Design, synthesis, and evaluation of N1,N3-dialkyldioxonaphthoimidazoliums as antibacterial agents against methicillin-resistant Staphylococcus aureus.

Increasing antibiotic resistance of bacterial pathogens poses a serious threat to human health worldwide. Methicillin-resistant Staphylococcus aureus (MRSA) is among the most deleterious bacterial pathogens owing to its multidrug resistance, necessitating the development of new antibacterial agents against it. We previously identified a novel dioxonaphthoimidazolium agent, c5, with moderate antibacterial activity against MRSA from an anticancer clinical candidate, YM155. In this study, we aimed to design and synthesize several novel cationic amphiphilic N1,N3-dialkyldioxonaphthoimidazolium bromides with enhanced lipophilicity of the two side chains in the imidazolium scaffold and improved antibacterial activities compared to those of c5 against gram-positive bacteria in vitro and in vivo. Our new antibacterial lead, N1,N3-n-octylbenzyldioxonaphthoimidazolium bromide (11), exhibited highly potent antibacterial activities against various gram-positive bacterial strains (MICs: 0.19-0.39 µg/mL), including MRSA, methicillin-sensitive S. aureus, and Bacillus subtilis. Moreover, antibacterial mechanism of 11 against MRSA based on the generation of reactive oxygen species (ROS) was evaluated. Although compound 11 exhibited cytotoxic effects in vitro and lacked a therapeutic index against the HEK293 and HDFa mammalian cell lines, it exhibited low toxicity in the Drosophila animal model. Remarkably, 11 exhibited better in vivo antibacterial efficacy than c5 and the clinically used antibiotic, vancomycin, in SA3-infected Drosophila model. Moreover, the development of bacterial resistance to 11 was not observed after 16 consecutive passages. Therefore, rational design of antibacterial cationic amphiphiles based on ROS-generating pharmacophores with optimized lipophilicity can facilitate the identification of potent antibacterial agents against drug-resistant infections.

Development and Evaluation of Self-Microemulsifying Drug Delivery System for Improving Oral Absorption of Poorly Water-Soluble Olaparib.

The purpose of this study is to develop and evaluate a self-microemulsifying drug delivery system (SMEDDS) to improve the oral absorption of poorly water-soluble olaparib. Through the solubility test of olaparib in various oils, surfactants and co-surfactants, pharmaceutical excipients were selected. Self-emulsifying regions were identified by mixing the selected materials at various ratios, and a pseudoternary phase diagram was constructed by synthesizing these results. The various physicochemical properties of microemulsion incorporating olaparib were confirmed by investigating the morphology, particle size, zeta potential, drug content and stability. In addition, the improved dissolution and absorption of olaparib were also confirmed through a dissolution test and a pharmacokinetic study. An optimal microemulsion was generated in the formulation of Capmul® MCM 10%, Labrasol® 80% and PEG 400 10%. The fabricated microemulsions were well-dispersed in aqueous solutions, and it was also confirmed that they were maintained well without any problems of physical or chemical stability. The dissolution profiles of olaparib were significantly improved compared to the value of powder. Associated with the high dissolutions of olaparib, the pharmacokinetic parameters were also greatly improved. Taken together with the results mentioned above, the microemulsion could be an effective tool as a formulation for olaparib and other similar drugs.

Shape Memory Alloy (SMA) Actuators: The Role of Material, Form, and Scaling Effects.

Shape memory alloys (SMAs) are smart materials that are widely used to create intelligent devices because of their high energy density, actuation strain, and biocompatibility characteristics. Given their unique properties, SMAs are found to have significant potential for implementation in many emerging applications in mobile robots, robotic hands, wearable devices, aerospace/automotive components, and biomedical devices. Here, the state-of-the-art of thermal and magnetic SMA actuators in terms of their constituent materials, form, and scaling effects are summarized, including their surface treatments and functionalities. The motion performance of various SMA architectures (wires, springs, smart soft composites, and knitted/woven actuators) is also analyzed. Based on the assessment, current challenges of SMAs that need to be addressed for their practical application are emphasized. Finally, how to advance SMAs by synergistically considering the effects of material, form, and scale is suggested.

Effect of fiber entanglement in chopped glass fiber reinforced composite manufactured via long fiber spray-up molding.

Long Fiber Spray-up Molding (LFSM) deviates from the conventional approach in liquid composite molding (LCM) processes by utilizing extremely long chopped strands of fibers as the primary reinforcement material in its fabrication process. In LFSM, chopped fibers are impregnated with resin that is sprayed vertically downwards before reaching the mold surface. The spraying mechanism is mounted on an actuator, which is capable of spraying freely in any specified pattern or direction. Under LFSM, it is extremely difficult to fabricate a composite part with uniformly distributed fiber content throughout its volume. The consequences of the non-uniform fiber volume distribution arise from the fiber entanglement as the length of the fiber reaches up to 100 mm in LFSM. In this study, the effect of fiber entanglement during LFSM was analyzed through various approaches. This included measuring the coefficient of friction between fibers in contact and examining the correlation between fiber lengths and the number of intersections. Furthermore, the viscoelastic properties of the uncured composite part were assessed by experimenting with the influence of viscosity on fiber length during compression molding. The results were then computed, modeled, and visualized in MATLAB, considering variations in viscosity and fiber length, both before and after compression molding.

All-in-One Process for Mass Production of Membrane-Type Carbon Aerogel Electrodes for Solid-State Rechargeable Zinc-Air Batteries.

This study presents a mass-production process for conductive carbon membrane-type sponge electrodes derived from recyclable cellulose biowaste. It includes an all-in-one hydrogel fabrication process for mass production, which significantly shortens the complex and expensive process for the conventional process of catalytic electrodes based on conductive supporting substrates such as the gas diffusion layer (GDL). The presence of pre-adsorbed melamine powder in the all-in-one hydrogel induces internal diffusion of the gaseous reactant for the uniform growth of carbon nanotubes (CNTs) onto the sponge-like porous carbon aerogel with a relatively thick and tortuous pore structure, thereby providing the electrochemical properties and mechanical strength simultaneously required for the air electrodes of rechargeable and quasi solid-state zinc-air batteries.

Improved performance of stretchable piezoelectric energy harvester based on stress rearrangement.

With the development of wearable devices and soft electronics, the demand for stretchable piezoelectric energy harvesters (SPEHs) has increased. Energy harvesting can provide energy when large batteries or power sources cannot be employed, and stretchability provides a user-friendly experience. However, the performance of SPEHs remains low, which limits their application. In this study, a wearable SPEH is developed by adopting a kirigami structure on a polyvinylidene fluoride film. The performance of the SPEH is improved by rearranging the stress distribution throughout the film. This is conducted using two approaches: topological depolarization, which eliminates the opposite charge generation by thermal treatment, and optimization of the neutral axis, which maximizes the stress applied at the surface of the piezoelectric film. The SPEH performance is experimentally measured and compared with that of existing SPEHs. Using these two approaches, the stress was rearranged in both the x-y plane and z-direction, and the output voltage increased by 21.57% compared with that of the original film with the same stretching motion. The generated energy harvester was successfully applied to smart transmittance-changing contact lenses.

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.

Fast dissolving nanofiber mat for the local antimicrobial application of roxithromycin in oral cavity.

Fast disintegrating and dissolving nanofiber (NF) mat was devised to deliver roxithromycin for the treatment of the respiratory tract infection. NF membrane was made by an electrospinning process with poly(vinyl alcohol) (PVA), hydroxypropyl-ß-cyclodextrin (HP-ß-CD), and d-α-tocopheryl polyethylene glycol succinate (TPGS) for local application of roxithromycin. Roxithromycin has a poor water solubility thus HP-ß-CD is introduced for enhancing drug solubility by forming an inclusion complex in this study. The addition of TPGS provided multiple roles such as accelerating wetting, disintegration, and dissolution speed and overcoming bacterial resistance. Roxithromycin was successfully entrapped in NF structure and drug amorphization occurred during the electrospinning process. PVA/HP-ß-CD/TPGS/roxithromycin (PHTR) NF exhibited faster wetting, disintegration, and dissolution speed rather than the other NF mats. PHTR NF displayed higher antibacterial potentials in Gram-negative bacteria (E. coli) and Gram-positive bacteria (S. aureus) compared to other NF mat formulations. The administration of PHTR NF to oral cavity in pneumococcal disease mouse model provided the most efficient therapeutic potentials in lung tissue. Designed multiple phase-based NF mat may be one of powerful local drug delivery systems for the therapy of respiratory tract infection.

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.

Shape memory alloy-driven undulatory locomotion of a soft biomimetic ray robot.

The objective of this study was to imitate undulatory motion, which is a commonly observed swimming mechanism of rays, using a soft morphing actuator. To achieve the undulatory motion, an artificial muscle built with shape memory alloy-based soft actuators was exploited to control the shape-changing behavior of a soft fin membrane. Artificial undulating fins were divided into two categories according to the method of generating the wave motion: single and multiple actuator-driven fins. For empirical research on the transformation and propulsion behavior of each fin type, the design and construction of bound propulsors were undertaken to mimic the structural and behavioral aspects of animals. To visualize the effect of undulatory motion on the swimming efficiency test of the fin beat frequency, a simplified soft undulating fin with a rectangular propulsor was constructed and tested. Additionally, dynamic modeling of the fin tip in wave-traveling was conducted for comparison and optimization. To optimize the thrust and propulsion efficiency of robot speed, the effects of the wave amplitude control and actuator sequence on the fin behavior were examined. An untethered robot was constructed according to the experimental results of the propulsors. Both exhibited exceptional swimming efficiency and maneuverability. The multiple actuator-driven ray robot exhibited a maximum swimming speed of 0.25 body lengths per second which is almost a similar swimming speed with previously reported robots. The developed robot achieved directional swimming (forward and backward) and turning (including rotation). Underwater exploration in an artificial environment was performed using the robot.

Deposition of Durable Micro Copper Patterns into Glass by Combining Laser-Induced Backside Wet Etching and Laser-Induced Chemical Liquid Phase Deposition Methods.

Glass is a well-known non-conductive material that has many useful properties, and considerable research has been conducted into making circuits on glass. Many deposition techniques have been studied, and laser-induced chemical liquid phase deposition (LCLD) is a well-known and cost-effective method for rapid prototyping of copper deposition on glass. However, the deposition results from the LCLD method on the surface of glass, which shows an issue in its detachment from the substrates because of the relatively low adhesion between deposited copper and the nontreated glass surface. This problem undermines the usability of deposited glass in industrial applications. In this study, the laser-induced backside wet etching (LIBWE) method was performed as a preceding process to fabricate microchannels, which were filled with copper by LCLD. Additional durable copper wire was produced as a result of the enhanced adhesion between the glass and the deposited copper. The adhesion was enhanced by a rough surface and metal layer, which are characteristics of LIBWE machining. Furthermore, the proposed method is expected to broaden the use of deposited glass in industrial applications, such as in stacked or covered multilayer structures with built-in copper wires, because the inserted copper can be physically protected by the microstructures.

Directly Printed Low-Cost Nanoparticle Sensor for Vibration Measurement during Milling Process.

A real-time, accurate, and reliable process monitoring is a basic and crucial enabler of intelligent manufacturing operation and digital twin applications. In this study, we represent a novel vibration measurement method for workpiece during the milling process using a low-cost nanoparticle vibration sensor. We directly printed the vibration sensor based on silver nanoparticles positioned onto a polyimide substrate using an aerodynamically-focused nanomaterials printing system, which is a direct printing technique for inorganic nanomaterials positioned onto a flexible substrate. Since it does not require any post-process such as chemical etching and heat treatment, a highly sensitive vibration sensor composed of a microscale porous structure was fabricated at a cost of several cents each. Furthermore, accurate and reliable vibration data was obtained by simple and direct attachment to a workpiece. In this study, we discussed the performance of vibration measurement of a fabricated sensor in comparison to a commercial vibration sensor. Using frequency and power spectrum analysis of obtained data, we directly measured the vibration of workpiece during the milling process, according to a process parameter. Lastly, we applied a fabricated sensor for the digital twins of turbine blade manufacturing in which vibration greatly affects the quality of the product to predict the process defects in real-time.

Potential Moracin M Prodrugs Strongly Attenuate Airway Inflammation In Vivo.

This study aims to develop new potential therapeutic moracin M prodrugs acting on lung inflammatory disorders. Potential moracin M prodrugs (KW01-KW07) were chemically synthesized to obtain potent orally active derivatives, and their pharmacological activities against lung inflammation were, for the first time, examined in vivo using lipopolysaccharide (LPS)-induced acute lung injury model. In addition, the metabolism of KW02 was also investigated using microsomal stability test and pharmacokinetic study in rats. When orally administered, some of these compounds (30 mg/kg) showed higher inhibitory action against LPSinduced lung inflammation in mice compared to moracin M. Of them, 2-(3,5-bis((dimethylcarbamoyl)oxy)phenyl)benzofuran-6-yl acetate (KW02) showed potent and dose-dependent inhibitory effect on the same animal model of lung inflammation at 1, 3, and 10 mg/kg. This compound at 10 mg/kg also significantly reduced IL-1ß concentration in the bronchoalveolar lavage fluid of the inflamed-lungs. KW02 was rapidly metabolized to 5-(6-hydroxybenzofuran-2-yl)-1,3-phenylene bis(dimethylcarbamate) (KW06) and moracin M when it was incubated with rat serum and liver microsome as expected. When KW02 was administered to rats via intravenous or oral route, KW06 was detected in the serum as a metabolite. Thus, it is concluded that KW02 has potent inhibitory action against LPS-induced lung inflammation. It could behave as a potential prodrug of moracin M to effectively treat lung inflammatory disorders.

Stretchable Biaxial and Shear Strain Sensors Using Diffractive Structural Colors.

Structural colors that can be changed dynamically, using either plasmonic nanostructures or photonic crystals, are rapidly emerging research areas for stretchable sensors. Despite the wide applications of various techniques to achieve strain-responsive structural colors, important factors in the feasibility of strain sensors-such as their sensing mechanism, stability, and reproducibility-have not yet been explored. Here, we introduce a stretchable, diffractive, color-based wireless strain sensor that can measure strain using the entire visible spectrum, based on an array of cone-shaped nanostructures on the surface of an elastomeric substrate. By stretching or compressing the substrate, the diffractive color can be tuned according to the changing grating pitch. Using the proposed method, we designed three types of strain-sensing modes: large-deformation (maximum 100%) tensile strain, biaxial 2D strain, and shear strain (maximum 78%). The strain sensors were fabricated, and applicability to strain-sensing was evaluated.

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.

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.

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.

Shape Memory Alloy-Based Soft Finger with Changeable Bending Length Using Targeted Variable Stiffness.

This work described a bioinspired soft robotic finger with variable bending length to conform objects with different sizes by means of selectively varying the structural stiffness of its segments. The basic design is a shape memory alloy-based soft actuator with embedded stiffness-varying structures serving as modifiable endoskeletons. The stiffness-varying structure is composed of shape memory polymer (SMP) embedded with Nichrome (Ni-Cr) wires as heating elements. Joule heating of SMP through Ni-Cr wire inducing its phase change from the glassy state to the rubbery state enables the actuator structure change from the stiff state (E = 125.65 MPa) to the compliant state (E = 3.33 MPa). The Ni-Cr wire was designed with multiple solder tabs to enable the SMP that can be heated segmentally leading to the stiffness reduction of desired segments of finger to obtain different bendable lengths. A finger with three segments was fabricated, and its deformation and actuation force were measured based on different bendable lengths. A gripper was then assembled using two identical fingers where the angle between them can be manually adjusted. The angles for the two fingers with specific bending length were determined to enable them to form a closed configuration when maximum bending is reached. The grasping force of the gripper was then measured, and it was used to grip different objects. Results show that the performance of the gripper in gripping the size and weight of the object was markedly improved compared with the gripper that cannot vary its gripping length.