Photo-Programmed Deformations in Rigid Liquid Crystalline Polymers Triggered by Body Temperature.

Deformations triggered by body heat are desirable in the context of shape-morphing applications because, under the majority of circumstances, the human body maintains a higher temperature than that of its surroundings. However, at present, this bioenergy-triggered action is primarily limited to soft polymeric networks. Thus, herein, the programming of body temperature-triggered deformations into rigid azobenzene-containing liquid crystalline polymers (azo-LCPs) with a glass-transition temperature of 100 °C is demonstrated. To achieve this, a mechano-assisted photo-programming strategy is used to create a metastable state with room-temperature stable residual stress, which is induced by the isomerization of azobenzene. The programmed rigid azo-LCP can undergo large-amplitude body temperature-triggered shape changes within minutes and can be regenerated without any performance degradation. By changing the programming photomasks and irradiation conditions employed, various 2D to 3D shape-morphing architectures, including folded clips, inch-worm structures, spiral structures, and snap-through motions are achieved. When programmed with polarized light, the proposed strategy results in domain-selective activation, generating designed characteristics in multi-domain azo-LCPs. The reported strategy is therefore expected to broaden the applications of azo-LCPs in the fields of biomedical and flexible microelectronic devices.

The Risk of Gastrointestinal Cancer on Daily Intake of Low-Dose BaP in C57BL/6 for 60 Days.

BACKGROUND: Benzo(a)pyrene (BaP) is a carcinogenic compound in contaminated foodstuffs. The effect of oral intake of the environmental carcinogen BaP under low doses and frequent exposure on a digestive system has not been thoroughly verified. METHODS: In this regard, this study was conducted to prove the toxicity effects of BaP on the stomach and colon tissue after exposure to C57BL/6 mouse (3 and 6 µg/kg) following daily oral administration for 60 days. This study investigated acute gastric mucosal injury, severe gastric edema, cell infiltration, and mononuclear cells, multifocal cells, and tumoral inflammatory cells. RESULTS: The results of ELISA showed that the expression of serum interleukin (IL)-6 and tumor necrosis factor-α in the BaP exposure group were significantly increased, and a high level of DNA adduct distribution in their stomach and colon. Moreover, this study has confirmed the expression of early carcinogenesis markers: nuclear factor (NF)-κB, p53, IL-6, superoxide dismutase 1 (SOD1), mucin (MUC1 and MUC2), and ß-catenin in the stomach and colon, and showed that there was a significant increase in IL-6, NF-κB, SOD1, ß-catenin, and MUC1 (P < 0.05). At the same time, there was a significant decrease in MUC2 and p53 (P < 0.05). Thus, even in low doses, oral intake of BaP can induce DNA damage, increasing the potential risk of gastrointestinal cancer. CONCLUSION: This study will provide a scientific basis for researching environmental contaminated food and intestinal health following daily oral administration of BaP.

Interoperable Nanoparticle Sensor Capable of Strain and Vibration Measurement for Rotor Blade Monitoring.

Recent advances in nanomaterials technology create the new possibility to fabricate high performance sensors. However, there has been limitations in terms of multivariate measurable and interoperable sensors. In this study, we fabricated an interoperable silver nanoparticle sensor fabricated by an aerodynamically focused nanomaterial (AFN) printing system which is a direct printing technique for inorganic nanomaterials onto a flexible substrate. The printed sensor exhibited the maximum measurable frequency of 850 Hz, and a gauge factor of 290.62. Using a fabricated sensor, we evaluated the sensing performance and demonstrated the measurement independency of strain and vibration sensing. Furthermore, using the proposed signal separation algorithm based on the Kalman filter, strain and vibration were each measured in real time. Finally, we applied the printed sensor to quadrotor condition monitoring to predict the motion of a quadrotor.

Single Ni Atoms and Clusters Embedded in N-Doped Carbon "Tubes on Fibers" Matrix with Bifunctional Activity for Water Splitting at High Current Densities.

Among the bifunctional catalysts for water splitting, recently emerged transition-metal single-atom catalysts are theoretically considered to possess high potential, while the experimental activity is not satisfactory yet. Herein, an exceptionally efficient trifunctional metal-nitrogen-carbon (M-N-C) catalyst electrode, composed of a hierarchical carbon matrix embedding isolated nickel atoms with nickel-iron (NiFe) clusters, is presented. 1D microfibers and nanotubes grow sequentially from 2D nanosheets as sacrificial templates via two stages of solution- and solid-phase reactions to form a 1D hierarchy. Exceptionally efficient bifunctional activity with an overpotential of only 13 mV at 10 mA cm-2 toward hydrogen evolution reaction (HER) and an overpotential of 210 mV at 30 mA cm-2 toward oxygen evolution reaction (OER) is obtained, surpassing each monofunctional activity ever reported. More importantly, an overpotential of only 126 and 326 mV is required to drive 500 mA cm-2 toward the HER and OER, respectively. For the first time, industrial-scale water splitting with two bifunctional catalyst electrodes with a current density of 500 mA cm-2 at a potential of 1.71 V is demonstrated. Lastly, trifunctional catalytic activity including oxygen reduction reaction is also proven with a half-wave potential at 0.848 V.

KRCA-0008 suppresses ALK-positive anaplastic large-cell lymphoma growth.

Anaplastic lymphoma kinase (ALK), which belongs to the insulin receptor tyrosine kinase superfamily, plays an important role in nervous system development. Due to chromosomal translocations, point mutations, and gene amplification, constitutively activated ALK has been implicated in a variety of human cancers, including anaplastic large-cell lymphoma (ALCL), non-small cell lung cancer, and neuroblastoma. We evaluated the anti-cancer activity of the ALK inhibitor KRCA-0008 using ALCL cell lines that express NPM (nucleophosmin)-ALK. KRCA-0008 strongly suppressed the proliferation and survival of NPM-ALK-positive ALCL cells. Additionally, it induced G0/G1 cell cycle arrest and apoptosis by blocking downstream signals including STAT3, Akt, and ERK1/2. Tumor growth was strongly suppressed in mice inoculated with Karpas-299 tumor xenografts and orally treated with KRCA-0008 (50 mg/kg, BID) for 2 weeks. Our results suggest that KRCA-0008 will be useful in further investigations of ALK signaling, and may provide therapeutic opportunities for NPM-ALK-positive ALCL patients.

In vitro and in vivo pharmacokinetic characterization of LMT-28 as a novel small molecular interleukin-6 inhibitor.

OBJECTIVE: Interleukin-6 (IL-6) is a T cell-derived B cell stimulating factor which plays an important role in inflammatory diseases. In this study, the pharmacokinetic properties of LMT-28 including physicochemical property, in vitro liver microsomal stability and an in vivo pharmacokinetic study using BALB/c mice were characterized. METHODS: LMT-28 has been synthesized and is being developed as a novel therapeutic IL-6 inhibitor. The physicochemical properties and in vitro pharmacokinetic profiles such as liver microsomal stability and Madin-Darby canine kidney (MDCK) cell permeability assay were examined. For in vivo pharmacokinetic studies, pharmacokinetic parameters using BALB/c mice were calculated. RESULTS: The logarithm of the partition coefficient value (LogP; 3.65) and the apparent permeability coefficient values (Papp; 9.7×10-6 cm/s) showed that LMT-28 possesses a moderate-high cell permeability property across MDCK cell monolayers. The plasma protein binding rate of LMT-28 was 92.4% and mostly bound to serum albumin. The metabolic half-life (t1/2) values of LMT-28 were 15.3 min for rat and 21.9 min for human at the concentration 1 µM. The area under the plasma drug concentration-time curve and Cmax after oral administration (5 mg/kg) of LMT-28 were 302±209 h∙ng/mL and 137±100 ng/mL, respectively. CONCLUSION: These data suggest that LMT-28 may have good physicochemical and pharmacokinetic properties and may be a novel oral drug candidate as the first synthetic IL-6 inhibitor to ameliorate mammalian inflammation.

A Low-Cost Vision-Based Monitoring of Computer Numerical Control (CNC) Machine Tools for Small and Medium-Sized Enterprises (SMEs).

In the new era of manufacturing with the Fourth Industrial Revolution, the smart factory is getting much attention as a solution for the factory of the future. Despite challenges in small and medium-sized enterprises (SMEs), such as short-term strategies and labor-intensive with limited resources, they have to improve productivity and stay competitive by adopting smart factory technologies. This study presents a novel monitoring approach for SMEs, KEM (keep an eye on your machine), and using a low-cost vision, such as a webcam and open-source technologies. Mainly, this idea focuses on collecting and processing operational data using cheaper and easy-to-use components. A prototype was tested with the typical 3-axis computer numerical control (CNC) milling machine. From the evaluation, availability of using a low-cost webcam and open-source technologies for monitoring of machine tools was confirmed. The results revealed that the proposed system is easy to integrate and can be conveniently applied to legacy machine tools on the shop floor without a significant change of equipment and cost barrier, which is less than $500 USD. These benefits could lead to a change of monitoring operations to reduce time in operation, energy consumption, and environmental impact for the sustainable production of SMEs.

Shape Memory Alloy (SMA)-Based Microscale Actuators with 60% Deformation Rate and 1.6 kHz Actuation Speed.

Shape memory alloys (SMAs) are widely utilized as an actuation source in microscale devices, since they have a simple actuation mechanism and high-power density. However, they have limitations in terms of strain range and actuation speed. High-speed microscale SMA actuators are developed having diamond-shaped frame structures with a diameter of 25 µm. These structures allow for a large elongation range compared with bulk SMA materials, with the aid of spring-like behavior under tensile deformation. These actuators are validated in terms of their applicability as an artificial muscle in microscale by investigating their behavior under mechanical deformation and changes in thermal conditions. The shape memory effect is triggered by delivering thermal energy with a laser. The fast heating and cooling phenomenon caused by the scale effect allows high-speed actuation up to 1600 Hz. It is expected that the proposed actuators will contribute to the development of soft robots and biomedical devices.

Cyp7a1 is continuously increased with disrupted Fxr-mediated feedback inhibition in hypercholesterolemic TALLYHO/Jng mice.

TALLYHO/Jng (TH) mice reveal hypercholesterolemia at an early age before their plasma glucose levels have increased. The increased plasma cholesterol should be related to bile acids (BAs) metabolism, because cholesterol is the precursor of BAs and BAs change cholesterol metabolism in a feedback manner. We analyzed the BAs pool size, BAs composition, and expression levels of several proteins that have key roles in BAs synthesis, excretion, and reabsorption and compared them to those of C57BL/6 (B6) mice to study BAs metabolism in TH mice. TH mice exhibited an increased total BAs pool size, increased BAs content in the cecum feces, and an increased ratio of muricholic acid (MCA)/cholic acid (CA). The mRNA and protein levels of cholesterol 7 alpha-hydroxylase (Cyp7a1) and the ATP-binding cassette sub-family G member 5 (Abcg5) were elevated in the liver but not in the apical sodium bile acid transporter (Asbt) and organic solute transporters (Osts) in the ileum. These results indicate that synthesis and the excretion of BAs from the liver to the gallbladder might be elevated, but the reabsorption rate of BAs in the ileum might be reduced. The declined expression of fibroblast growth factor 15 (Fgf15) and fibroblast growth factor receptor 4 (Fgfr4) was respectively identified in the ileum and the liver, indicating the disrupted feedback inhibition of Cyp7a1. Consequently, hypercholesterolemia in TH mice might increase the BAs amounts via the interrupted Fxr/Fgf15/Fgfr4-mediated feedback regulation of Cyp7a1.

Cobalt Phosphide Coupled with Heteroatom-Doped Nanocarbon Hybrid Electroctalysts for Efficient, Long-Life Rechargeable Zinc-Air Batteries.

Metal phosphides and heteroatom-doped carbons have been regarded as promising candidates as bifunctional catalysts for oxygen evolution reaction (OER) and oxygen reduction reaction (ORR). However, both have suffered from stability issues during repeated ORR and OER operations in zinc-air batteries (ZABs). Herein, this study reports a versatile cobalt-based hybrid catalyst with a 1D structure by integrating the metal-organic framework-derived conversion approach and an in situ crosslinking method. Among them, the 1D hybrid catalyst composed of ultrasmall cobalt phosphide nanoparticles supported by nitrogen-, sulfur-, phosphorus-doped carbon matrix shows remarkable bifunctional activity close to that of the benchmark precious-metal catalysts along with an excellent durability in the full potential range covering both the OER and ORR. The overall overpotential of the rechargeable ZABs can be greatly reduced with this bifunctional hybrid catalyst as an air-electrode, and the cycling stability outperforms the commercial Pt/C catalyst. It is revealed that the cobalt phosphide nanoparticles are in situ converted to cobalt oxide under the accelerated conditions during OER (and/or ORR) of the ZABs and reduces the anodic current applied to the carbon. This contributes to the stability of the carbon material and in maintaining the high initial catalytic properties of the hybrid catalyst.

Self-Templated Synthesis of Co- and N-Doped Carbon Microtubes Composed of Hollow Nanospheres and Nanotubes for Efficient Oxygen Reduction Reaction.

A facile, self-templated strategy for the synthesis of Co- and N-doped carbon microtubular structures composed of nanoscale hollow spheres and nanotubes is proposed. Cobalt oxalate microtubes serve simultaneously as the solid cobalt precursor for the in situ conversion reaction to metal-organic framework and self-templates for the 1D tubular structure.

"On the Dot"-The Timing of Self-Assembled Growth to the Quantum Scale.

Understanding the complex world of material growth and tunability has mystified the minds of material scientists and has been met with increasing efforts to close the gap between controllability and applicability. The reality of this journey is frustratingly tortuous but is being eased through better conceptual appreciation of metal crystalline frameworks that originate from shape and size dependent solvent responsive growth patterns. The quantum confinement of TiO2 in the range of 0.8-2 nm has been synthetically challenging to achieve but lessons from biomineralization processes have enabled alternative routes to be explored via self-induced pre-nucleation events. In driving this concept, we have incorporated many of these key features integrating aspects of low temperature annealing at the interface of complex heterogeneous nucleation between hard and soft materials to arrest the biomimetic amorphous phase of TiO2 to a tunable crystalline quantumized state. The stabilization of metastable states of quantum sized TiO2 driven by kinetic and thermodynamic processes show hallmarks of biomineralized controlled events that suggest the inter-play between new pathways and interfacial energies that preferentially favor low dimensionality at the quantum scale. This provides the potential to re-direct synthetic assemblies under tightly controlled parameters to generate a host of new materials with size, shape and anisotropic properties as smart stimuli responsive materials. These new stabilities leading to the growth arrest of TiO2 are discussed in terms of molecular interactions and structural frameworks that were previously inaccessible via conventional routes. There exists an undiscovered parallel between synthetic and biomineralized routes enabling unprecedented access to the availability and tunability of novel quantum confined materials. The parametrics of complex material design at the crossroads of synthetically and biologically driven processes is only now surfacing.

A Novel Small-Molecule Inhibitor Targeting the IL-6 Receptor ß Subunit, Glycoprotein 130.

IL-6 is a major causative factor of inflammatory disease. Although IL-6 and its signaling pathways are promising targets, orally available small-molecule drugs specific for IL-6 have not been developed. To discover IL-6 antagonists, we screened our in-house chemical library and identified LMT-28, a novel synthetic compound, as a candidate IL-6 blocker. The activity, mechanism of action, and direct molecular target of LMT-28 were investigated. A reporter gene assay showed that LMT-28 suppressed activation of STAT3 induced by IL-6, but not activation induced by leukemia inhibitory factor. In addition, LMT-28 downregulated IL-6-stimulated phosphorylation of STAT3, gp130, and JAK2 protein and substantially inhibited IL-6-dependent TF-1 cell proliferation. LMT-28 antagonized IL-6-induced TNF-α production in vivo. In pathologic models, oral administration of LMT-28 alleviated collagen-induced arthritis and acute pancreatitis in mice. Based on the observation of upstream IL-6 signal inhibition by LMT-28, we hypothesized IL-6, IL-6Rα, or gp130 to be putative molecular targets. We subsequently demonstrated direct interaction of LMT-28 with gp130 and specific reduction of IL-6/IL-6Rα complex binding to gp130 in the presence of LMT-28, which was measured by surface plasmon resonance analysis. Taken together, our data suggest that LMT-28 is a novel synthetic IL-6 inhibitor that functions through direct binding to gp130.

Quantification of mequitazine in human plasma by gas chromatography- quadrupole mass spectrometry and its application to a human pharmacokinetic study.

A specific and sensitive gas chromatography-mass spectrometry (GC-MS) with quadrupole mass analyzer type was developed and validated for the quantitative analysis of mequitazine in human plasma. After liquid-liquid extraction of plasma samples containing mequitazine and promethazine (internal standard, IS) using hexane with pH adjustment, the extract was evaporated and an aliquot of reconstituted residue was injected into the GC-MS system. The assay showed linearity over a concentration range from 1 to 50 ng/mL. Intra- and inter-day precision for mequitazine was <9.09 and 9.29%, respectively, and intra- and inter-day accuracy ranged from -7.97 to 9.05% and from -1.51 to 7.89%, respectively. The lower limit of quantification was 1 ng/mL in the present assay. The developed analytical method was successfully applied to a pharmacokinetic study after a single oral administration of mequitazine in human subjects.

Gender differences in the hepatic elimination and pharmacokinetics of lobeglitazone in rats.

The pharmacokinetics of lobeglitazone (LB) was studied after intravenous administration at a dose of 1 mg/kg and oral administration at doses of 0.1, 1 and 10 mg/kg in male and female rats. The area under the plasma concentration-time curve from time zero to infinity (AUCinf ) after intravenous administration was approximately 7.1 times higher in female rats than in male rats. In addition, the AUCinf in the case of oral administration was at least 4.4 times higher in female rats and appeared to increase in proportion to the dose in both genders. The in vitro half-lives were 18.8 ± 4.45 min and 60.7 ± 11.2 min, as evidenced by incubating liver microsomes obtained from male and female rats, respectively. As a result, the estimated CLint for LB for male rat liver microsomes (0.0779 ± 0.0233 ml/min/mg protein) was much higher than that for female rat liver microsomes (0.0233 ± 0.0039 ml/min/mg protein, p < 0.05). These observations suggest that there are gender differences in the pharmacokinetics and hepatic metabolism for LB in rats. Copyright © 2015 John Wiley & Sons, Ltd.

Structural control of hierarchically-ordered TiO2 films by water for dye-sensitized solar cells.

A facile way of controlling the structure of TiO(2) by changing the amount of water to improve the efficiency of dye-sensitized solar cells (DSSCs) is reported. Hierarchically ordered TiO(2) films with high porosity and good interconnectivity are synthesized in a well-defined morphological confinement arising from a one-step self-assembly of preformed TiO(2) (pre-TiO(2)) nanocrystals and a graft copolymer, namely poly(vinyl chloride)-g-poly(oxyethylene methacrylate). The polymer-solvent interactions in solution, which are tuned by the amount of water, are shown to be a decisive factor in determining TiO(2) morphology and device performance. Systematic control of wall and pore size is achieved and enables the bifunctionality of excellent light scattering properties and easy electron transport through the film. These properties are characterized by reflectance spectroscopy, incident photon-to-electron conversion efficiency, and electrochemical impedance spectroscopy analyses. The TiO(2) photoanode that is prepared with a higher water ratio, [pre-TiO(2)]:[H(2)O]=1:0.3, shows a larger surface area, greater light scattering, and better electron transport, which result in a high efficiency (7.7 %) DSSC with a solid polymerized ionic liquid. This efficiency is much greater than that of commercially available TiO(2) paste (4.0 %).

Preclinical pharmacokinetic characterization of 2-(4-(4-(5-(2-phenyl-5-(trifluoromethyl)oxazole-4-carboxamido)-1H-benzo[d]imidazol-2-yl)phenyl)cyclohexyl) acetic acid, a novel DGAT-1 inhibitor.

1. A novel diacylglyceride acyltransferase-1 (DGAT-1) inhibitor, 2-(4-(4-(5-(2-phenyl-5-(trifluoromethyl) oxazole-4-carboxamido)-1H-benzo[d]imidazol-2-yl)phenyl)cyclohexyl) acetic acid (KR-69232), was synthesized for a potential therapeutic use against several metabolic disorders, such as obesity, insulin resistance, and type II diabetes, characterized by excessive triglycerides (TGs) in the blood. 2. The half-lives against phase I metabolism were measured as 75.3 ± 20.9 min and over 120 min in rat and human liver microsomes, respectively. In Caco-2 cell monolayers, extremely low permeability (<0.13 × 10⁻6cm/s) was seen in the absorptive direction, predicting limited intestinal absorption of KR-69232. This compound was highly bound to rat and human plasma proteins (>99.8%). 3. With the intravenous administration of KR-69232 in rats (1, 2, and 5 mg/kg), non-linear kinetics were observed at the highest dose, with significantly higher systemic clearance, higher volume of distribution, and lower dose-normalized AUC. Following oral administration, it exhibited low bioavailability (<10%) and was absorbed slowly (T(max), 3.8-5.2 h) over the dose range. We also confirmed that considerable KR-69232 remained in the intestine at T(max), demonstrating its limited absorption into the systemic circulation.

Determination of a novel diacylglycerol acyltransferase 1 inhibitor, 2-[4-(4-{5-[2-phenyl-5-(trifluoromethyl) oxazole-4-carboxamido]-1H-benzo[d]imidazol-2-yl} phenyl) cyclohexyl] acetic acid (KR-69232) in rat plasma using liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study.

A liquid chromatography-tandem mass spectrometry method was developed and validated for the quantification of KR-69232, a diacyltransferase 1 inhibitor, in rat plasma. KR-69232 in the concentration range of 0.004-4 µg/mL was linear. The intra-and inter-day precision and accuracy were acceptable (<20%). KR-69232 was stable under various storage and handling conditions. The method was applied successfully in a pharmacokinetic study of KR-69232 in rats.

Quantitative determination of enzalutamide, an anti-prostate cancer drug, in rat plasma using liquid chromatography-tandem mass spectrometry, and its application to a pharmacokinetic study.

This report details a method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) that allows one to determine the concentration of an atypical anticancer drug, enzalutamide, in rat plasma. Specifically, this method involves the addition of an acetonitrile and bicalutamide (internal standard) solution to plasma samples. Following centrifugation of this mixture, an aliquot of the supernatant was directly injected into the LC-MS/MS system. Separation was achieved using a column packed with octadecylsilica (5 µm, 2.1 × 50 mm) with 10 mM ammonium acetate in acetonitrile as the mobile phase; detection was accomplished using MS/MS by multiple-reaction monitoring via an electrospray ionization source. This method demonstrated a linear standard curve (r = 0.997) over a concentration range of 0.001-1 µg/mL, as well as an intra- and inter-assay precision of 2.7 and 5.1%, respectively, and an accuracy range from 100.8 to 105.6%. The lower limit of quantification was 1.0 ng/mL in 50 µL of rat plasma sample. We also demonstrated that this analytical method could be successfully applied to the pharmacokinetic study of enzalutamide in rats.

Macrocyclization strategy for improving candidate profiles in medicinal chemistry.

Macrocycles are defined as cyclic compounds with 12 or more members. In medicinal chemistry, they are categorized based on their core chemistry into cyclic peptides and macrocycles. Macrocycles are advantageous because of their structural diversity and ability to achieve high affinity and selectivity towards challenging targets that are often not addressable by conventional small molecules. The potential of macrocyclization to optimize drug-like properties while maintaining adequate bioavailability and permeability has been emphasized as a key innovation in medicinal chemistry. This review provides a detailed case study of the application of macrocyclization over the past 5 years, starting from the initial analysis of acyclic active compounds to optimization of the resulting macrocycles for improved efficacy and drug-like properties. Additionally, it illustrates the strategic value of macrocyclization in contemporary drug discovery efforts.