Effect of α-Lipoic Acid on the Development of Human Skin Equivalents Using a Pumpless Skin-on-a-Chip Model

Owing to the prohibition of cosmetic animal testing, various attempts have recently been made using skin-on-a-chip (SOC) technology as a replacement for animal testing. Previously, we reported the development of a pumpless SOC capable of drug testing with a simple drive using the principle that the medium flows along the channel by gravity when the chip is tilted using a microfluidic channel. In this study, using pumpless SOC, instead of drug testing at the single-cell level, we evaluated the efficacy of α-lipoic acid (ALA), which is known as an anti-aging substance in skin equivalents, for skin tissue and epidermal structure formation. The expression of proteins and changes in genotyping were compared and evaluated. Hematoxylin and eosin staining for histological analysis showed a difference in the activity of fibroblasts in the dermis layer with respect to the presence or absence of ALA. We observed that the epidermis layer became increasingly prominent as the culture period was extended by treatment with 10 μM ALA. The expression of epidermal structural proteins of filaggrin, involucrin, keratin 10, and collagen IV increased because of the effect of ALA. Changes in the epidermis layer were noticeable after the ALA treatment. As a result of aging, damage to the skin-barrier function and structural integrity is reduced, indicating that ALA has an anti-aging effect. We performed a gene analysis of filaggrin, involucrin, keratin 10, integrin, and collagen I genes in ALA-treated human skin equivalents, which indicated an increase in filaggrin gene expression after ALA treatment. These results indicate that pumpless SOC can be used as an in vitro skin model similar to human skin, protein and gene expression can be analyzed, and it can be used for functional drug tests of cosmetic materials in the future. This technology is expected to contribute to the development of skin disease models.     

Modeling Sialidosis with Neural Precursor Cells Derived from Patient-Derived Induced Pluripotent Stem Cells

Sialidosis, caused by a genetic deficiency of the lysosomal sialidase gene (NEU1), is a systemic disease involving various tissues and organs, including the nervous system. Understanding the neurological dysfunction and pathology associated with sialidosis remains a challenge, partially due to the lack of a human model system. In this study, we have generated two types of induced pluripotent stem cells (iPSCs) with sialidosis-specific NEU1^G227R and NEU1^V275A/R347Q mutations (sialidosis-iPSCs), and further differentiated them into neural precursor cells (iNPCs). Characterization of NEU1^G227R- and NEU1^V275A/R347Q- mutated iNPCs derived from sialidosis-iPSCs (sialidosis-iNPCs) validated that sialidosis-iNPCs faithfully recapitulate key disease-specific phenotypes, including reduced NEU1 activity and impaired lysosomal and autophagic function. In particular, these cells showed defective differentiation into oligodendrocytes and astrocytes, while their neuronal differentiation was not notably affected. Importantly, we found that the phenotypic defects of sialidosis-iNPCs, such as impaired differentiation capacity, could be effectively rescued by the induction of autophagy with rapamycin. Our results demonstrate the first use of a sialidosis-iNPC model with NEU1^G227R- and NEU1^V275A/R347Q- mutation(s) to study the neurological defects of sialidosis, particularly those related to a defective autophagy–lysosome pathway, and may help accelerate the development of new drugs and therapeutics to combat sialidosis and other LSDs.     

Spray pressure variation effect on the properties of CdS thin films for photodetector applications

Herein, we report the photosensing property of CdS thin films. CdS thin films were coated onto glass substrates via a spray pyrolysis method using different spray pressures. Prepared films were characterized using X-ray diffraction (XRD), scanning electron microscopy (SEM), and optical and photoluminescence spectroscopy. XRD analysis demonstrated the growth of crystalline CdS films with crystallite sizes varying from 26 to 29 nm depending on the pressure. The SEM and EDAX analyses revealed nearly-stoichiometric CdS films with smooth surfaces and slight variation in grain morphology due to pressure changes. Optical measurements showed a direct bandgap varying from 2.37 eV to 2.42 eV due to pressure changes. A photodetector was also fabricated using the grown CdS films; the fabricated photodetector exhibited good performance depending on the spray pressure. A spray pressure of 1.5 GPa resulted in high photoresponsivity and external quantum efficiency.     

Inhibition of RANKL-Induced Osteoclastogenesis by Novel Mutant RANKL

Background: Recently, it was reported that leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4, also called GPR48) is another receptor for RANKL and was shown to compete with RANK to bind RANKL and suppress canonical RANK signaling during osteoclast differentiation. The critical role of the protein triad RANK–RANKL in osteoclastogenesis has made their binding an important target for the development of drugs against osteoporosis. In this study, point-mutations were introduced in the RANKL protein based on the crystal structure of the RANKL complex and its counterpart receptor RANK, and we investigated whether LGR4 signaling in the absence of the RANK signal could lead to the inhibition of osteoclastogenesis.; Methods: The effects of point-mutated RANKL (mRANKL-MT) on osteoclastogenesis were assessed by tartrate-resistant acid phosphatase (TRAP), resorption pit formation, quantitative real-time polymerase chain reaction (qPCR), western blot, NFATc1 nuclear translocation, micro-CT and histomorphological assay in wild type RANKL (mRANKL-WT)-induced in vitro and in vivo experimental mice model. Results: As a proof of concept, treatment with the mutant RANKL led to the stimulation of GSK-3β phosphorylation, as well as the inhibition of NFATc1 translocation, mRNA expression of TRAP and OSCAR, TRAP activity, and bone resorption, in RANKL-induced mouse models; and Conclusions: The results of our study demonstrate that the mutant RANKL can be used as a therapeutic agent for osteoporosis by inhibiting RANKL-induced osteoclastogenesis via comparative inhibition of RANKL. Moreover, the mutant RANKL was found to lack the toxic side effects of most osteoporosis treatments.     

Diphenyl-Methane Based Thyromimetic Inhibitors for Transthyretin Amyloidosis

Thyromimetics, whose physicochemical characteristics are analog to thyroid hormones (THs) and their derivatives, are promising candidates as novel therapeutics for neurodegenerative and metabolic pathologies. In particular, sobetirome (GC-1), one of the initial halogen-free thyromimetics, and newly synthesized IS25 and TG68, with optimized ADME-Tox profile, have recently attracted attention owing to their superior therapeutic benefits, selectivity, and enhanced permeability. Here, we further explored the functional capabilities of these thyromimetics to inhibit transthyretin (TTR) amyloidosis. TTR is a homotetrameric transporter protein for THs, yet it is also responsible for severe amyloid fibril formation, which is facilitated by tetramer dissociation into non-native monomers. By combining nuclear magnetic resonance (NMR) spectroscopy, computational simulation, and biochemical assays, we found that GC-1 and newly designed diphenyl-methane-based thyromimetics, namely IS25 and TG68, are TTR stabilizers and efficient suppressors of TTR aggregation. Based on these observations, we propose the novel potential of thyromimetics as a multi-functional therapeutic molecule for TTR-related pathologies, including neurodegenerative diseases.     

Bi-templated grain growth maximizing the effects of texture on piezoelectricity

Templated grain growth is beneficial for piezoelectric materials, the properties of which become the best in their single crystalline form. Nevertheless, a textured ceramic prepared by a templated grain growth technique often fails in exhibiting as good properties as expected in single crystals even with a high degree of orientation factor. Here, we propose a new strategy for maximizing texturing effect by suppressing the growth of untextured matrix grains. The textured ceramics made by our method, so-called bi-templated grain growth, are featured by ultrahigh piezoelectric properties (d₃₃ = ～1,031 pC/N, d?g = ～59,000, k_p = ～0.76). A special emphasis is on the achieved electric-field-induced strain of 0.13 % at 1 kV/mm, which is as high as that of single crystals. This work demonstrates that not only the degree of texture but also the coarsening of untextured matrix grains should be well-controlled to best exploit the templated grain growth technique.     

Low thermal conductivity in porous SiC–SiO2–Al2O3–TiO2 ceramics induced by multiphase thermal resistance

The introduction of multiple heterogeneous interfaces in a ceramic is an efficient way to increase its thermal resistance. Novel porous SiC–SiO₂–Al₂O₃–TiO₂ (SSAT) ceramics were fabricated to achieve multiple heterogeneous interfaces by sintering equal volumes of SiC, SiO₂, Al₂O₃, and TiO₂ compacted powders with polysiloxane as a bonding phase and carbon as a template at 600 °C in air. The porosity could be controlled between 66% and 74% by adjusting the amounts of polysiloxane and the carbon template. The lowest thermal conductivity (0.059 W/(m·K) at 74% porosity) obtained in this study is an order of magnitude lower than those (0.2–1.3 W/(m·K)) of porous monolithic SiC, SiO₂, Al₂O₃, and TiO₂ ceramics at an equivalent porosity. The typical specific compressive strength value of the porous SSAT ceramics at 74% porosity was 3.2 MPa cm³/g.     

Self-healing capacity of Mullite-Yb2SiO5 environmental barrier coating material with embedded Ti2AlC MAX phase particles

Repetitive heating and cooling cycles inevitably cause crack damage of hot gas components of gas turbine engines, such as blades and vanes. In this study the self-healing capacity is investigated of mullite + ytterbium monosilicate (Yb₂SiO₅) as EBC material with Ti₂AlC MAX phase particles embedded as a crack-healing agent. The effect of Ti₂AlC in the EBC was compared with the self-healing ability of the mullite + Yb₂SiO₅ material. After introducing cracks by Vickers indentation on the surface of each sample, crack healing was realized by controlling the temperature and time during the post-heat-treatment process. For the mullite + Yb₂SiO₅ composite with Ti₂AlC particles, crack healing occurred at 1000 °C, while in the case of the mullite + Yb₂SiO₅ composite without Ti₂AlC, a sustained temperature of 1300 °C or higher was required. Compared with the healing of the mullite + Yb₂SiO₅ composite by the formation of a eutectic phase, the addition of Ti₂AlC promoted healing via the oxidation of Ti and Al. Notably, the surface formation of a ternary oxide of Ti–Yb–O was confirmed, which completely covered the damage area. Consequently, the addition of a Ti₂AlC MAX phase to the EBC composite resulted in a complete strength recovery, while the mullite + Yb₂SiO₅ composite without Ti₂AlC showed a strength recovery of about 80%. Furthermore, by analyzing the indentation load–displacement curve to indicate the role of Ti₂AlC, the addition of Ti₂AlC improved both the hardness and stiffness of the composite.     

Lithiophilic MXene-Guided Lithium Metal Nucleation and Growth Behavior

The positive effects of a lithiophilic substrate on the electrochemical performance of lithium metal anodes are confirmed in several reports, while the understanding of lithiophilic substrate-guided lithium metal nucleation and growth behavior is still insufficient. In this study, the effect of a lithiophilic surface on lithium metal nucleation and growth behaviors is investigated using a large-area Ti₃C₂T_x MXene substrate with a large number of oxygen and fluorine dual heteroatoms. The use of the MXene substrate results in a high lithium-ion concentration as well as the formation of uniform solid–electrolyte-interface (SEI) layers on the lithiophilic surface. The solid–solid interface (MXene-SEI layer) significantly affects the surface tension of the deposited lithium metal nuclei as well as the nucleation overpotential, resulting in the formation of uniformly dispersed lithium nanoparticles ( ≈ 10–20 nm in diameter) over the entire MXene surface. The primary lithium nanoparticles preferentially coalesce and agglomerate into larger secondary particles while retaining their primary particle shapes. Subsequently, they form close-packed structures, resulting in a dense metal layer composed of particle-by-particle microstructures. This distinctive lithium metal deposition behavior leads to highly reversible cycling performance with high Columbic efficiencies >  99.0% and long cycle lives of over 1000 cycles.