Effects of cytochalasin D on relaxation process of skinned taenia cecum and carotid artery from guinea pig.

Actin linked regulatory mechanisms are known to contribute contraction/relaxation in smooth muscle. In order to clarify whether modulation of polymerization/depolymerization of actin filaments affects relaxation process, we examined the effects of cytochalasin D on relaxation process by Ca2+ removal after Ca2+-induced contraction of ß-escin skinned (cell membrane permeabilized) taenia cecum and carotid artery preparations from guinea pigs. Cytochalasin D, an inhibitor of actin polymerization, significantly suppressed the force during relaxation both in skinned taenia cecum and carotid artery. The data fitting analysis of the relaxation processes indicates that cytochalasin D accelerates slow (latch-like) bridge dissociation. Cytochalasin D seems to directly disrupts actin filament organization or its length, resulting in modulation of actin filament structure that prevents myosin binding.

Long-term follow-up results from KEYNOTE-041: Phase 1b study of pembrolizumab in Japanese patients with advanced melanoma.

Pembrolizumab demonstrated an acceptable safety profile and promising antitumor activity in Japanese patients with advanced melanoma in the phase 1b KEYNOTE-041 (Study of Pembrolizumab [MK-3475] in Participants With Advanced Melanoma) trial. To evaluate the long-term efficacy and safety of pembrolizumab in Japanese patients with advanced melanoma in KEYNOTE-041. The current analysis reports results of additional follow-up of approximately 12 months since the initial analysis. Eligible patients had locally advanced (unresectable stage III) or metastatic (stage IV) melanoma not amenable to local therapy and had received two or fewer prior systemic therapies. Pembrolizumab 2 mg/kg was given every 3 weeks for up to 2 years or until confirmed progression or unacceptable toxicity. Primary end points included safety, tolerability, and overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 by independent central review. The data cutoff for this analysis was August 30, 2017. Forty-two patients were followed up for a median of 22.3 months (range, 2.63-30.82 months). The ORR was 24.3% (nine of 37 evaluable patients [95% confidence interval (CI), 11.8%-41.2%]). Two patients with partial response at the time of the initial analysis achieved complete response. The median overall survival (OS) was 25.1 months (95% CI, 13.1-not reached] and the 30-month OS rate was 46.3% (95% CI, 29.8%-61.3%). The median duration of response was not reached. Treatment-related adverse events (TRAEs) were reported in 78.6% of patients; the incidence of grade 3 to 5 TRAEs was 23.8%. No additional treatment-related deaths occurred since the initial analysis. Pembrolizumab provided durable antitumor activity and an acceptable safety profile in Japanese patients with advanced melanoma.

Progress on Separation and Hydrothermal Carbonization of Rice Husk Toward Environmental Applications.

Owing to the increasing global demand for carbon resources, pressure on finite materials, including petroleum and inorganic resources, is expected to increase in the future. Efficient utilization of waste resources has become crucial for sustainable resource acquisition for creating the next generation of industries. Rice husks, which are abundant worldwide as agricultural waste, are a rich carbon source with a high silica content and have the potential to be an effective raw material for energy-related and environmental purification materials such as battery, catalyst, and adsorbent. Converting these into valuable resources often requires separation and carbonization; however, these processes incur significant energy losses, which may offset the benefits of using biomass resources in the process steps. This review summarizes and discusses the high value of RHs, which are abundant as agricultural waste. Technologies for separating and converting RHs into valuable resources by hydrothermal carbonization are summarized based on the energy efficiency of the process.

A high-capacity, high-power organic electrode via supercritical CO2 impregnation into activated carbon micropores.

Herein, we report the impregnation of chloranil into activated carbon micropores using scCO2. The sample prepared under 105 °C and 15 MPa showed a specific capacity of 81 mAh gelectrode-1, except for the electric double layer capacity at 1 A gelectrode-Polytetrafluoroethylene (PTFE)-1. Additionally, approximately 90% of the capacity was retained even at 4 A gelectrode-PTFE-1.

Reflection on feasibility and usability of interactive online international exchange program for occupational therapy students.

The COVID-19 pandemic affected international exchange programs due to travel restrictions. There are few reports of online international exchange programs in medical area and no report of interactive activities among students together for several months. To the best of our knowledge, we needed to seek the feasible approach to conduct online exchange program. We experienced online collaboration works to promote internationalization in occupational therapy (OT) undergraduate education. The aim of this study is to examine the feasibility and usability of an interactive online international exchange program, and discuss its challenges and advantages. The three-month program was newly developed, and aimed at cultivating an international perspective, understanding OT, and learning basic research skills. Students' interests and the development of their motivation were considered in the program consisting of synchronous and asynchronous lectures, a collaboration research project, group work, and report assignments. Through the program, students were satisfied with the program contents and had the precious experience to develop international relationships. The online exchange program provided students with the opportunity to experience and learn OT education internationally at an economical cost, and to achieve program goal during the regular semester. In this program, students not only acquired knowledge in their professional field, but also cultivated their international communication skills in English from small group activities and social activities. Considering various communication methods was an important aspect in the virtual environment leading to a successful program. In medical education, an online program can be an effective and practical measure for international exchange. Supplementary Information: The online version contains supplementary material available at 10.1007/s44217-023-00031-4.

Prognostic impact of pretreatment T790M mutation on outcomes for patients with resected, EGFR-mutated, non-small cell lung cancer.

BACKGROUND: Many previous studies have demonstrated that minor-frequency pretreatment T790M mutation (preT790M) could be detected by ultrasensitive methods in a considerable number of treatment-naïve, epidermal growth factor receptor (EGFR)-mutated, non-small cell lung cancer (NSCLC) cases. However, the impact of preT790M in resected cases on prognosis remains unclear. METHODS: We previously reported that preT790M could be detected in 298 (79.9%) of 373 surgically resected, EGFR-mutated NSCLC patients. Therefore, we investigated the impact of preT790M on recurrence-free survival (RFS) and overall survival (OS) in this cohort by multivariate analysis. All patients were enrolled from July 2012 to December 2013, with follow-up until November 30, 2017. RESULTS: The median follow-up time was 48.6 months. Using a cutoff value of the median preT790M allele frequency, the high-preT790M group (n = 151) had significantly shorter RFS (hazard ratio [HR] = 1.51, 95% confidence interval [CI]: 1.01-2.25, P = 0.045) and a tendency for a shorter OS (HR = 1.87, 95% CI: 0.99-3.55, P = 0.055) than the low-preT790M group (n = 222). On multivariate analysis, higher preT790M was independently associated with shorter RFS (high vs low, HR = 1.56, 95% CI: 1.03-2.36, P = 0.035), irrespective of advanced stage, older age, and male sex, and was also associated with shorter OS (high vs low, HR = 2.16, 95% CI: 1.11-4.20, P = 0.024) irrespective of advanced stage, older age, EGFR mutation subtype, and history of adjuvant chemotherapy. CONCLUSIONS: Minor-frequency, especially high-abundance of, preT790M was an independent factor associated with a poor prognosis in patients with surgically resected, EGFR-mutated NSCLC.

Series module of quinone-based organic supercapacitor (> 6 V) with practical cell structure.

Inexpensive, high-performing, and environmentally friendly energy storage devices are required for smart grids that efficiently utilize renewable energy. Energy storage devices consisting of organic active materials are promising because organic materials, especially quinones, are ubiquitous and usually do not require harsh conditions for synthesis, releasing less CO2 during mass production. Although fundamental research-scale aqueous quinone-based organic supercapacitors have shown excellent energy storage performance, no practical research has been conducted. In this study, we aimed to develop a practical-scale aqueous-quinone-based organic supercapacitor. By connecting 12 cells of size 10 cm × 10 cm × 0.5 cm each in series, we fabricated a high-voltage (> 6 V) aqueous organic supercapacitor that can charge a smartphone at a 1 C rate. This is the first step in commercializing aqueous organic supercapacitors that could solve environmental problems, such as high CO2 emissions, air pollution by toxic metals, and limited electricity generation by renewable resources.

Colloidal Stability of Emulsifier-free Triolein-in-Water Emulsions: Effects of Temperature.

Herein, we report the colloidal stability of emulsifier-free (EF-) triolein-in-water (TO/W) emulsions prepared by mixing TO and water using a high-powered bath-type ultrasonicator (HPBath-US; 28 kHz, 300 W) in the absence of emulsifiers such as surfactants. In particular, the effect of the temperature (15-60℃) on the colloidal stability of EF-TO/W emulsions was examined because this is important for the practical application of EF-TO/W emulsions, for example, in foods, pharmaceuticals, and cosmetics. We found that the colloidal stability of the EF-TO/W emulsions decreased with increase in the temperature from 15 to 25°C, whereas it increased with increase in temperature from 25 to 40°C, and the high colloidal stability of the EF-TO/W emulsions was maintained above 40°C. The reduction in the colloidal stability of EF-TO/W emulsions between 15 and 25°C is likely a result of the TO droplets formed by thermal motion, as well as enhanced Ostwald ripening at higher temperatures. On the other hand, the increase in the colloidal stability of the EF-TO/W emulsions from 25 to 40°C and their high colloidal stability above 40℃ is attributed to the reduction in the interfacial tension between TO and water at higher temperatures. This decrease in the interfacial tension between TO and water with temperature increase is related to the transformation of short-range ordered domains (clusters) of TO molecules in the liquid state, which increases the colloidal stability of the EF-TO/W emulsions.

Cervical Myelopathy Screening with Machine Learning Algorithm Focusing on Finger Motion Using Noncontact Sensor.

STUDY DESIGN: Cross-sectional study. OBJECTIVE: To develop a binary classification model for cervical myelopathy (CM) screening based on a machine learning algorithm using Leap Motion (Leap Motion, San Francisco, CA), a novel noncontact sensor device. SUMMARY OF BACKGROUND DATA: Progress of CM symptoms are gradual and cannot be easily identified by the patients themselves. Therefore, screening methods should be developed for patients of CM before deterioration of myelopathy. Although some studies have been conducted to objectively evaluate hand movements specific to myelopathy using cameras or wearable sensors, their methods are unsuitable for simple screening outside hospitals because of the difficulty in obtaining and installing their equipment and the long examination time. METHODS: In total, 50 and 28 participants in the CM and control groups were recruited, respectively. The diagnosis of CM was made by spine surgeons. We developed a desktop system using Leap Motion that recorded 35 parameters of fingertip movements while participants gripped and released their fingers as rapidly as possible. A support vector machine was used to develop the binary classification model, and a multiple linear regression analysis was performed to create regression models to estimate the total Japanese Orthopaedic Association (JOA) score and the JOA score of the motor function of the upper extremity (MU-JOA score). RESULTS: The binary classification model indexes were as follows: sensitivity, 84.0%; specificity, 60.7%; accuracy, 75.6%; area under the curve, 0.85. The Spearman rank correlation coefficient between the estimated score and the total JOA score was 0.44 and that between the estimated score and the MU-JOA score was 0.51. CONCLUSION: Our binary classification model using a machine learning algorithm and Leap Motion could classify CM with high sensitivity and would be useful for CM screening in daily life before consulting doctors and telemedicine.Level of Evidence: 3.

Synthesis of unused-wood-derived C-Fe-N catalysts for oxygen reduction reaction by heteroatom doping during hydrothermal carbonization and subsequent carbonization in nitrogen atmosphere.

There is an urgent need to develop renewable sources of energy and use existing resources in an efficient manner. In this study, in order to improve the utilization of unused biomass and develop green processes and sustainable technologies for energy production and storage, unused Douglas fir sawdust (SD) was transformed into catalysts for the oxygen reduction reaction. Fe and N were doped into SD during hydrothermal carbonization, and the N- and Fe-doped wood-derived carbon (Fe/N/SD) was carbonized in a nitrogen atmosphere. After the catalyst had been calcined at 800°C, its showed the highest current density (-5.86 mAcm-2 at 0.5 V versus reversible hydrogen electrode or RHE) and Eonset value (0.913 V versus RHE). Furthermore, its current density was higher than that of Pt/C (20 wt% Pt) (-5.66 mA cm-2 @0.5 V versus RHE). Finally, after 50 000 s, the current density of sample Fe/N/SD (2 : 10 : 10) remained at 79.3% of the initial value. Thus, the synthesized catalysts, which can be produced readily at a low cost, are suitable for use in various types of energy generation and storage devices, such as fuel cells and air batteries. This article is part of the theme issue 'Bio-derived and bioinspired sustainable advanced materials for emerging technologies (part 2)'.

Rational Route for Increasing Intercalation Capacity of Hard Carbons as Sodium-Ion Battery Anodes.

Hard carbon (HC) is the most promising candidate for sodium-ion battery anode materials. Several material properties such as intensity ratio of the Raman spectrum, lateral size of HC crystallite (La ), and interlayer distance (d002 ) have been discussed as factors affecting anode performance. However, these factors do not reflect the bulk property of the Na+ intercalation reaction directly, since Raman analysis has high surface sensitivity and La and d002 provide only one-dimensional crystalline information. Herein, it was proposed that the crystallite interlayer area (Ai ) defined using La , d002 , and stacking height (Lc ) governs Na+ intercalation behavior of various HCs. It was revealed that various wood-derived HCs exhibited the similar total capacity of approximately 250 mAh g-1 , whereas the Na+ intercalation capacity (Ci ) was proportional to Ai with the correlation coefficient of R2 =0.94. The evaluation factor of Ai was also adaptable to previous reports and strongly correlated with their Ci , indicating that Ai is more widely adaptable than the conventional evaluation methods.

Accelerating effects of blebbistatin on relaxation process of cell membrane permeabilized trachea and taenia cecum from guinea pig.

Blebbistatin, a potent inhibitor of myosin II, is known to suppress smooth muscle contraction without affecting myosin light chain phosphorylation level. In order to clarify the regulatory mechanisms of blebbistatin on phasic and tonic smooth muscles in detail, we examined the effects of blebbistatin on relaxation process by Ca2+ removal after Ca2+-induced contraction of ß-escin skinned (cell membrane permeabilized) trachea and taenia cecum preparations from guinea pigs. Blebbistatin significantly suppressed the force during relaxation both in skinned trachea and taenia cecum. The data fitting analysis of the relaxation processes indicates that blebbistatin accelerates slow (latch-like) bridge dissociation.

Hypoxia Inducible Factor-1α Inhibition in Von Hippel Lindau-mutant Malignant Pleural Mesothelioma Cells.

BACKGROUND/AIM: Molecular targeted agents have been successfully developed against solid tumors and their use is also being investigated for the treatment of malignant pleural mesothelioma (MPM). We have previously reported von Hippel Lindau (VHL) mutations detected by massive parallel sequencing technology in samples of patients with MPM. Here, we conducted an in vitro study to investigate the therapeutic approaches in VHL-mutant MPM. MATERIALS AND METHODS: Three MPM cell lines with or without a VHL mutation were used and the effects of molecular-targeted agents on growth inhibition were evaluated. Based on the characteristics of the molecular targeted agents that exhibited growth inhibitory effect, the effects of knockdown by siRNA were also evaluated. RESULTS: NCI-H28 MPM cells harboring the VHL L89H mutation were sensitive to YC-1, known as an inhibitor of hypoxia inducible factor (HIF)-1α, and YC-1treatment induced massive apoptosis in a dose-and-time-dependent manner. Knockdown of HIF-1α by siRNA partially inhibited the growth of NCI-H28 cells, suggesting that an additional blockade may be required to completely inhibit growth signaling. CONCLUSION: The VHL mutation may predict tumor responses to YC-1, a HIF-1α inhibitor.

Increased hydrostatic pressure induces nuclear translocation of DAF-16/FOXO in C. elegans.

Mechanical stimulation is well known to be important for maintaining tissue and organ homeostasis. Here, we found that hydrostatic pressure induced nuclear translocation of a forkhead box O (FOXO) transcription factor DAF-16, in C. elegans within minutes, whereas the removal of this pressure resulted in immediate export of DAF-16 to the cytoplasm. We also monitored DAF-16-dependent transcriptional changes by exposure to 1 MPa pressure for 5 min, and found significant changes in collagen and other genes in a DAF-16 dependent manner. Lifespan was markedly prolonged with exposure to cyclic pressure treatment (1 MPa once a day for 5 min from L1 larvae until death). Furthermore, age-dependent decline in locomotor activity was suppressed by the treatment. In contrast, the nuclear translocation of the yes-associated protein YAP-1 was not induced under the same pressure conditions. Thus, moderate hydrostatic pressure improves ageing progression through activation of DAF-16/FOXO in C. elegans.

Inhibitory effects of rubratoxin A, a potent inhibitor of protein phosphatase 2, on the Ca2+-dependent contraction of skinned carotid artery from guinea pig.

Rubratoxin A, a potent inhibitor of PP2A, is known to suppress smooth muscle contraction. The inhibitory role of PP2A in smooth muscle contraction is still unclear. In order to clarify the regulatory mechanisms of PP2A on vascular smooth muscle contractility, we examined the effects of rubratoxin A on the Ca2+-induced contraction of ß-escin skinned carotid artery preparations from guinea pigs. Rubratoxin A at 1 µM and 10 µM significantly inhibited skinned carotid artery contraction at any Ca2+ concentration. The data fitting to the Hill equation in [Ca2+]-contraction relationship indicated that rubratoxin A decreased Fmax-Ca2+ and increased [Ca2+]50, indices of Ca2+ sensitivity for the force and myosin-actin interaction, respectively. These results suggest that PP2A inhibition causes downregulation of the myosin light chain phosphorylation and direct interference with myosin-actin interaction.

N-formyl-stabilizing quasi-catalytic species afford rapid and selective solvent-free amination of biomass-derived feedstocks.

Nitrogen-containing compounds, especially primary amines, are vital building blocks in nature and industry. Herein, a protocol is developed that shows in situ formed N-formyl quasi-catalytic species afford highly selective synthesis of formamides or amines with controllable levels from a variety of aldehyde- and ketone-derived platform chemical substrates under solvent-free conditions. Up to 99% yields of mono-substituted formamides are obtained in 3 min. The C-N bond formation and N-formyl species are prevalent in the cascade reaction sequence. Kinetic and isotope labeling experiments explicitly demonstrate that the C-N bond is activated for subsequent hydrogenation, in which formic acid acts as acid catalyst, hydrogen donor and as N-formyl species source that stabilize amine intermediates elucidated with density functional theory. The protocol provides access to imides from aldehydes, ketones, carboxylic acids, and mixed-substrates, requires no special catalysts, solvents or techniques and provides new avenues for amination chemistry.

Isolation and molecular analysis of circulating tumor cells from lung cancer patients using a microfluidic chip type cell sorter.

Circulating tumor cells (CTCs) are a tumor-derived material utilized for liquid-based biopsy; however, capturing rare CTCs for further molecular analysis remains technically challenging, especially in non-small-cell lung cancer. Here, we report the results of a clinical evaluation of On-chip Sort, a disposable microfluidic chip-based cell sorter, for capture and molecular analysis of CTCs from patients with lung adenocarcinoma. Peripheral blood was collected from 30 metastatic lung adenocarcinoma patients to enumerate CTCs using both On-chip Sort and CellSearch in a blind manner. Captured cells by On-chip Sort were subjected to further molecular analysis. Peripheral blood samples were also used for detection of EGFR mutations in plasma using droplet digital PCR. Significantly more CTCs were detected by On-chip Sort (22/30; median 5; range, 0-18 cells/5 mL blood) than by CellSearch (9/30; median, 0; range, 0-12 cells/7.5 mL) (P < 0.01). Thirteen of 30 patients who had a negative CTC count by CellSearch had a positive CTC count by On-chip Sort. EGFR mutations in CTCs captured by On-chip Sort were observed in 40.0% (8/20) of patients with EGFR-mutated primary tumor. EGFR mutations were often observed in 53.3% (8/15) of patients detected in plasma DNA. Expressions of EGFR and vimentin protein on CTCs were also successfully assessed using On-chip Sort. These results suggest that On-chip Sort is an efficient method to detect and capture rare CTCs from patients with lung adenocarcinoma that are undetectable with CellSearch. Mutation detection using isolated CTCs remains to be further tackled (UMIN000012488).

Correction to: Protein phosphatases 1 and 2A and their naturally occurring inhibitors: current topics in smooth muscle physiology and chemical biology.

The article Protein phosphatases 1 and 2A and their naturally occurring inhibitors: current topics in smooth muscle physiology and chemical biology, written by Akira Takai, Masumi Eto, Katsuya Hirano, Kosuke Takeya, Toshiyuki Wakimoto and Masaru Watanabe, was originally published electronically on the publisher's internet portal (currently SpringerLink) on 5th July 2017 without open access.

Protein phosphatases 1 and 2A and their naturally occurring inhibitors: current topics in smooth muscle physiology and chemical biology.

Protein phosphatases 1 and 2A (PP1 and PP2A) are the most ubiquitous and abundant serine/threonine phosphatases in eukaryotic cells. They play fundamental roles in the regulation of various cellular functions. This review focuses on recent advances in the functional studies of these enzymes in the field of smooth muscle physiology. Many naturally occurring protein phosphatase inhibitors with different relative PP1/PP2A affinities have been discovered and are widely used as powerful research tools. Current topics in the chemical biology of PP1/PP2A inhibitors are introduced and discussed, highlighting the identification of the gene cluster responsible for the biosynthesis of calyculin A in a symbiont microorganism of a marine sponge.