The residue of salinomycin in the muscles of olive flounder (Paralichthys olivaceus) and black rockfish (Sebastes Schlegeli) after oral administration analyzed by LC-Tandem-MS.

BACKGROUND: Salinomycin, an antibiotic, have potential as a veterinary drug for fish due to its anti-parasitic activity against several fish parasites. Thus the residual levels of salinomycin in muscles of two significant aquaculture species in Korea, olive flounder and black rockfish, were analyzed using HPLC-MS-MS. RESULTS: The proper method to analyze the residual salinomycin in fish muscles using LC-MS-MS was settled and the method was validated according to CODEX guidelines. The residues in three distinct groups for two fish species were analyzed using the matrix match calibration curves at points of five different times following oral administration. After oral administration, salinomycin rapidly breaks down in both olive flounder and black rockfish. After 7th days, the average residue in all groups of two fish spp. decreased below limit of quantitation (LOQ). CONCLUSION: Due to low residue levels in fish muscles, salinomycin may therefore be a treatment that is safe for both fish and humans. This result could contribute to establishment of MRL (minimal residual limit) for approval of salinomycin for use in aquaculture.

Discovery of Naphthol Tetramers from Endolichenic Fungus Daldinia childiae 047219 Based on MS/MS Molecular Networking.

Feature-based molecular networking analysis suggested the presence of naphthol tetramers in Daldinia childae 047219, the same species but a different strain from one used previously for the discovery of naphthol trimers promoting adiponectin synthesis. The new tetramers were composed of 5-methoxy-4-naphthol, each of which was connected to one another in various positions. Targeted isolation afforded six previously unreported naphthol tetramers (1-6) together with 13 known polyketides (7-19) including naphthol monomers, dimers, and trimers. Structures of the isolated compounds were established by using NMR and mass spectroscopic analysis. Nodulisporin A (13), nodulisporin B (14), and 1,1',3',3″-ternaphthalene-5,5',5″-trimethoxy-4,4',4″-triol (16) demonstrated anti-inflammatory activities against NO production, but the new compounds were less active.

Discovery of Bioactive Metabolites by Acidic Stress to a Geldanamycin Producer, Streptomyces samsunensis.

In an effort to activate silent biosynthetic gene clusters, Streptomyces samsunensis DSM42010, a producer of geldanamycin, was cultured at four different pHs (4.5, 5.4, 6.6, and 7.4). An acidic culture condition (pH 5.4) was selected for a chemical investigation since S. samsunensis showed a different metabolic profile compared to when it was cultured under other conditions. Seven new (1-7) and four known (8-11) compounds were isolated from these cultures. The structures of the isolated compounds were determined by spectroscopic techniques and chemical derivatization. Relative and absolute configurations of the new compounds (1-5) were established using JBCA, PGME method, advanced Marfey's method, modified Mosher's method, and comparison of observed and calculated ECD data. Interestingly, compounds 1-3 were truncated versions of geldanamycin, and compound 4 was also deduced to originate from geldanamycin. Compound 5 was composed of 3-methyltyrosine and 6-hydroxy-2,4-hexadienoic acid connected through an amide bond. Compounds 6 and 7 were dihydrogenated forms of geldanamycin with a hydroxy substitution. It is possible that culturing this strain under acidic conditions interfered to some degree with the geldanamycin polyketide synthase, leading to production of truncated versions as well as analogues of geldanamycin. Compounds 1, 8, and 9 showed significant antivirulence activity, inhibiting production of α-toxin by methicillin-resistant Staphylococcus aureus without growth attenuation and global regulatory inhibition; compounds 1, 8, and 9 may become promising α-toxin-specific antivirulence leads with less risk of resistance development.

Adiponectin-Secretion-Promoting Cyclic Peptide-Polyketide Hybrids from a Halophyte-Associated Fungus, Colletotrichum gloeosporioides JS0417.

Three new cyclic peptide-polyketide hybrids (1-3) and two new chaetiacandin-type polyketides (4 and 5) along with nine known compounds were isolated from cultures of a halophyte-associated fungus, Colletotrichum gloeosporioides JS0417. Spectroscopic analysis revealed that 1-3 were cyclic depsipeptides where 3,5,11-trihydroxy-2,6-dimethyldodecanoic acid was linked to two amino acids through amide and ester bonds to form a 12-membered ring. Relative and absolute configurations for the peptides were determined with spectroscopic analysis and chemical reactions. The cyclic depsipeptides 2 and 6 were determined to act as strong adiponectin-secretion-promoting modulators with potential to treat metabolic diseases associated with hypoadiponectinemia. Notably, a known compound, tryptophol, significantly inhibited PGE2 synthesis and also promoted adiponectin secretion, exhibiting a similar biological activity profile to aspirin, but with greater potency. The presence of an isoleucine moiety and non-glycosylation may be important for biological activity of the cyclic peptide-polyketide hybrids, and non-methoxylation of the side chain may influence activity of the indole derivatives.

Discovery of Pan-peroxisome Proliferator-Activated Receptor Modulators from an Endolichenic Fungus, Daldinia childiae.

Adiponectin-synthesis-promoting compounds possess therapeutic potential to treat diverse metabolic diseases, including obesity and diabetes. Phenotypic screening to find adiponectin-synthesis-promoting compounds was performed using the adipogenesis model of human bone marrow mesenchymal stem cells. The extract of the endolichenic fungus Daldinia childiae 047215 significantly promoted adiponectin production. Bioactivity-guided isolation led to 13 active polyketides (1-13), which include naphthol monomers, dimers, and trimers. To the best of our knowledge, trimers of naphthol (1-4) have not been previously isolated as either natural or synthetic products. The novel naphthol trimer 3,1',3',3″-ternaphthalene-5,5',5″-trimethoxy-4,4',4″-triol (2) and a dimer, nodulisporin A (12), exhibited concentration-dependent adiponectin-synthesis-promoting activity (EC50 30.8 and 15.2 µM, respectively). Compounds 2 and 12 bound to all three peroxisome proliferator-activated receptor (PPAR) subtypes, PPARα, PPARγ, and PPARδ. In addition, compound 2 transactivated retinoid X receptor α, whereas 12 did not. Naphthol oligomers 2 and 12 represent novel pan-PPAR modulators and are potential pharmacophores for designing new therapeutic agents against hypoadiponectinemia-associated metabolic diseases.

Rare ß-Resorcylic Acid Derivatives from a Halophyte-Associated Fungus Colletotrichum gloeosporioides JS0419 and Their Antifungal Activities.

Six new ß-resorcylic acid derivatives (1-5 and 7) were isolated from a halophyte-associated fungus, Colletotrichum gloeosporioides JS0419, together with four previously reported ß-resorcylic acid lactones (RALs). The relative and absolute stereochemistry of 1 was completely established by a combination of spectroscopic data and chemical reactions. The structures of the isolated compounds were elucidated by analysis of HRMS and NMR data. Notably, compounds 1-3 had a ß-resorcylic acid harboring a long unesterified aliphatic side chain, whereas the long aliphatic chains were esterified to form macrolactones in 4-9. Among the isolated compounds, monocillin I and radicicol showed potent antifungal activities against Cryptococcus neoformans, comparable to clinically available antifungal agents and radicicol showed weak antifungal activity against Candida albicans. These findings provide insight into the chemical diversity of fungal RAL-type compounds and their pharmacological potential.

Azaphilones from an Endophytic Penicillium sp. Prevent Neuronal Cell Death via Inhibition of MAPKs and Reduction of Bax/Bcl-2 Ratio.

Fourteen azaphilone-type polyketides (1-14), including nine new ones (1-6 and 8-10), were isolated from cultures of Vitex rotundifolia-associated Penicillium sp. JVF17, and their structures were determined by spectroscopic analysis together with computational methods and chemical reactions. Neuroprotective effects of the isolated compounds were evaluated against glutamate-induced neurotoxicity. Treatment with compounds 3, 6, 7, and 11-14 increased cell viabilities of hippocampal neuronal cells damaged by glutamate, with compound 12 being the most potent. Compound 12 markedly decreased intracellular Ca2+ and nuclear condensation levels. Mechanistically, molecular markers of apoptosis induced by treatment with glutamate, i.e., phosphorylation of MAPKs and elevated Bax/Bcl-2 expression ratio, were significantly lowered by compound 12. The azaphilones with an isoquinoline core structure were more active than those with pyranoquinones, but N-substitution decreased the activity. This study, including the structure-activity relationship, indicates that the azaphilone scaffold is a promising lead toward the development of novel neuroprotective agents.

New secondary metabolites produced by Paraphoma radicina FB55 as potential antifungal agents.

Microorganisms in specific environments are rich sources of bioactive natural products as they produce compounds that can aid their survival in harsh environments. In an effort to investigate antifungal compounds produced by microorganisms, the fungal strain Paraphoma radicia FB55, isolated from a marine sediment of the Beaufort Sea, north of Alaska, was subjected to chemical investigation. Chromatography of the culture extracts yielded two new compounds (1 and 2) and eight known compounds (3-10). Their structures were determined using spectroscopic and chemical methods. Compound 1 was a new analog of the known compound (3) with an isobenzofuranone skeleton. The absolute configuration of the chiral center in 1 was established by comparison of its ECD and specific rotation values with those for a known analogue. Compound 2 is a polyketide-amino acid hybrid. Comprehensive Nuclear Magnetic Resonance (NMR) analysis indicated that 2 consisted of two substructures:5-methyl-6-oxo-2,4-heptadienoic acid and isoleucinol. The absolute configuration of the isoleucinol moiety in 2 was determined to be D using Marfey's method. All the isolated compounds were evaluated for antifungal activities. Although the antifungal activity of the isolated compounds was not potent, co-treatment of compounds 7 and 8 with a clinically available amphotericin B (AmB) lowered the IC50 values of AmB by synergism against human pathogenic yeast.

New Anti-Inflammatory ß-Resorcylic Acid Lactones Derived from an Endophytic Fungus, Colletotrichum sp.

The endophytic fungus Colletotrichum gloeosprioides JS0419, isolated from the leaves of the halophyte Suaeda japonica, produced four new ß-resorcylic acid derivatives, colletogloeopyrones A and B (1 and 2) and colletogloeolactones A and B (3 and 4), and seven known ß-resorcylic acid lactones (RALs). The structures of these compounds were elucidated via analysis of the high-resolution mass spectrometry and nuclear magnetic resonance data. Compounds 1 and 2 showed a dihydrobenzopyranone ring with a linear C9 side chain, which is rarely observed in RALs. All isolated compounds were evaluated for their anti-inflammatory activities. Colletogloeopyrone A (1), monocillin II (5), and monocillin II glycoside (6) were effective in reducing nitric oxide production without cytotoxicity. They also inhibited the secretion of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), as demonstrated by the expression of mRNA corresponding to IL-6 and TNF-α. Mechanistically, compounds 5 and 6 significantly inhibited the protein expression of nuclear factor-κB, IκBα, IKKα/ß, inducible nitric oxide synthase, and cyclooxygenase (COX)-2, whereas compound 1 only inhibited COX-2 expression. This study indicated that RAL-type compounds 1, 5, and 6 demonstrated potential anti-inflammatory activity by inhibiting the synthesis of pro-inflammatory cytokines.

Assessment of Salinomycin's Potential to Treat Microcotyle sebastis in Korean Rockfish (Sebastes schlegelii).

Aquaculture, a crucial sector of the global food industry, faces a myriad of issues due to parasitic invasions. One such parasite, Microcotyle sebastis, which afflicts Korean rockfish in South Korea, has a significant economic impact. The impending danger of resistance to traditional anthelmintics necessitates the exploration of new antiparasitic candidates. Although the efficacy of salinomycin against aquatic parasites such as ciliates and sporozoans is known, its influence on monogeneans has yet to be studied. Therefore, this study investigated the efficacy and safety of salinomycin for the treatment of M. sebastis infections, presenting the first exploration of salinomycin's therapeutic potential against monogeneans. In vitro examinations revealed a minimum effective concentration of salinomycin of 5 mg/kg, which led to necrosis of the haptor upon dislodging from the gill filaments. The one-time oral administration of the drug at concentrations of 5 mg/kg and 10 mg/kg showed a significant dose-dependent reduction in parasite counts, with no apparent behavioral side effects in Korean rockfish. Biochemical analyses monitored the liver, heart, and kidney enzymes, specifically aspartate transaminase (AST), alanine transaminase (ALT), blood urea nitrogen (BUN), and creatine kinase-myocardial band (CK-MB). At both 20 °C and 13 °C, no significant differences were observed in the levels of AST and ALT. However, at 20 °C, alterations in BUN levels were evident on Day 14, a deviation not observed at 13 °C. The CK-MB analysis revealed elevated enzyme levels at both temperatures when compared to the control group, reflecting the similar changes observed in terrestrial animals administered salinomycin. The biochemical data suggest that the oral administration of salinomycin is potentially more favorable at 13 °C than at 20 °C. Although our findings warrant further comprehensive studies, including on the long-term and potential effects on nontarget species and water quality, they also suggest that salinomycin could be considered as an alternative or adjunctive treatment if resistance to the currently used praziquantel against M. sebastis is confirmed.

Development and Evaluation of Machine Learning-Based High-Cost Prediction Model Using Health Check-Up Data by the National Health Insurance Service of Korea.

In this study, socioeconomic, medical treatment, and health check-up data from 2010 to 2017 of the National Health Insurance Service (NHIS) of Korea were analyzed. This year's socioeconomic, treatment, and health check-up data are used to develop a predictive model for high medical expenses in the next year. The characteristic of this study is to derive important variables related to the high cost of domestic medical expenses users by using data on health check-up items conducted by the country. In this study, we tried to classify data and evaluate its performance using classification supervised learning algorithms for high-cost medical expense prediction. Supervised learning for predicting high-cost medical expenses was performed using the logistic regression model, random forest, and XGBoost, which have been known to result the best performance and explanatory power among the machine learning algorithms used in previous studies. Our experimental results show that the XGBoost model had the best performance with 77.1% accuracy. The contribution of this study is to identify the variables that affect the prediction of high-cost medical expenses by analyzing the medical bills using the health check-up variables and the Korea Classification Disease (KCD) large group as input variables. Through this study, it was confirmed that musculoskeletal disorders (M) and respiratory diseases (J), which are the most frequently treated diseases, as important KCD disease groups for high-cost prediction in Korea, affect the future high cost prediction. In addition, it was confirmed that malignant neoplasia diseases (C) with high medical cost per treatment are a group of diseases related to high future medical cost prediction. Unlike previous studies, it is the result of analyzing all disease data, so it is expected that the study will be more meaningful when compared with the results of other national health check-up data.

High-load capacity origami transformable wheel.

Composite membrane origami has been an efficient and effective method for constructing transformable mechanisms while considerably simplifying their design, fabrication, and assembly; however, its limited load-bearing capability has restricted its application potential. With respect to wheel design, membrane origami offers unique benefits compared with its conventional counterparts, such as simple fabrication, high weight-to-payload ratio, and large shape variation, enabling softness and flexibility in a kinematic mechanism that neutralizes joint distortion and absorbs shocks from the ground. Here, we report a transformable wheel based on membrane origami capable of bearing more than a 10-kilonewton load. To achieve a high payload, we adopt a thick membrane as an essential element and introduce a wireframe design rule for thick membrane accommodation. An increase in the thickness can cause a geometric conflict for the facet and the membrane, but the excessive strain energy accumulation is unique to the thickness increase of the membrane. Thus, the design rules for accommodating membrane thickness aim to address both geometric and physical characteristics, and these rules are applied to basic origami patterns to obtain the desired wheel shapes and transformation. The capability of the resulting wheel applied to a passenger vehicle and validated through a field test. Our study shows that membrane origami can be used for high-payload applications.

Mindlink: A stigma-free youth-friendly community-based early-intervention centre in Korea.

AIM: In many Asian countries, youth mental health services are not well-developed and access to treatment is generally delayed. Here, we present a community-based service model based on our experience with Mindlink, the first early-intervention centre of its kind in Korea. METHODS: We describe the history of this mental health early-intervention service and the characteristics of users, as well as its intervention programmes and research directions. We also propose ways to further develop youth mental health services. RESULTS: A community-based early-intervention service for youth was first introduced in 2012, when a special team was formed in a community mental health centre of Korea. As the numbers of young clients increased, a youth-friendly, early-intervention centre called Mindlink was opened in 2016. Mindlink targets those aged 15-30 years with mental illness less than 5 years in duration. Its goal is to detect mental illness in young people early and provide comprehensive multidisciplinary interventions. It provides intensive case management and group programmes including cognitive-behavioural therapy, family intervention, psychoeducation, behavioural activation and physical health promotion. The Korean government has officially announced that the Mindlink model is effective and is currently in the process of scaling it up on a national level. CONCLUSION: An accessible, youth-friendly, stigma-free, community mental health centre such as Mindlink allows early detection and appropriate management of mental illness in young patients.

Validation of the Korean Version of the 15-Item Community Assessment of Psychic Experiences in a College Population.

OBJECTIVE: To investigate the reliability and validity of the Korean version of the Community Assessment of Psychic Experiences-15 item positive scale (CAPE-15) in college students. METHODS: This study had two stages: initial screening with self-report questionnaires including the CAPE-15, and semi-structured interviews to investigate the instrument's diagnostic validity. The initial screening involved 1,749 college students. The modified Korean version of Prodromal Questionnaire-16 item (mKPQ-16) was also administered. The criteria for ultra-high risk (UHR) of psychosis in the Comprehensive Assessment of At-Risk Mental States (CAARMS) were the gold standard for diagnosis. RESULTS: Twelve of the interviewed subjects met the CAARMS criteria for UHR of psychosis. The area under the receiver operating characteristic curve was highest (0.936) for the CAPE-15 distress score (p<0.001). The use of 6 as the cutoff for the CAPE-15 distress score resulted in the best balance of sensitivity (91.7%) and specificity (85.2%), with a favorable positive predictive value of 32.4%. The coefficients of correlation between the CAPE-15 and mKPQ-16 were significant. CONCLUSION: The Korean version of the CAPE-15 is a good instrument for screening for psychosis risk in collegiate settings. The validation of this scale could contribute to the early identification of psychosis in the Korean community.

Bioinspired dual-morphing stretchable origami.

Nature demonstrates adaptive and extreme shape morphing via unique patterns of movement. Many of them have been explained by monolithic shape-changing mechanisms, such as chemical swelling, skin stretching, origami/kirigami morphing, or geometric eversion, that were successfully mimicked in artificial analogs. However, there still remains an unexplored regime of natural morphing that cannot be reproduced in artificial systems by a "single-mode" morphing mechanism. One example is the "dual-mode" morphing of Eurypharynx pelecanoides (commonly known as the pelican eel), which first unfolds and then inflates its mouth to maximize the probability of engulfing the prey. Here, we introduce pelican eel-inspired dual-morphing architectures that embody quasi-sequential behaviors of origami unfolding and skin stretching in response to fluid pressure. In the proposed system, fluid paths were enclosed and guided by a set of entirely stretchable origami units that imitate the morphing principle of the pelican eel's stretchable and foldable frames. This geometric and elastomeric design of fluid networks, in which fluid pressure acts in the direction that the whole body deploys first, resulted in a quasi-sequential dual-morphing response. To verify the effectiveness of our design rule, we built an artificial creature mimicking a pelican eel and reproduced biomimetic dual-morphing behavior. By compositing the basic dual-morphing unit cells into conventional origami frames, we demonstrated architectures of soft machines that exhibit deployment-combined adaptive gripping, crawling, and large range of underwater motion. This design principle may provide guidance for designing bioinspired, adaptive, and extreme shape-morphing systems.

Evaluation of subjective perceived rating for grip strength depending on handedness for various target force levels.

BACKGROUND: Measurement of hand exertion is very important to quantify the risk of Work-related Musculoskeletal Disorders (WMSDs) in manufacturing fields. Although a direct measurement is the most accurate way to quantify physical load, it is expensive and time consuming. To solve this limitation, a subjective self-report method has been proposed as a possible alternative. OBJECTIVE: The purpose of this study was to analyze the accuracy of subjective perception for grip force exertions associated with handedness (dominant and non-dominant hands). METHODS: A total of nine healthy adults participated in this study. All participants were asked to exert hand grip forces for randomly selected target force levels without any information about the actual target force levels. Then, participants were also asked to rate the subjective perception of their exertion level using % Maximum Voluntary Contraction (MVC) after each hand grip force exertion. RESULTS: The trend of subjective perception for various target force levels was different according to the handedness. In the case of the dominant hand, participants tend to rate less MVC levels (under-estimation) than the actual target force levels at lower than 50% MVC, whereas they tend to rate more MVC levels (over-estimation) than the actual target force levels at higher than 50% MVC, respectively. In case of non-dominant hand, generally participants showed over-estimate for all levels of MVCs in this study. CONCLUSIONS: According to the results of this study, subjective perception of exertion showed different patterns on the handedness (S-shape for dominant hand vs. over-estimation for non-dominant hand) for various target force levels. Therefore, it would be necessary to apply different criteria for each hand to evaluate subjective perception of hand grip exertion tasks.

Validation of the Korean version of the 16-Item Prodromal Questionnaire in a Non-Help-Seeking College Population.

OBJECTIVE: To examine the reliability and validity of the Korean version of the 16-item Prodromal Questionnaire (KPQ-16) in non-help-seeking university students. METHODS: Among 2,246 university students participated in the initial screening, 257 subjects with KPQ-16 scores ≥4 were interviewed. The criteria for ultra-high risk (UHR) of psychosis of the Comprehensive Assessment of At-Risk Mental States (CAARMS) were the gold standard for diagnosis. An exploratory modified version of the questionnaire (mKPQ-16), to which three items from the Eppendorf Schizophrenia Inventory were added, was also used to compensate for items on thought and cognitive problems. RESULTS: Seventeen subjects met the CAARMS criteria for UHR of psychosis. The area under the receiver operating characteristic curve (AUROC) was highest for the mKPQ-16 total score (AUROC=0.831, p<0.001). The use of cutoff total scores of 7 for the mKPQ-16 and 6 for the KPQ-16 resulted in the best balance of sensitivity (76.5% and 64.7%, respectively) and specificity (75.4% and 71.2%, respectively). CONCLUSION: The Korean versions of the PQ-16 are good instruments for screening for psychosis risk in university students. This validation of a questionnaire version with a small number of items may make it feasible to screen large numbers of young adults in the community.