Proline-hydroxyproline (Pro-Hyp) stimulated hyaluronic acid production in cultured synovium cells. It was detected in guinea pig blood after oral ingestion of collagen hydrolysates. Oral ...administration of collagen hydrolysates increased the amount of proteoglycans in the epiphyses. It also reduced the morphological changes associated with osteoarthritic cartilage destruction of the knee joint. The results suggest that collagen hydrolysates have therapeutic potential for treatment of osteoarthritis.
Cell fate determination in plants relies on positional cues. To investigate the position-dependent gene regulation in plants, we focused on shoot epidermal cell specification, which occurs only in ...the outermost cells.
, which encodes an HD-ZIP class IV transcription factor, is a positive regulator of shoot epidermal cell identity. Despite the presence of a weak
promoter activity in the inner cells, ATML1 protein was detected mostly in the outermost cells, which suggests that ATML1 accumulation is inhibited in the inner cells. ATML1 nuclear localization was reduced in the epidermis and there was a positive, albeit weak, correlation between the amount of ATML1 in the nuclei and the expression of a direct target of ATML1. Nuclear accumulation of ATML1 was more strongly inhibited in the inner cells than in the outermost cells. Domain deletion analyses revealed that the ZLZ-coding sequence was necessary and partially sufficient for the post-transcriptional repression of
Our results suggest that post-transcriptional repressions contribute to the restriction of master transcriptional regulator activity in specific cells to enable position-dependent cell differentiation.
Plant cell fate determination depends on the relative positions of the cells in developing organisms. The shoot epidermis, the outermost cell layer of the above-ground organs in land plants, protects ...plants from environmental stresses. How the shoot epidermis is formed only from the outermost cells has remained unknown. Here we show that when inner leaf mesophyll cells are exposed to the surface, these cells show up-regulation of ATML1, a master regulator for epidermal cell identity in Arabidopsis thaliana. Epidermal cell types such as stomatal guard cells regenerate from young inner-lineage tissues that have a potential to accumulate ATML1 protein after epidermal injury. Surgical analyses indicate that application of pressure to the exposed site was sufficient to inhibit ATML1 derepression in the outermost mesophyll cells, suggesting this process requires pressure release. Furthermore, pharmacological analyses suggest that ATML1 derepression in the outermost mesophyll cells require cortical microtubule formation, MAPK signaling and proteasome activity. Our results suggest that surface-positional cues involving mechanical signaling are used to restrict ATML1 activity to the outermost cells and facilitate epidermal differentiation.
EP4, a prostaglandin E2 receptor, has shown an immunosuppressive activity on cancer cells. This first‐in‐human study evaluated ONO‐4578, a highly selective EP4 antagonist, as monotherapy and in ...combination with nivolumab in patients with advanced or metastatic solid tumors. A daily dose ranging from 30 mg to 100 mg of ONO‐4578 monotherapy and that ranging from 2 mg to 60 mg of ONO‐4578 with biweekly nivolumab 240 mg were administered. A total of 31 patients were enrolled, 10 receiving monotherapy and 21 receiving combination therapy. Overall, 26 patients experienced treatment‐related adverse events. Dose‐limiting toxicities were observed in three patients; one of six patients receiving 100 mg monotherapy developed grade 3 duodenal ulcer and two of six patients receiving 60 mg combination therapy developed either grade 3 erythema multiforme or grade 3 increased amylase and grade 4 increased lipase. One patient with small‐cell lung cancer who received 40 mg combination therapy had a partial response, and three patients with monotherapy and six patients with combination therapy had stable disease. Pharmacodynamics analyses showed that ONO‐4578 had EP4 antagonistic activity at doses as low as 2 mg. In conclusion, the maximum tolerated dose of ONO‐4578 alone or in combination with nivolumab was not reached. ONO‐4578 was well tolerated at the tested doses and showed signs of antitumor activity. Considering safety, efficacy, and pharmacokinetics/pharmacodynamics results, ONO‐4578 40 mg daily with nivolumab 240 mg biweekly was selected as the recommended dose for future clinical trials. (Registration: JapicCTI‐173,496 and NCT03155061).
ONO‐4578 is a selective antagonist of the EP4 receptor for prostaglandin E2. ONO‐4578 alone or in combination with nivolumab was well tolerated and showed signs of anti‐tumor activity in patients with advanced or metastatic solid tumors. Considering safety, efficacy, and pharmacokinetics/pharmacodynamics results, ONO‐4578 40 mg daily with nivolumab 240 mg biweekly was selected as the recommended dose for future clinical trials.
The development of games had been seen as an essential field of study in artificial intelligence. Although game concepts have been adopted in various problem domains, understanding the nature of game ...playing's underlying mechanism has been limited. This study investigates such a mechanism by adopting a logistic model of game outcome uncertainty where a measure of game refinement had been derived. Application of such a measure to the popular board and sports games have been conducted to determine its implication in determining sophisticated design and has defined the harmonic balance between skill and chance. A theoretical analysis using practical data confirms the effectiveness of the proposed model, where reasonable game length is determined based on the definition of a gamified experience. The model is further expanded with the analogy of physics in mind. The law of motions in the game is formalized by considering the derivatives of the game progress model, where the link between game refinement theory and flow theory is identified and discussed. In essence, the sophisticated game's underlying mechanism leads to a more natural yet pleasurable human experience.
The gaming industry had rapidly been expanding globally, where it encompasses more than the purpose of recreational and increasingly becomes more immersive and engaging, and potentially leads to ...pathological gaming behaviors that lead to addiction. Such experience of engagement and addiction involves understanding the fundamental functions of the human mind's dynamic state. This study uncovers the mind's underlying physics via the analogy of motion (i.e., mass, velocity, etc.) using games as the source of information. This study also conjectures that the law of conservation in mind occurred in games where momentum and energy were conserved over time, where game-playing experience relative to the gambling psychology and perceptive force were identified from the objective and subjective perspectives. It was found that momentum conservation provides new engagement measures while energy conservation, considering several other factors, provides the necessary components of understanding the addiction mechanism in the game-playing context. This measurement is examined in various domains, such as popular boards and sports games, and public gambling, where its effectiveness is determined.
An optical fiber coupler composed of two side-polished fibers with different curvature is proposed. The live-fiber is polished with a typical radius of curvature of 0.25 m, while the branch-fiber is ...polished with a larger radius of curvature. Analysis shows that the proposed asymmetric structure improves the highest cross-transmission of the coupled light by up to 0.26 just by increasing the curvature of the branch-fiber (compared to the conventional symmetric arrangement) without increasing the insertion loss created by side-polishing. Experiments confirm that the proposed structure raises the highest cross-transmission by 0.15 on average when the curvature of the branch-fiber is set to 0.5 m while the curvature of the live-fiber is kept to the typical value as expected from the analysis. Our study will contribute to realizing a simple and compact machine for polishing live-fibers that offers the improved workability and portability needed for adding optical fiber couplers to live-fibers in the field.
Multiple-choice questions (MCQs) have been considerably used for assessing the individual's performance in various contexts. The optimal number of options in MCQs is a debatable issue, followed by ...contradictions and discussions, and is needed for a firm conclusion from empirical and hypothetical findings. This study aims to link theoretical concepts, including challenge-based gamification, zone of proximal development, and prospect theory, and generate insight into educational assessment using motion-in-mind measures. Classical test theory was used to determine reliability and validity. Variations of MCQs experimented: the number of options, settings, and scoring methods. The experimental data was gathered from human and AI simulations and measured using motion-in-mind. It was found that increasing the number of options in the MCQ makes the test more challenging, explaining an increase of mass in mind m . The findings also revealed that time pressure provides competitiveness while scaffolding provides support. In addition, the hybrid system demonstrates the balance of education and entertainment. Finally, the results addressed the general discussion and analogical interpretation in the education context based on physics-in-mind values. These findings can be promising for analyzing the balance between competitiveness and entertainment while enabling the learning process in the practical assessment.
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