Disco (japan)

In this work, an attempt was made to optimize the process of synthesizing diamond powders without metal catalysts at high pressures and temperatures and to determine the features of diamond crystallization in C–O–H fluid. For this purpose, a comparative study of diamond powders synthesized at a pressure of 7.5 GPa from a mixture of carbon black (55wt%) with pentaerythritol (45wt%) and the same mixture modified with detonation nanodiamonds (DNDs) (5wt%) was carried out. The addition of DND leads to the formation of aggregates with a size of ∼10 μm, consisting of high quality diamond crystals with a size of ∼0.5–3 µm, and a decrease in the synthesis temperature from ∼1600 to ∼1500 °C. The addition of DNDs into the reaction medium has no effect on the concentration of N0, N2 and NV– centers in the synthesized diamonds, while the content of N3VH0 increases.

This work addresses the issue of the convergence of an $N$-player game towards a limit model involving a continuum of players, as the number of agents $N$ goes to infinity. More precisely, we investigate the convergence of Nash equilibria to a Cournot--Nash equilibrium of the limit model. When the cost function of the players is the first variation of some potential function, equilibria can be characterized by a stationarity condition, satisfied in particular by the minimizers of the potential. We demonstrate such a characterization under low regularity assumptions. Then we focus on the case where the players interact in a pairwise fashion; in this case we show that the original sequence of $N$-player games also admit a potential structure and prove that their corresponding potential functions converge in the sense of $Γ$-convergence to the potential function of the limit game.

Abstract Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by excessive matrix deposition and vascular dysfunction. Vascular abnormalities, including aberrant angiogenesis and vascular leak have been shown to accompany IPF progression. Recent findings from our group and others have revealed a marked heterogeneity within the lung vasculature, yet the specific contribution of distinct endothelial cell (EC) subpopulations to IPF pathogenesis remains unclear. We reported the expansion of venous ECs (VECs) expressing atypical chemokine receptor 1 (ACKR1) in mouse lungs with progressive fibrosis and in human IPF lungs. Here, we sought to investigate the role of ACKR1+VEC remodeling following lung injury and explore ACKR1-associated signaling pathways in lung fibrosis pathogenesis. Methods: We analyzed scRNA-seq datasets from bleomycin-treated mouse lungs and human IPF lungs. Additionally, we carried out spatial transcriptomic analysis on human IPF lungs exhibiting different degree of fibrosis. Immunohistochemistry was performed to validate gene expression at the protein level. ACKR1+VECs were isolated using MACS and characterized by qPCR and Western blot. Finally, co-cultures of ACKR1+VECs with lung fibroblasts were carried out to assess the paracrine effect of ACKR1+VECs. Results: scRNA-seq analysis showed that ACKR1 was selectively expressed in an expanding population of VECs in bleomycin-treated and human IPF lungs. Transcriptional analysis revealed that ACKR1+VECs expressed high levels of genes associated with glycolysis, hypoxia, and immune cell recruitment. Spatial transcriptomics coupled with immunohistochemistry analysis of IPF lungs demonstrated that ACKR1+VECs were surrounded by CD45+ immune cells, suggesting a role of these VECs in immune cell recruitment. ACKR1+VECs were primarily located around airways as well as in distal alveolar regions exhibiting fibroblastic foci and aberrant basaloid cell accumulation, indicating cross communications between these pathogenic cells. In vitro analysis of freshly isolated IPF-derived ACKR1+VECs showed elevated expression of pro-fibrotic genes compared to ACKR1 negative (ACKR1-) ECs. Strikingly, co-culture of ACKR1+VECs with lung fibroblasts resulted in a strong upregulation of profibrotic genes and enhanced contractility relative to ACKR1-ECs. Conclusion: ACKR1+VECs are spatially restricted to lung areas exhibiting immune cell aggregation, fibroblastic foci, and aberrant basaloid cells in fibrotic lungs supporting their profibrotic function. IPF-derived ACKR1+VECs promote fibroblast activation in vitro, suggesting that ACKR1+VEC expansion contributes to fibrosis progression through paracrine signaling-mediated fibroblast activation. Taken together, our data offer a distinctive picture of the VEC dynamics associated with pulmonary fibrosis and suggest that aberrant expansion of ACKR1+VECs in IPF lungs may play a critical role in lung fibroblast activation and fibrosis progression.

Making room for subjectification during classroom discussions A Conversation Analytic study of interactional practices in the Dutch language classroom<br/><br/>This dissertation examines classroom discussions in which Dutch language and literature teachers in secondary education make room for subjectification, one of the three educational functions of education. Subjectification concerns the emancipation and freedom of the student and the responsibility that comes with it. One way to introduce students to this freedom and responsibility is through conducting equal dialogues in which participants can present themselves as unique, independent individuals and in which encounters can take place.<br/><br/>By applying Conversation Analysis (CA) as a research method, this dissertation, consisting of four sub-studies, demonstrates that asking for opinions and experiences allows students to express themselves as subjects, and that the teacher’s response, after expressing an opinion or experience, is crucial for the emergence of a dialogue. It also becomes clear that moments when students take turns without being prompted lead to dialogical interaction. The results of this dissertation show that during such dialogical interactions, students mainly express opinions, which in turn provoke new opinions. It becomes clear that students often stick to their own perspectives and rarely ask questions on their own initiative. This means that if teachers want to work on subjectification, they should explicitly encourage students to understand and appreciate perspectives of others.<br/><br/>This dissertation thus provides both fundamental knowledge about stimulating dialogical interaction and practical insights for teachers who want to make room for subjectification during their lessons through conducting classroom discussions.

BackgroundBruton’s tyrosine kinase (Btk) is an enzyme expressed in leukocytes other than T lymphocytes and plasma cells and involved in B-cell receptor- and Fcγ receptor (FcγR)-mediated signal transduction. Btk inhibitors potentially suppress autoantibody production due to the expected inhibitory ability of B lymphocyte differentiation into antibody-producing plasma cells and reduce FcγR-mediated neutrophil activation, including the release of neutrophil extracellular traps (NETs). Microscopic polyangiitis (MPA) is a systemic small-vessel vasculitis characterized by the pathogenic autoantibody, antineutrophil cytoplasmic antibody (ANCA) that reacts with myeloperoxidase (MPO). MPO and MPO-ANCA immune complex (IC)-induced FcγR-mediated NETs are critically involved in MPA pathogenesis. This study aimed to demonstrate the therapeutic efficacy of the Btk inhibitor tirabrutinib on MPA.MethodsVarious doses of tirabrutinib or vehicle were orally administered to Sprague–Dawley rats daily. Four weeks later, the number of peripheral B lymphocytes was counted, and Btk phosphorylation in B lymphocytes was evaluated by flow cytometry. Human peripheral blood neutrophils were stimulated by MPO and anti-MPO antibody ICs (MPO and anti-MPO-ICs), and Btk and its downstream Vav phosphorylation were assessed by western blotting. The effects of tirabrutinib on MPO and anti-MPO-IC-induced NET formation were examined in vitro. Wistar Kyoto rats were immunized with human MPO to induce experimental MPA and given drug-free or tirabrutinib-containing feed (0.0037% or 0.012%) from day 0 or 28. All rats were euthanized on day 42 for serological and histological evaluation.ResultsTirabrutinib inhibited Btk phosphorylation without decreasing B lymphocytes in vivo. Neutrophil Btk and Vav were phosphorylated when stimulated with MPO and anti-MPO-ICs. Tirabrutinib suppressed MPO and anti-MPO-IC-induced NET formation in vitro and ameliorated experimental MPA in a dose-dependent manner in vivo. Although MPO-ANCA production was not affected, NET-forming neutrophils in the blood were significantly reduced by tirabrutinib.ConclusionsThe Btk inhibitor tirabrutinib suppressed MPO and anti-MPO-IC-induced NET formation in vitro and ameliorated experimental MPA by reducing NET-forming neutrophils but not decreasing MPO-ANCA titer in vivo. This study suggests that Btk is a possible therapeutic target in MPA.

The light of deuterium shines in the darkness of the molecular mechanism of the oxidized phosphatidylcholine synthesis. A concise protocol for the controlled tetradeuteration of straight-chain fatty acids is reported by Kotaro Hama, Ryo Takita, and co-workers (e202202779). The use of four deuterium atoms in fatty acids as well as a diagnostic peak of phosphatidylcholines thus obtained enabled the identification of acyltransferases that transfer the acyl moiety derived from an oxidized linoleic acid.

A multi-terminal Si capacitor with low equivalent series inductance (ESL) for power delivery systems in 2.5D/3D applications was demonstrated. The shortest parallel interconnects with a length of 20 μm from a power delivery network of RDL to the capacitor were successfully fabricated, in a 3D functional interposer, a Si capacitor is connected through Cu pads and through silicon vias (TSVs) formed by a bumpless Chip-on-Wafer (COW) process. By optimizing the capacitor direct-stack process with an adhesive curing profile and a TSV profile hy dry etching, 700 TSV connections with no open failures were achieved.

Currently, an optimal therapeutic strategy comprising molecularly targeted agents for treating EGFR-mutated non-small cell lung cancer (NSCLC) patients with acquired resistance to osimertinib is not available. Therefore, the initial therapeutic intervention is crucial for the prolonged survival of these patients. The activation of anexelekto (AXL) signaling is known to be associated with intrinsic and acquired resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs). In this study, we investigated the best therapeutic strategy to combat AXL-induced tolerance to EGFR-TKIs using the novel AXL inhibitor ONO-7475. We examined the efficacy of ONO-7475 in combination with EGFR-TKIs in EGFR-mutated NSCLC cells using in vitro and in vivo experiments. We investigated the correlation between AXL expression in tumors and clinical outcomes with osimertinib for EGFR-mutated NSCLC patients with acquired resistance to initial EGFR-TKIs. ONO-7475 sensitized AXL-overexpressing EGFR-mutant NSCLC cells to the EGFR-TKIs osimertinib and dacomitinib. In addition, ONO-7475 suppressed the emergence and maintenance of EGFR-TKI-tolerant cells. In the cell line-derived xenograft models of AXL-overexpressing EGFR-mutated lung cancer treated with osimertinib, initial combination therapy of ONO-7475 and osimertinib markedly regressed tumors and delayed tumor regrowth compared with osimertinib alone or the combination after acquired resistance to osimertinib. AXL expression in EGFR-TKI refractory tumors did not correlate with the sensitivity of osimertinib. These results demonstrate that ONO-7475 suppresses the emergence and maintenance of tolerant cells to the initial EGFR-TKIs, osimertinib or dacomitinib, in AXL-overexpressing EGFR-mutated NSCLC cells, suggesting that ONO-7475 and osimertinib is a highly potent combination for initial treatment.

This paper presents the design and implementation of engineered nanoscale bonding interfaces as an effective strategy to improve manufacturability of Cu-Cu bonding to the level where it can, for the first time, be applied to chip-to-substrate (C2S) assembly. All-Cu interconnections are highly sought after to meet the escalating electrical, thermal, and reliability requirements of a wide range of emerging digital and analog systems. Such applications require low-cost processes with bonding temperatures and pressures ideally below 200°C and 20MPa, respectively, far from existing solutions established in wafer-level packaging. GT-PRC and its industry partners address this technology gap through innovative designs of bonding interfaces, introducing: 1) novel ultra-thin surface finish metallurgies applied on Cu bumps and pads to prevent oxidation and achieve low-temperature assembly, 2) low-cost fly-cut planarization technique to lower bonding pressures, and 3) low-modulus nanocopper foam caps to provide tolerance to non-coplanarities, and further reduce bonding temperatures and pressures.