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Abstract Thus far, attempts to develop drugs that target corticotropin-releasing hormone receptor 1 (CRF1R), a drug target in stress-related therapy, have been unsuccessful. Studies have focused on using high-resolution G protein-coupled receptor (GPCR) structures to develop drugs. X-ray free-electron lasers (XFELs), which prevent radiation damage and provide access to high-resolution compositions, have helped accelerate GPCR structural studies. We elucidated the crystal structure of CRF1R complexed with a BMK-I-152 antagonist at 2.75 Å using fixed-target serial femtosecond crystallography. The results revealed that two unique hydrogen bonds are present in the hydrogen bond network, the stalk region forms an alpha helix and the hydrophobic network contains an antagonist binding site. We then developed two antagonists—BMK-C203 and BMK-C205—and determined the CRF1R/BMK-C203 and CRF1R/BMK-C205 complex structures at 2.6 and 2.2 Å, respectively. BMK-C205 exerted significant antidepressant effects in mice and, thus, may be utilized to effectively identify structure-based drugs against CRF1R.

Human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) have emerged as a promising tool for studying cardiac physiology and drug responses. However, their use is largely limited by an immature phenotype and lack of high-throughput analytical methodology. In this study, we developed a high-throughput testing platform utilizing hPSC-CMs to assess the cardiotoxicity and effectiveness of drugs. Following an optimized differentiation and maturation protocol, hPSC-CMs exhibited mature CM morphology, phenotype, and functionality, making them suitable for drug testing applications. We monitored intracellular calcium dynamics using calcium imaging techniques to measure spontaneous calcium oscillations in hPSC-CMs in the presence or absence of test compounds. For the cardiotoxicity test, hPSC-CMs were treated with various compounds, and calcium flux was measured to evaluate their effects on calcium dynamics. We found that cardiotoxic drugs withdrawn due to adverse drug reactions, including encainide, mibefradil, and cetirizine, exhibited toxicity in hPSC-CMs but not in HEK293-hERG cells. Additionally, in the effectiveness test, hPSC-CMs were exposed to ATX-II, a sodium current inducer for mimicking long QT syndrome type 3, followed by exposure to test compounds. The observed changes in calcium dynamics following drug exposure demonstrated the utility of hPSC-CMs as a versatile model system for assessing both cardiotoxicity and drug efficacy. Overall, our findings highlight the potential of hPSC-CMs in advancing drug discovery and development, which offer a physiologically relevant platform for the preclinical screening of novel therapeutics.

In recent years, automated guided vehicles (AGVs) have been widely adopted to automate material handling procedures in manufacturing shopfloors and distribution centers. AGV scheduling is the procedure of allocating a transportation task to an AGV, which has large impacts on the efficiency of an AGV system with multiple AGVs. In order to optimize the operations of multi-AGV systems, AGV scheduling decisions should be made with consideration of practical issues such as buffer space limitations and battery charging. However, previous studies have often overlooked those issues. To fill this gap, this paper proposes a simulation-based multi-AGV scheduling procedure for practical shopfloors with limited buffer capacity and battery charging. Furthermore, we propose three kinds of rules: job selection rules, AGV selection rules, and charging station selection rules, for AGV scheduling in practical shopfloors. The performance of the rules is evaluated through multi-scenario simulation experiments. The FlexSim software v.2022 is used to develop a simulation model for the experiments, and the experimental findings indicate that the job selection rules have larger impacts on the average waiting time than the other kinds of rules.

Occupational safety and health is among the most challenging issues in many industrial workplaces, in that various factors can cause occupational illness and injury. Robotics, automation, and other state-of-the-art technologies represent risks that can cause further injuries and accidents. However, the tools currently used to assess risks in workplaces require manual work and are highly subjective. These tools include checklists and work assessments conducted by experts. Modern Industry 4.0 technologies such as a digital twin, a computerized representation in the digital world of a physical asset in the real world, can be used to provide a safe and healthy work environment to human workers and can reduce occupational injuries and accidents. These digital twins should be designed to collect, process, and analyze data about human workers. The problem is that building a human-focused digital twin is quite challenging and requires the integration of various modern hardware and software components. This paper aims to provide a brief survey of recent research papers on digital twins, focusing on occupational safety and health applications, which is considered an emerging research area. The authors focus on enabling technologies for human data acquisition and human representation in a virtual environment, on data processing procedures, and on the objectives of such applications. Additionally, this paper discusses the limitations of existing studies and proposes future research directions.

This paper proposes a novel genetic algorithm (GA) approach that utilizes a multichromosome to solve the flexible job-shop scheduling problem (FJSP), which involves two kinds of decisions: machine selection and operation sequencing. Typically, the former is represented by a string of categorical values, whereas the latter forms a sequence of operations. Consequently, the chromosome of conventional GAs for solving FJSP consists of a categorical part and a sequential part. Since these two parts are different from each other, different kinds of genetic operators are required to solve the FJSP using conventional GAs. In contrast, this paper proposes a unified GA approach that enables the application of an identical crossover strategy in both the categorical and sequential parts. In order to implement the unified approach, the sequential part is evolved by applying a candidate order-based GA (COGA), which can use traditional crossover strategies such as one-point or two-point crossovers. Such crossover strategies can also be used to evolve the categorical part. Thus, we can handle the categorical and sequential parts in an identical manner if identical crossover points are used for both. In this study, the unified approach was used to extend the existing COGA to a unified COGA (u-COGA), which can be used to solve FJSPs. Numerical experiments reveal that the u-COGA is useful for solving FJSPs with complex structures.

The use of halogen-based materials has been regulated since toxic substances are released during combustion. In this study, polyurethane foam was coated with cationic starch (CS) and montmorillonite (MMT) nano-clay using a spray-assisted layer-by-layer (LbL) assembly to develop an eco-friendly, high-performance flame-retardant coating agent. The thickness of the CS/MMT coating layer was confirmed to have increased uniformly as the layers were stacked. Likewise, a cone calorimetry test confirmed that the heat release rate and total heat release of the coated foam decreased by about 1/2, and a flame test showed improved fire retardancy based on the analysis of combustion speed, flame size, and residues of the LbL-coated foam. More importantly, an additional cone calorimeter test was performed after conducting more than 1000 compressions to assess the durability of the flame-retardant coating layer when applied in real life, confirming the durability of the LbL coating by the lasting flame retardancy.

The overall five-year survival rate for late-stage patients of ovarian cancer is below 29% due to disease recurrence and drug resistance. Cancer stem cells (CSCs) are known as a major contributor to drug resistance and recurrence. Accordingly, therapies targeting ovarian CSCs are needed to overcome the limitations of present treatments. This study evaluated the effect of trimebutine maleate (TM) targeting ovarian CSCs, using A2780-SP cells acquired by a sphere culture of A2780 epithelial ovarian cancer cells. TM is indicated as a gastrointestinal motility modulator and is known to as a peripheral opioid receptor agonist and a blocker for various channels. The GI50 of TM was approximately 0.4 µM in A2780-SP cells but over 100 µM in A2780 cells, demonstrating CSCs specific growth inhibition. TM induced G0/G1 arrest and increased the AV+/PI+ dead cell population in the A2780-SP samples. Furthermore, TM treatment significantly reduced tumor growth in A2780-SP xenograft mice. Voltage gated calcium channels (VGCC) and calcium-activated potassium channels (BKCa) were overexpressed on ovarian CSCs and targeted by TM; inhibition of both channels reduced A2780-SP cells viability. TM reduced stemness-related protein expression; this tendency was reproduced by the simultaneous inhibition of VGCC and BKCa compared to single channel inhibition. In addition, TM suppressed the Wnt/β-catenin, Notch, and Hedgehog pathways which contribute to many CSCs characteristics. Specifically, further suppression of the Wnt/β-catenin pathway by simultaneous inhibition of BKCa and VGCC is necessary for the effective and selective action of TM. Taken together, TM is a potential therapeutic drug for preventing ovarian cancer recurrence and drug resistance.

As the operating speed of a train increases, there is a growing interest in reducing damage caused by derailment and collision accidents. Since a collision with the surrounding structure after a derailment accident causes a great damage, protective facilities like a barrier wall or derailment containment provision (DCP) are installed to reduce the damage due to the secondary collision accident. However, the criteria to design a protective facility such as locations and design loads are not clear because of difficulties in predicting post-derailment behaviors. In this paper, we derived a simplified frame model that can predict post derailment behaviors in the design phase of the protective facilities. The proposed vehicle model can simplify for various frames to reduce the computation time. Also, the actual derailment tests were conducted on a real test track to verify the reliability of the model. The simulation results of the proposed model showed reasonable agreement to the test results.

According to the Mualem capillary model, hydraulic conductivity (HC) is integrated theoretically from the function related to soil water retention curves (SWRC). On the other hand, based on the smooth type of SWRC, the predicted HC function decreases abruptly near saturation, which often challenges the stability of numerical solutions. To improve the Mualem HC, van Genuchten’s function for SWRC was modified within the range of low matric suction. The van Genuchten-Mualem HC was then modified to integrate the proposed SWRC for each interval decomposed by a tangential curve. The analytical solutions of the modified HC were derived to prevent an abrupt decrease near saturation. The SWRC and HC data were acquired from laboratory tests for unsaturated soils sampled from five areas in Korea. The results of the HC tests were compared with the theoretical HC models using both the van Genuchten SWRCs and the modified curves. For fine grained soils, the modified model predicts a saturated HC at very small suctions. Furthermore, the modified model was shown to accurately predict the unsaturated behavior of the HC functions for Korean weathered soils.

Primary cutaneous mucinous carcinoma (PCMC) is a rare malignancy of the sweat glands that most commonly affects the periorbital area. It is characterized by slow growth over a prolonged period, and its morphology can be easily confused with a benign tumor, such as an epidermal cyst. Consequently, many patients experience recurrence after undergoing multiple resections. However, there are few reports concerning the surgical management of PCMC. We present two cases of PCMC originating in the periorbital area. The first case involved a 76-year-old man with a mass measuring 3.0× 1.5 cm that had been increasing in size. The second case was a 61-year-old man with two masses, each measuring 1.0× 1.0 cm, that were also growing. Both patients underwent wide excision with a 5-mm safety margin, which was determined based on the widest view of the cross-section of the mass on the magnetic resonance imaging. Subsequently, based on the intraoperative frozen biopsy results, both patients underwent additional excision with a 5-mm safety margin in only one direction. This report shows that, when determining the surgical margin of PCMC in periorbital area, employing imaging modalities and intraoperative frozen biopsies can be helpful for narrowing the surgical margin. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to evaluate the impact of preimplantation genetic testing for aneuploidy (PGT-A) on clinical outcomes among high-risk patients. Methods: This retrospective study involved 1,368 patients and the same number of cycles, including 520 cycles with PGT-A and 848 cycles without PGT-A. The study participants comprised women of advanced maternal age (AMA) and those affected by recurrent implantation failure (RIF), recurrent pregnancy loss (RPL), or severe male factor infertility (SMF). Results: PGT-A was associated with significant improvements in the implantation rate (IR) and the ongoing pregnancy rate/live birth rate (OPR/LBR) per embryo transfer cycle in the AMA (39.3% vs. 16.2% [p<0.001] and 42.0% vs. 21.8% [p<0.001], respectively), RIF (41.7% vs. 22.0% [p<0.001] and 47.0% vs. 28.6% [p<0.001], respectively), and RPL (45.6% vs. 19.5% [p<0.001] and 49.1% vs. 24.2% [p<0.001], respectively) groups, as well as the IR in the SMF group (43.3% vs. 26.5%, p=0.011). Additionally, PGT-A was associated with lower overall incidence rates of early pregnancy loss in the AMA (16.7% vs. 34.3%, p=0.001) and RPL (16.7% vs. 50.0%, p<0.001) groups. However, the OPR/LBR per total cycle across all PGT-A groups did not significantly exceed that for the non-PGT-A groups. Conclusion: PGT-A demonstrated beneficial effects in high-risk patients. However, our findings indicate that these benefits are more pronounced in carefully selected candidates than in the entire high-risk patient population. [ABSTRACT FROM AUTHOR]

Background: The clinical characteristics of pediatric nasal fractures can vary depending on the child's age, social activities, and environment. Therefore, this study aimed to analyze these characteristics in different age groups. Methods: We retrospectively reviewed of a series of patients aged under 12 years who received treatment between 2013 and 2021. The initial study design involved dividing the patients into four age groups, corresponding to different developmental ages, but there were no cases in infants aged 0 to 1 year. Therefore, the patients were divided into three groups: group I, between 2 and 5; group II, between 6 and 9; and group III, between 10 and 12 years of age. The following parameters were evaluated: sex, age, etiology, fracture type and severity, and the incidence of septal injuries. Results: In total, 98 patients were included in this study. In group III, the ratio of boys to girls was 3.88:1, exceeding the overall ratio of 1.97:1. The most common cause varied with age: slipping down in group I, bumping accidents in group II, and sports accidents in group III. Concomitant septal injuries were present in 4.17% of patients in group I, 5.71% of patients in group II, and 28.21% of patients in group III. Conclusion: Increasing age was accompanied by a greater tendency for male predominance and a higher prevalence of sports-related causes and septal injuries. Violence was infrequent but started to become a contributing factor during school age. These varying environmental factors across age groups can offer valuable insights into the epidemiology and clinical characteristics of pediatric nasal bone fractures. [ABSTRACT FROM AUTHOR]