film formation. The PI precursor segment was imidized and micro-pores were developed by removal of by-product, CO 2 via supercritical CO 2 media. The PMSSQ precursor segment was cured and nano-pores were generated by supercritical extraction. Average micro-pore size and nano-pore size were 10  μm and 40  nm respectively. The dielectric constant of the multi-porous PI/PMSSQ hybrid film was calculated to 2.5. [ABSTRACT FROM AUTHOR]

Systematic evolution of ligands by exponential enrichment (SELEX) is a method that is generally used for developing aptamers, which have arisen the promising alternatives for antibodies. However, conventional SELEX methods have limitations, such as a limited selection of target molecules, time-consuming and complex fabrication processes, and labor-intensive processes, which result in low selection yields. Here, we used (i) graphene oxide (GO)-coated magnetic nanoparticles in the selection process for separation and label-free detection and (ii) a multilayered microfluidic device manufactured using a three-dimensionally printed mold that is equipped with automated control valves to achieve precise fluid flows. The developed on-chip aptamer selection device and GO-coated magnetic nanoparticles were used to screen aptamer candidates for adenosine in eight cycles of the selection process within approximately 2 h for each cycle. Based on results from isothermal titration calorimetry, an aptamer with a dissociation constant of 18.6 ± 1.5 μM was selected. Therefore, the on-chip platform based on GO-coated magnetic nanoparticles provides a novel label-free screening technology for biosensors and micro/nanobiotechnology for achieving high-quality aptamers. [ABSTRACT FROM AUTHOR]

• A practical dual-scale finite element modeling is developed to simulate the hole expansion formability of a hyper-burring steel sheet. • The microscale RVE model could take the pile up of dislocation density near the grain boundaries into account to estimate local strengthening at the grain boundary and inhomogeneous plastic deformation in the grain interior. • The hole expansion simulations with different fracture models showed that HER could be better captured when the fracture criterion considered the stress triaxiality developed in the microstructure. • From the microscopic simulation of hole expansion test, the higher hole expansion ratio could be predicted as the grain size increases and the degree of pile-up decreases. A practical dual-scale finite element model is developed to enable the formability prediction in the hole expansion of a hyper-burring steel sheet. This numerical approach resorts to the isotropic macroscale hole expansion simulation for calculating the deformation histories near the hole edge, since they are known to be the potential fracture initiation site. The deformation histories are used as boundary conditions in the lower microscale model for calculating the local fracture of the steel sheet. The microscale simulation utilizes the dislocation density based constitutive model and a microstructure-based representative volume element (RVE), with realistic grain morphology taken from experimental microscopy. The fracture initiation at the hole edge region is evaluated from the microscale simulation using four frequently employed uncoupled ductile fracture models, which enable the definition of the critical fracture strain. The proposed dual-scale model can better predict the failure initiation and location near the hole edge when the modeling parameters are calibrated taking into account not only the deformation histories of the hole edge, but also the local stress triaxiality. Moreover, the proposed dual-scale model is applied to analyze the microstructure effect on the hole expansion ratio by providing the insights into the effect of grain size and grain boundary characteristics. [ABSTRACT FROM AUTHOR]

Mechanically induced martensitic transformation (MIMT) and consequent plastic flow behavior with respect to austenitic texture were investigated in a lean duplex stainless steel. Different grain sizes and textures with fixed phase fractions were obtained via varying the thermomechanical processes. Nearly random distribution of austenitic orientation exhibited a distinguished flow curve from the others with a major D {4 4 11}〈11 11 8〉 component due to more gradual enhancement of hardening by less martensitic transformation. In order to compare the susceptibility to the transformation with respect to individual austenitic orientations and the experimental textures, interaction energy between the imposed stress and transformation strain was calculated by a classical transformation and a crystal plasticity model. The results indicated that a larger stress imposed on the D component led to higher interaction energy and a steeper progress of MIMT observed in the textured materials. [ABSTRACT FROM AUTHOR]

Simple Summary: Rampant use of growth-promoting antibiotics in the poultry industry has resulted in enhanced harmful concentrations in livestock products ushering in the evolution of multidrug resistance strains. Plant feed additives are being explored, and among them, Chinese chives (CC), which contain various phytonutrients, can offer a promising alternative. We performed a comparative study to examine the effects of non-fermented and fermented CC feed additives on broiler productivity, chicken meat quality, blood composition, intestinal properties, and gut microbiota. We observed a high broiler productivity for the treatment group subjected to fermented CC juice on par with growth-promoting antibiotics. Fermented CC juice influenced low cholesterol content in the broilers while inhibiting the growth of intestinal pathogens. The present study explores the application of CC juice as a suitable feed additive and alternative to conventional antibiotics. We performed a comparative study to investigate the effects of non-fermented and fermented CC juice on broiler productivity, meat quality, blood characteristics, intestinal characteristics, and microbiota associated with intestinal characteristics. A total of 800 one-day-old Ross 308 broiler chickens were randomly assigned to one of the four dietary treatment groups: (1) basal diet (negative control; NC); (2) basal diet + 0.01% enramycin (positive control; PC); (3) basal diet + 3% non-fermented CC juice (NCC; CC juice 10%, water 90%); and (4) basal diet + 3% fermented CC juice (FCC; CC juice 10%, water 90%, Lactobacillus plantarum SK4719). Feed and water were provided ad libitum. Intriguingly, all treatments showed similar results in terms of broiler productivity and chicken meat quality. Considering organ characteristics, the FCC group showed a low spleen weight and lower (p < 0.05) blood levels of AST and total cholesterol (TCHO). Regarding intestinal characteristics, the CC feed additive (NCC and FCC) resulted in a heavier intestinal weight (p < 0.05) without affecting the length ratio of the villi or the crypt compared to the control (NC or PC). NCC and FCC lowered the growth of intestinal pathogens (p < 0.01). In summary, the addition of FCC can maintain poultry health by improving blood compositions and inhibiting the growth of intestinal pathogens, leading to a productivity comparable to that of poultry treated with growth-promoting antibiotics. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigated the probiotic characteristics of Paenibacillus konkukensis and its dietary effects on growth performance, intestinal characteristics, intestinal microbiota, and meat quality in broilers. Through this study, P. konkukensis showed non-hemolytic activity, variable antibiotic susceptibility, and moderate acid and bile tolerance. Supplementary feeding of P. konkukensis as bacterial culture did not affect the growth performance parameters and meat quality, with positive effects on meat yield and intestinal microflora. Overall, dietary P. konkukensis may not have any adverse effects and might be considered as a probiotic feed additive in poultry. This study evaluates the in vitro probiotic characteristics of P. konkukensis sp. nov. SK-3146, which was isolated from animal feed, and its dietary effects on growth performance, intestinal characteristics, intestinal microbiota, and meat quality in broilers. In vitro experiments revealed that P. konkukensis was non-hemolytic with variable antibiotic susceptibility, and acid as well as bile tolerance. To assess the effect of P. konkukensis on broilers, a total of four hundred eighty 1-day-old Ross 308 broiler chicks were allocated to 3 treatment groups with 4 replicates of 40 birds each; the negative control group was fed a basal diet without any feed additives (NC), the positive control group was fed a basal diet containing 0.01% enramycin (PC), and the experimental group was fed a basal diet containing P. konkukensis bacterial culture (PK) at 104 CFU/g of the diet based on bacterial count. The experiment lasted for 35 days. Results indicated that there were no significant differences in any growth performance parameters among the dietary treatments (p > 0.05). In addition, the inclusion of P. konkukensis in the broilers' diet did not affect meat cooking loss, color, and pH but increased the relative weight of breast meat (p < 0.05). The PK group showed heavier intestinal weight and shorter intestinal length than the NC group (p < 0.05). The ratio of the intestinal weight to length of jejunum was the highest in the PK group (p < 0.05). The PK group showed increased counts of Streptococcus thermophilus (p < 0.05) with no adverse effects of P. konkukensis on other intestinal microbiota in the jejunum. This study implies that P. konkukensis might have the potential to be applied as a probiotic feed additive in poultry. [ABSTRACT FROM AUTHOR]

Soft ferromagnetic properties of nano-crystalline metallic glass considerably depend on microstructure and its magnetic domain structure. Here, we investigated the microstructure evolution and its impact on magnetic domain structure, coercivity (H c), and saturation flux density (B s) by manipulating nano-crystallization behavior of Fe–Si–B commercial metallic glass. We revealed that mean grain size of system is affected by both annealing temperature and resulting crystalline phases owing to the competition between grain growth of α-Fe(Si) matrix phase and grain refinement by secondary phase Fe 2 B formation. As a result, the changed grain sizes played a significant role in deciding the H c and B s. However, H c of nano-crystalline structure increased than that of amorphous state. Our findings will give insight to producing soft ferromagnetic metallic glass by controlling microstructure and domain structure. Image 1 • Nano-crystallization and magnetic behavior of Fe 80 Si 9 B 11 was observed by Lorentz microscopy. • The lowest and highest coercive field (H c) were reached at as-cast state and ∼500 °C annealing, respectively. • Magnetic domain structures such as vortex-type, ripple structure, and grain boundary pinned state were observed. • The mean grain size affected the H c and B s values and magnetic domain structures. [ABSTRACT FROM AUTHOR]

This study proposed a practical method to evaluate the anisotropy of yield stress using spherical indentation with in-plane surface radial displacements around residual imprint measured by the digital image correlation method for metallic material without indentation curve. The relation between the ratio of yield stresses and the in-plane displacements developed on the surface was analyzed using finite element method (FEM) simulations for the materials with various mechanical properties. The development of radial displacements depends on the anisotropy of the yield stresses, and the ratio between radial displacement values on principal directions has a strong relation with the anisotropy of the yield stresses. An analytical solution for predicting the ratio of yield stresses was developed and it was verified using experimental data with anisotropic materials. The results for various metallic materials showed the feasibility of the proposed model with good accuracy. • We estimated anisotropy of yield stresses using surface in-plane displacements after spherical indentation. • Ratio of surface radial displacements along principal directions has a strong relation with anisotropy of yield stresses. • Anisotropic materials were tested and the prediction of anisotropy of yield stresses using the proposed method show good accuracy within a 10% error. [ABSTRACT FROM AUTHOR]

Abstract: Receptor-interacting protein 3 (RIP3) has been implicated in ischemic necrosis of retinal cells. An in silico analysis followed by experimental validation identified death associated protein (Daxx) as a novel substrate of RIP3. In vitro binding studies revealed that RIP3 binds to the serine/proline/threonine-rich domain (amino acid 625–740) of Daxx. Upon ischemic insult, RIP3 phosphorylated Daxx at Ser-668 in the retinal ganglion cells, triggering nuclear export of Daxx. Depletion of RIP3 significantly inhibited nuclear export of Daxx and attenuated cell death to a great extent. Collectively, the findings of this study demonstrate that phosphorylation of Daxx by RIP3 comprises an important part of ischemic necrosis in rat retinal ganglion cells. Structured summary of protein interactions: Daxx binds to Rip3 by pull down(View Interaction: 1, 2) Rip3 and Daxx colocalize by fluorescence microscopy(View interaction) Rip3 physically interacts with Daxx by anti bait coimmunoprecipitation (View interaction) Daxx binds to Rip1 bypull down(View interaction) [Copyright &y& Elsevier]

Furans, thiazoles, fluorene or thiophene incorporated calix[4]pyrrole analogues were synthesized and characterized. The synthesis was achieved by utilization of various building blocks such as 7, 13, 14, 18 and 21. Acid catalyzed condensation of those building blocks with acetone or meso-disubstituted dipyrromethanes afforded desired macrocycles. [Copyright &y& Elsevier]