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Background/Objectives: TREM2 is a transmembrane receptor highly expressed in microglia and macrophages, and its involvement in Alzheimer’s disease, obesity, and cancer has garnered significant attention. Although its biological function has been actively investigated, the mechanisms by which its expression is regulated remain incompletely characterized. In this study, we aimed to identify transcription factors that modulate TREM2 expression among those reported to be expressed in microglia. Methods: We inserted a 5 kb upstream region of TREM2 into a luciferase reporter vector. This construct was co-expressed with 15 transcription factors, and the TREM2 transcriptional activity was evaluated using luciferase assays. The most promising transcription factor was subsequently knocked down in HMC3 cells, which are derived from human microglia, to assess its effect on endogenous TREM2 expression. Results: Among the 15 transcription factor candidates tested, SPI1 (PU.1), MAFB, CEBPA, ZEB2, and SALL1 most strongly enhanced TREM2 transcriptional activity. ZEB2 was prioritized due to its limited study in microglia and higher co-expression with TREM2. In HMC3 cells, ZEB2 knockdown reduced both TREM2 mRNA and protein levels. Further analysis using domain-deleted mutants of ZEB2 indicated that the zinc finger domains are essential for its transcriptional activity. Analysis using truncated mutants of the TREM2 upstream region suggests that ZEB2 acts on multiple sites within this region. Chromatin immunoprecipitation also suggested an interaction between ZEB2 and the upstream region of TREM2. Conclusions: This study novelly suggests ZEB2 as a transcription factor that promotes TREM2 expression. Further investigation into the role of ZEB2 in various TREM2-associated diseases is warranted.

Microphysiological systems (MPS) are an emerging technology for next-generation drug screening in non-clinical tests. Microphysiological systems are microfluidic devices that reconstitute the physiological functions of a human organ using a three-dimensional in vivo-mimicking microenvironment. In the future, MPSs are expected to reduce the number of animal experiments, improve prediction methods for drug efficacy in clinical settings, and reduce the costs of drug discovery. However, drug adsorption onto the polymers used in an MPS is a critical issue for assessment because it changes the concentration of the drug. Polydimethylsiloxane (PDMS), a basic material used for the fabrication of MPS, strongly adsorbs hydrophobic drugs. As a substitute for PDMS, cyclo-olefin polymer (COP) has emerged as an attractive material for low-adsorption MPS. However, it has difficulty bonding with different materials and, therefore, is not commonly used. In this study, we assessed the drug adsorption properties of each material constituting an MPS and subsequent changes in drug toxicity for the development of a low-adsorption MPSs using COP. The hydrophobic drug cyclosporine A showed an affinity for PDMS and induced lower cytotoxicity in PDMS-MPS but not in COP-MPS, whereas adhesive tapes used for bonding adsorbed a significant quantity of drugs, lowering their availability, and was cytotoxic. Therefore, easily-adsorbed hydrophobic drugs and bonding materials having lower cytotoxicity should be used with a low-adsorption polymer such as COP.

Of late, numerous microphysiological systems have been employed to model the renal proximal tubule. Yet there is lack of research on refining the functions of the proximal tubule epithelial layer—selective filtration and reabsorption. In this report, pseudo proximal tubule cells extracted from human-induced pluripotent stem cell-derived kidney organoids are combined and cultured with immortalized proximal tubule cells. It is shown that the cocultured tissue is an impervious epithelium that offers improved levels of certain transporters, extracellular matrix proteins collagen and laminin, and superior glucose transport and P-glycoprotein activity. mRNA expression levels higher than those obtained from each cell type were detected, suggesting an anomalous synergistic crosstalk between the two. Alongside, the improvements in morphological characteristics and performance of the immortalized proximal tubule tissue layer exposed, upon maturation, to human umbilical vein endothelial cells are thoroughly quantified and compared. Glucose and albumin reabsorption, as well as xenobiotic efflux rates through P-glycoprotein were all improved. The data presented abreast highlight the advantages of the cocultured epithelial layer and the non-iPSC-based bilayer. The in vitro models presented herein can be helpful in personalized nephrotoxicity studies. A microfluidic device can help analyse the functions of pseudo proximal tubule cells coming from hiPSC-derived kidney organoids, with the future potential for applications in personalized nephrotoxicity studies.

This paper proposes a method for alloy composition screening using the creep property of a single crystal (SC) for designing new Ni-base powder metallurgy (P/M) turbine disc superalloys. A commercial Ni-base disc alloy, U720Li®, a Ni-Co-base disc alloy, TMW-4M3, and a Ni-base conventionally cast alloy, TM-47, were selected for investigation. Their SC and P/M samples were prepared such that their γ/γ′ structures were similar. Moreover, tensile creep tests were performed on SC samples, and compressive creep tests were performed on SC and P/M samples. The tensile creep test results of SC samples at 1073 K (800 °C) and 735 MPa indicate that 0.2 and 1 pct creep times, as well as rupture life, are long in the order of TM-47 SC, TMW-4M3 SC, and U720Li SC. These results simulate the intragranular creep resistances of the corresponding P/M alloys. Furthermore, there is no significant difference in 0.2 and 1 pct compressive creep times between the SC and P/M samples of each alloy. Additionally, the 0.2 and 1 pct creep times of tensile and compressive creep tests of every alloy had an identical order. Therefore, alloy composition screening using SC creep property enables the design of new disc alloys with excellent creep resistance.

In this study, we investigated the creep deformation mechanism of a single-crystal high-entropy superalloy (HESA) with the spherical γ′ precipitates at 760 °C. Before the creep tests, long-term aging tests at 760 °C without load were conducted, which showed Ostwald ripening of the secondary γ′ precipitates up to 50 h. The creep tests revealed that in the range of 500 and 600 MPa at 760 °C, the creep deformation mechanism of HESA was independent of applied stress in both the primary and secondary creep regions. The deformation mechanism of HESA was further investigated under the condition of 760 °C and 520 MPa by performing creep interrupted tests and microstructural analysis. Scanning electron microscope observation showed elongated γ′ precipitates along the applied stress axis near the ruptured surface. This could have been caused by the multi-slip around preceded by the lattice rotation into along the tensile axis, which was confirmed by the electron backscatter diffraction analysis. Transmission electron microscope observation of the creep interrupted and ruptured specimens showed bypass and climb motion of dislocations in the 2-h interrupted, shearing of the γ′ precipitates by the paired straight dislocations in the 50-h interrupted, and shearing of the γ′ precipitates by both the straight and the curved paired dislocations in the ruptured specimens, respectively. The secondary γ′ precipitates do not affect creep behavior as long as the deformation mechanism is a bypass and climb motion of dislocations.

The effect of solution heat treatment as well as primary and secondary aging treatment conditions on the microstructural evolution of a high-entropy superalloy was investigated. The as-cast sample shows coarsened γ′ precipitates and other extra phases at interdendrite region due to microsegregation. This microsegregation makes γ′ solvus unclear and decreases the solidus. After conducting the solution treatment determined in this study, primary aging conditions showing an aligned cubic γ′ phase at 1050 °C for 4 h and random spherical γ′ precipitates at 950 °C for 20 h in similar size were found. By using both samples, secondary aging conditions showing coarsened secondary γ′ precipitates and γ particles inside the γ′ precipitates at 800 °C for 20 h and fine secondary γ′ precipitates at 850 and 870 °C for 20 h were found.

Although brain disorders are not the main indication for radon therapy, our previous study suggested that radon inhalation therapy might mitigate brain disorders. In this study, we assessed whether radon inhalation protects against transient global cerebral ischemic injury in gerbils. Gerbils were treated with inhaled radon at a concentration of 2,000 Bq/m 3 for 24 h. After radon inhalation, transient global cerebral ischemia was induced by bilateral occlusion of the common carotid artery. Results showed that transient global cerebral ischemia induced neuronal damage in hippocampal CA1, and the number of damaged neurons was significantly increased compared with control. However, radon treatment inhibited ischemic damage. Superoxide dismutase (SOD) activity in the radon-treated gerbil brain was significantly higher than that in sham-operated gerbils. These findings suggested that radon inhalation activates antioxidative function, especially SOD, thereby inhibiting transient global cerebral ischemic injury in gerbils.

The effect of Pb on the creep properties of Ni-base single crystal superalloy was evaluated and compared with the reference data of polycrystalline superalloys. Alloy variants containing 0.04 (no Pb added), 0.9, and 31 ppm of Pb were prepared, and creep tests under different temperatures and stresses (i.e., 800/735, 900/392, 1000/245, 1100/137, and 1150 °C/137 MPa) as well as microstructural observations were conducted. The initial microstructure, such as the γ′ size and volume fraction of γ′, and the γ/γ′ microstructure after the creep test, such as the extent of raft structure formation, were almost identical in all the alloy variants. Moreover, the extent of topologically close-packed or precipitate phase formation could not be correlated with the Pb content. Based on these results and those of the creep tests, it was concluded that Pb did not affect the creep rupture life. In single crystal superalloy, no grain boundary exists, and the results of the field-emission electron-probe microanalysis indicated that Pb was dispersed in the substrate and its segregation did not occur during the creep test. Thus, in contrast to the Ni-base polycrystalline superalloy, no negative effect of Pb on the creep properties of the Ni-base single crystal superalloy was detected.

This study evaluated the feasibility and efficacy of three postoperative adjuvant chemotherapy regimens for endometrial cancer. Endometrioid cancer patients with intermediate‐risk stage I and II or high‐risk stage III and IV disease were randomly assigned to receive six cycles of either paclitaxel‐epirubicin‐carboplatin (TEC), paclitaxel‐anthracycline (doxorubicin)‐carboplatin (TAC), or dose‐dense paclitaxel‐carboplatin (ddTC). The primary end‐point was the completion rate (CRate) of six cycles of treatment. The secondary end‐points were progression‐free survival (PFS) and overall survival (OS). One hundred and one patients were treated as follows: 33 received TEC, 33 TAC, and 35 ddTC. The CRates for TEC, TAC, and ddTC were 94%, 64%, and 69%, respectively (P = .005). The TEC CRate was significantly higher than for the other two groups. However, the PFS and OS outcomes were not statistically different between the three groups. The 2‐year survival rates were 94%, 97%, and 97% for TEC, TAC, and ddTC, respectively. When compared to the current standard treatments for endometrial cancer, TEC is a promising candidate for a phase III trial based on its significantly superior CRate and equivalent PFS and OS. This study is registered with UMIN Clinical Trials Registry (UMIN000008911). We undertook a randomized phase II study for advanced endometrial carcinoma and showed that the completion rate of TEC (paclitaxel and epirubicin plus carboplatin) was significantly higher than for the other two groups, TAC (paclitaxel and adriamycin plus carboplatin) and ddTC (dose‐dense paclitaxel‐carboplatin).

A brain atlas is necessary for analyzing structure and function in neuroimaging research. Although various annotation volumes (AVs) for the mouse brain have been proposed, it is common in magnetic resonance imaging (MRI) of the mouse brain that regions-of-interest (ROIs) for brain structures (nodes) are created arbitrarily according to each researcher’s necessity, leading to inconsistent ROIs among studies. One reason for such a situation is the fact that earlier AVs were fixed, i.e. combination and division of nodes were not implemented. This report presents a pipeline for constructing a flexible annotation atlas (FAA) of the mouse brain by leveraging public resources of the Allen Institute for Brain Science on brain structure, gene expression, and axonal projection. A mere two-step procedure with user-specified, text-based information and Python codes constructs FAA with nodes which can be combined or divided objectively while maintaining anatomical hierarchy of brain structures. Four FAAs with total node count of 4, 101, 866, and 1381 were demonstrated. Unique characteristics of FAA realized analysis of resting-state functional connectivity (FC) across the anatomical hierarchy and among cortical layers, which were thin but large brain structures. FAA can improve the consistency of whole brain ROI definition among laboratories by fulfilling various requests from researchers with its flexibility and reproducibility.