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Background Apelin is an endogenous neuropeptide that binds to the G-protein-coupled receptor (APJ) and participates in a variety of physiological processes in the heart, lungs and other peripheral organs. Intriguingly, [Pyr1]-Apelin-13, a highly potent pyroglutamic form of apelin, has the potential to bind to and be degraded by angiotensin-converting enzyme 2 (ACE2). ACE2 is known to operate as a viral receptor in the early stages of severe acute respiratory coronavirus (SARS-CoV-2) infection. Aim This study aimed to determine if apelin protects against SARS-CoV-2 infection by inhibiting ACE2 binding to SARS-CoV-2 spike protein. Design and methods To determine whether [Pyr1]-Apelin-13 inhibits ACE2 binding to the SARS-CoV-2 spike protein (S protein), we performed a cell-to-cell fusion assay using ACE2-expressing cells and S protein-expressing cells and a pseudovirus-based inhibition assay. We then analyzed publicly available transcriptome data while focusing on the beneficial effects of apelin on the lungs. Results We found that [Pyr1]-Apelin-13 inhibits cell-to-cell fusion mediated by ACE2 binding to the S protein. In this experiment, [Pyr1]-Apelin-13 protected human bronchial epithelial cells, infected with pseudo-typed lentivirus-producing S protein, against viral infection. In the presence of [Pyr1]-Apelin-13, the level of viral spike protein expression was also reduced in a concentration-dependent manner. Transcriptome analysis revealed that apelin may control inflammatory responses to viral infection by inhibiting the nuclear factor kappa B pathway. Conclusion Apelin is a potential therapeutic candidate against SARS-CoV-2 infection.

Arabidopsis thaliana blue-light inhibitor of cryptochromes 1 (AtBIC1) suppresses the dimerization of cryptochromes, which is necessary for cryptochrome function in plants. Additionally, AtBIC1 interacts with brassinazole-resistant 1 (BZR1) and phytochrome-interacting factor 4 (PIF4) transcription factors for integrating brassinosteroid (BR) and light signaling to promote plant growth. Thus, AtBIC1 overexpression is postulated to facilitate a desirable plant architecture for a high yield of crops. We first confirmed the phenotypes of transgenic Arabidopsis plants overexpressing AtBIC1, showing increases in leaf growth, plant height, and seed productivity. Next, we applied the AtBIC1 overexpression approach to soybean as a target crop. The transgenic soybean plants overexpressing AtBIC1 exhibited a significantly tall phenotype (i.e., an increased plant height) but with reduced root growth. In particular, the transgenic soybean plants displayed altered plant architecture, such as greatly elongated hypocotyls, during growth under both greenhouse and field conditions. Due to the phenotype of increased plant height, the total seed weights from the transgenic soybean plants decreased. These results suggest that the greater growth of above-ground parts might result in diminished growth of underground parts (i.e., roots), reducing the seed productivity of soybean. Collectively, these results suggest that AtBIC1 overexpression functions similarly in elongated growth to increase plant heights in both Arabidopsis and soybean, whereas it functions differently in root growth between the two plants.

Background Red ginseng contains components, including microelements, vitamins, essential oils, and fatty acids, that can be used in skincare to delay the aging process. We investigated the effects of red ginseng treatment on skin elasticity by assessing cellular stiffness and measuring collagen protein synthesis. Methods Human dermal fibroblasts were treated with red ginseng, and the resulting changes in stiffness were investigated using atomic force microscopy. Cytoskeletal changes and mRNA expression of biomarkers of aging, including that of procollagens I and VII, elastin, and fibrillin-1, were investigated. Collagen in a human skin equivalent treated with red ginseng was visualized via hematoxylin and eosin staining, scanning electron microscopy, and atomic force microscopy. Results and conclusion The stiffness of fibroblasts was significantly reduced by treatment with red ginseng concentrations of ≥ 0.8 mg/mL. The ratio of F-actin to G-actin decreased after treatment, which corresponded to a change in fibroblast stiffness. The storage modulus (G′) and loss modulus (G″) of the skin equivalent were both lowered by red ginseng treatment. This result indicates that the viscoelasticity of the skin equivalent can be restored by red ginseng treatment.

Purpose Robotics has evolved rapidly in terms of mechanical design and control in the past few years. Collaborative robots that have direct contact with humans are being introduced in various fields, including industrial and medical services. Because collaborative robot systems are being introduced rapidly, the safety of the humans who work with them is becoming an important issue. In this study, we investigated skin injuries resulting from a collision between robots and humans using a freefall experiment system. Methods We particularly focused on closed skin injuries caused by a collision. To induce a closed injury, we struck mini-pigs with cubic-edge square and semi-sphere impactors at collision speeds of 1 and 3 m/s. We did not observe any open injuries with those conditions. Closed injuries were observed in the dermal layer of the skin after the collision test at both speeds and with both impactors. Results The collagen fiber in the dermal layer was separated and fragmented, and the subcutaneous fat layer became dense as a result of the collision. Conclusions We closely observed and analyzed the histopathologic changes in the dermal and subcutaneous layers with intact epidermis after mechanical trauma to the inner skin layers.

In recent years, conventional industrial manipulators are being converted to collaborative robots to increase the efficiency and flexibility of production operations. Because of those advantages, collaborative robots are also being applied even in the manufacturing sites where manipulators could not be used in the past. This trend is increasing the use of collaborative robots, and since the collaborative robot shares the workspace with the human, working environments in which the robot and the human frequent contact are created. Therefore, the importance of robot safety is also increasing because of the increasing possibility of injury from the physical collision between robots and humans. One of the methods to make a robot safe is power and force limiting. To apply the power and force limiting method to the robot for the collaborative operation, the biomechanical limits should be identified. These limits can be confirmed by a clinical test measuring the threshold of pain onset. In this paper, a protocol for measuring the mechanical pain threshold is presented. The robot can be safely used if it does not exceed the biomechanical limitations derived from this study.

OBJECTIVES: This study compared the results of meta-analysis with and without adjustment for the healthy worker effect on the association between working in the semiconductor industry and cancer mortality.METHODS: Six studies that reported standardized mortality ratios (SMRs) for cancers were selected for meta-analysis. Using a random-effects model, the SMR results from each study were combined for all cancers and leukemias to estimate the summary SMRs (95% confidence interval, CI). To adjust for the healthy worker effect, the relative standardized mortality ratio (rSMR=SMRx/SMRnot x) were calculated using observed and expected counts for the specific cause of interest (i.e., all cancers and leukemias) and the observed and expected counts for all other causes of mortality. Then, the rSMR results were combined to estimate the summary rSMRs (95% CIs).RESULTS: The SMRs for all causes of mortality among semiconductor industry workers ranged from 0.25 to 0.80, which reflects a significant healthy worker effect. A remarkable difference was found between the summary SMRs and the summary rSMRs. The summary SMR for all cancers was 0.70 (95% CI, 0.63 to 0.79) whereas the summary rSMR was 1.38 (95% CI, 1.20 to 1.59). The summary SMR for leukemia was 0.88 (95% CI, 0.72 to 1.07), and the summary rSMR was 1.88 (95% CI, 1.20 to 2.95).CONCLUSIONS: Our results suggest that adjustment for the healthy worker effect (i.e., rSMR) may be useful in meta-analyses of cohort studies reporting SMRs.

Purpose An electric field (EF) can be used to change the mechanical properties of cells and skin tissues. We demonstrate EF-induced elasticity changes in human dermal fibroblasts (HDFs) and a human skin equivalent and identify the underlying principles related to the changes. Methods HDFs and human skin equivalent were stimulated with electric fields of 1.0 V/cm. Change in cellular elasticity was determined by using atomic force microscopy. Effects of EF on the biomechanical and chemical properties of a human skin equivalent were analyzed. In cells and tissues, the effects of EF on biomarkers of cellular elasticity were investigated at the gene and protein levels. Results In HDFs, the cellular elasticity was increased and the expression of biomarkers of cellular elasticity was regulated by the EF. Expression of the collagen protein in the human skin equivalent was changed by EF stimulation; however, changes in density and microstructure of the collagen fibrils were not significant. The viscoelasticity of the human skin equivalent increased in response to EF stimulation, but molecular changes were not observed in collagen. Conclusions Elasticity of cells and human skin equivalent can be regulated by electrical stimulation. Especially, the change in cellular elasticity was dependent on cell age.

Previous studies have not detected transcripts of the gene encoding anthocyanidin synthase (ANS) in white pomegranates (Punica granatum L.) and suggest that a large-sized insertion in the coding region of the ANS gene might be the causal mutation. To elucidate the identity of the putative insertion, 3887-bp 5′ and 3392-bp 3′ partial sequences of the insertion site were obtained by genome walking and a gene coding for an expansin-like protein was identified in these genome-walked sequences. An identical protein (GenBank accession OWM71963) isolated from pomegranate was identified from BLAST search. Based on information of OWM71963, a 5.8-Mb scaffold sequence with genes coding for the expansin-like protein and ANS were identified. The scaffold sequence assembled from a red pomegranate cultivar also contained all genome-walked sequences. Analysis of positions and orientations of these genes and genome-walked sequences revealed that the 27,786-bp region, including the 88-bp 5′ partial sequences of the ANS gene, might be translocated into an approximately 22-kb upstream region in an inverted orientation. Borders of the translocated region were confirmed by PCR amplification and sequencing. Based on the translocation mutation, a simple PCR codominant marker was developed for efficient genotyping of the ANS gene. This molecular marker could serve as a useful tool for selecting desirable plants at young seedling stages in pomegranate breeding programs.

Exendin-4, a 39 amino acid peptide isolated from the saliva of the Gila monster, plays an important role in regulating glucose homeostasis, and is used clinically for the treatment of type 2 diabetes. Exendin-4 shares 53% sequence identity with the incretin hormone glucagon-like peptide 1 (GLP-1) but, unlike GLP-1, is highly resistant to proteolytic enzymes such as dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidase 24.11 (NEP 24.11). Herein, we focused on the structure and function of the C-terminal Trp-cage of exendin-4, and suggest that it may be structurally required for resistance to proteolysis by NEP 24.11. Using a series of substitutions and truncations of the C-terminal Trp-cage, we found that residues 1-33, including the N-terminal and helical regions of wild-type (WT) exendin-4, is the minimum motif required for both high peptidase resistance and potent activity toward the GLP-1 receptor comparable to WT exendin-4. To improve the therapeutic utility of C-terminally truncated exendin-4, we incorporated various fatty acids into exendin-4(1-33) in which Ser33 was substituted with Lys for acylation. Exendin-4(1-32)K-capric acid exhibited the most well balanced activity, with much improved therapeutic utility for regulating blood glucose and body weight relative to WT exendin-4.

AGM-130 is a cyclin-dependent kinase inhibitor that exhibits dose-dependent efficacy in xenograft mouse models. During preclinical pharmacokinetic (PK) studies, mice and rats showed comparable PK parameters while dogs showed unusually high clearance (CL), which has made human PK prediction challenging. To address this discrepancy, we performed a human microdosing PK and developed a mouse PK/PD model in order to guide the first-in-human studies. A microdose of AGM-130 was given via intravenous injection to healthy subjects. Efficacy data obtained using MCF-7 breast cancer cells implanted in mice was analyzed using pre-existing tumor growth inhibition models. We simulated a human PK/PD profile with the PK parameters obtained from the microdose study and the PD parameters estimated from the xenograft PK/PD model. The human CL of AGM-130 was 3.08 L/h/kg, which was comparable to CL in mice and rats. The time-courses of tumor growth in xenograft model was well described by a preexisting model. Our simulation indicated that the human doses needed for 50 and 90% inhibition of tumor growth were about 100 and 400 mg, respectively. This is the first report of using microdose PK and xenograft PK/PD model to predict efficacious doses before the first-in-human trial in cancer patients. In addition, this work highlights the importance of integration of all of information in PK/PD analysis and illustrates how modeling and simulation can be used to add value in the early stages of drug development.

Over the last few years, the robotics technology has rapidly evolved in terms of the safety enhancement. With the improvement the collaborative operation between the industrial robot and the human is now an appealing viable option. As the collaboration between the human and robot becomes more frequent, the requirement for the safety of the human in the case of collision with the robot draws much more attention. From this point of view, lot of research about the collision safety of the human has been reported recently. Most of them, however, are focused on the severe collision cases of the fatal injury. Which is mainly due to the lack of the analysis data for the minor injury. In this paper, the skin injury that is defined as a minor injury is analyzed with experimental data. Based on the analysis result, the acceptable impact (collision) condition for the robot is estimated.

A liquid chromatography–triple quadrupole mass spectrometric (LC-MS/MS) method was developed and validated for the determination of 5-nitro-5′-hydroxy-indirubin-3′-oxime (AGM-130) in human plasma to support a microdose clinical trial. The method consisted of a liquid–liquid extraction for sample preparation and LC-MS/MS analysis in the positive ion mode using TurboIonSprayTM for analysis. d3-AGM-130 was used as the internal standard. A linear regression (weighted 1/concentration) was used to fit calibration curves over the concentration range of 10–2000 pg/mL for AGM-130. There were no endogenous interference components in the blank human plasma tested. The accuracy at the lower limit of quantitation was 96.6% with a precision (coefficient of variation, CV) of 4.4%. For quality control samples at 30, 160 and 1600 pg/mL, the between run CV was ≤5.0 %. Between-run accuracy ranged from 98.1 to 101.0%. AGM-130 was stable in 50% acetonitrile for 168 h at 4°C and 6 h at room temperature. AGM-130 was also stable in human plasma at room temperature for 6 h and through three freeze–thaw cycles. The variability of selected samples for the incurred sample reanalysis was ≤12.7% when compared with the original sample concentrations. This validated LC-MS/MS method for determination of AGM-130 was used to support a phase 0 microdose clinical trial. Copyright © 2015 John Wiley & Sons, Ltd.

Objectives: The purpose of this study was to assess excavator drivers in order to determine the proportion showing subjective symptoms of musculoskeletal disorders and to evaluate the association between the symptoms and characteristics of the subjects. Methods: A questionnaire survey was conducted to collect the information on participants’ age, average working hours per day, duration of career (years), work-related musculoskeletal symptoms, and more. The final dataset included 141 excavator drivers. Frequency and percentage were summarized and then the associations between the characteristics of the subjects and symptoms were evaluated as odds ratios (ORs) and 95% confidence intervals (CIs) using multiple logistic regression analysis. Results: Seventy-six percent of the currently reported musculoskeletal symptoms. Those who have musculoskeletal symptoms attributed their symptoms to unstable posture at work, mental stress or vibrations. There was a significant association between symptoms of musculoskeletal disorders and career of excavator drivers (P for trend=0.04). Conclusions: The results of this study suggest that the prevalence of musculoskeletal disorders may be high among excavator drivers and warrants well-designed studies on work-related disorders among excavator drivers.

In general, the storage life of hardy kiwifruit (Actinidia arguta ) is approximately one month, even in cold storage, which is a limiting factor for its commercialization due to the short marketing period. This short shelf life is in contrast to those of green kiwifruit (A. deliciosa , 6 to 8 months) and gold kiwifruit (A. chinensis , 4 to 6 months). To increase the storage life of hardy kiwifruit, we performed a cross between A. arguta (a local collection, ‘Hy2-1’, female) and A. deliciosa (‘Matua’, male) at Wando station at the Fruit Research Institute of JARES, Korea in 1999. After the first selection in 2006, we clonally propagated the hybrid plants by grafting them onto A. arguta seedlings in Gwangyang and Haenam province, Korea. We performed the final selection of this cultivar in 2012 and applied for plant protection rights from the Korea Forest Research Institute in 2013. Several experimental orchards have been established for commercial production. ‘Mansu’ begins to flower on May 20 in Gwangyang. The horticultural maturity date in ‘Mansu’, when the soluble solid content reaches 7°Bx, is October 15, whereas that of the control variety (‘Chiak’) is October 5. The average fruit size of ‘Mansu’ is approximately 15 g. The soluble solid content of ‘Mansu’ is approximately 16 to 17°Bx after ripening. The total yield of mature ‘Mansu’ vines is estimated to be 2.2 to 2.5 tons per 10a. The fruit firmness of ‘Mansu’ exceeded 1.5 ㎏/5 ㎜O until 70 days after storage (at 0 and 1℃). Therefore, ‘Mansu’ fruits have much longer storability than the control. The cultivation and production of ‘Mansu’ may extend the marketing period for hardy kiwifruit.

The Korean kiwifruit growers have a limited access to 'Hort16A', although the yellow flesh varieties are very appreciated in Korea. As a result a demand for Korean variety of gold kiwifruit was increasing. Fruit research institute of Jeonnam Agricultural Research and Extension Services (JARES) in Korea carried out a breeding program performing crosses between Actinidia chinensis species since mid-1990s. A round and very fruitful accession was selected from a 1997s cross between late 2002 and early 2003. The variety named 'Haegeum' in 2007 was grafted on 'Hayward' and followed in both experimental sites and farm orchards since then. 'Haegeum' flowers in mid-May and reaches maturity (disappearance of green color in fruit flesh) at mid-late October although some differences among cultural conditions and seasons were observed. The fruit average size is between 70 to 100 g and the soluble solid content after ripening is around 14 to 16%. This new selection was released and at the end of 2009 the potential acreages reached 25 ha in Korea.

A liquid chromatography-triple quadrupole mass spectrometric (LC-MS/MS) method was developed and validated for the determination of 5-nitro-5'-hydroxy-indirubin-3'-oxime (AGM-130) in human plasma to support a microdose clinical trial. The method consisted of a liquid-liquid extraction for sample preparation and LC-MS/MS analysis in the positive ion mode using TurboIonSpray(TM) for analysis. d3 -AGM-130 was used as the internal standard. A linear regression (weighted 1/concentration) was used to fit calibration curves over the concentration range of 10-2000 pg/mL for AGM-130. There were no endogenous interference components in the blank human plasma tested. The accuracy at the lower limit of quantitation was 96.6% with a precision (coefficient of variation, CV) of 4.4%. For quality control samples at 30, 160 and 1600 pg/mL, the between run CV was ≤5.0 %. Between-run accuracy ranged from 98.1 to 101.0%. AGM-130 was stable in 50% acetonitrile for 168 h at 4°C and 6 h at room temperature. AGM-130 was also stable in human plasma at room temperature for 6 h and through three freeze-thaw cycles. The variability of selected samples for the incurred sample reanalysis was ≤12.7% when compared with the original sample concentrations. This validated LC-MS/MS method for determination of AGM-130 was used to support a phase 0 microdose clinical trial.