Nonthreaded Isomers of Sungsanpin and Ulleungdin Lasso Peptides Inhibit H1299 Cancer Cell Migration.

Lasso peptides are a structurally distinct class of biologically active natural products defined by their short sequences with impressively interlocked tertiary structures. Their characteristic peptide [1]rotaxane motif confers marked proteolytic and thermal resiliency, and reports on their diverse biological functions have been credited to their exceptional sequence variability. Because of these unique properties, taken together with improved technologies for their biosynthetic production, lasso peptides are emerging as a designable scaffold for peptide-based therapeutic discovery and development. Although the defined structure of lasso peptides is recognized for its remarkable properties, the role of the motif in imparting bioactivity is less understood. For example, sungsanpin and ulleungdin are natural lasso peptides that similarly exhibit encouraging cell migration inhibitory activities in A549 lung carcinoma epithelial cells, despite sharing only one-third of the sequence homology. We hypothesized that the shape of the lasso motif is beneficial for the preorganization of the conserved residues, which might be partially retained in variants lacking the threaded structure. Herein, we describe solid-phase peptide synthesis strategies to prepare acyclic, head-to-side chain (branched), and head-to-tail (macrocyclic) cyclic variants based on the sungsanpin (Sun) and ulleungdin (Uln) sequences. Proliferation assays and time-lapse cell motility imaging studies were used to evaluate the cell inhibitory properties of natural Sun compared with the synthetic Sun and Uln isomers. These studies demonstrate that the lasso motif is not a required feature to slow cancer cell migration and more generally show that these nonthreaded isomers can retain similar activity to the natural lasso peptide despite the differences in their overall structures.

Case report of laryngeal infection by Clinostomum complanatum 24 days after ingestion of raw fish.

RATIONALE: Clinostomum complanatum is a laryngeal fluke whose hosts include birds and mammals.[1] In humans, infection occurs accidentally during the consumption of raw freshwater fish.[1,2]. PATIENT CONCERNS: A 59-year-old female presented to our hospital with throat pain and globus sensation. The patient had been prescribed Proton Pump Inibitor for 3 weeks at another hospital. The patient continued the medication, but the discomfort persisted, and she was admitted to our hospital for further examination. The patient had eaten raw fish 24 days before, and the symptoms occurred after eating the raw fish. Endoscopy under sedation showed a fluke, with an approximate length of 8.0 mm and width of 3.2 mm, on the interaryepiglottic fold, with active motility on the mucosa. DIAGNOSIS INTERVENTIONS: It was extracted from the larynx using biopsy forceps and identified as C complanatum. OUTCOMES: After the fluke was removed, symptoms improved, and the patient was discharged. The globus symptoms completely resolved at the last follow-up visit. LESSONS: To the best of our knowledge, this is an endoscopically diagnosed and treated case of human infection by C complanatum in Korea after the longest period of infection. This suggests that C complanatum can survive for up to 3 weeks or more in the gastrointestinal tract. Endoscopy is a useful tool for the diagnosis and treatment of patients with atypical extraesophageal symptoms who do not respond to Proton Pump Inibitors.

Discovery and Biosynthesis of Cihunamides, Macrocyclic Antibacterial RiPPs with a Unique C-N Linkage Formed by CYP450 Catalysis.

Cihunamides A-D (1-4), novel antibacterial RiPPs, were isolated from volcanic-island-derived Streptomyces sp. The structures of 1-4 were elucidated by 1 H, 13 C, and 15 N NMR, MS, and chemical derivatization; they contain a tetrapeptide core composed of WNIW, cyclized by a unique C-N linkage between two Trp units. Genome mining of the producer strain revealed two biosynthetic genes encoding a cytochrome P450 enzyme and a precursor peptide. Heterologous co-expression of the core genes demonstrated the biosynthesis of cihunamides through P450-mediated oxidative Trp-Trp cross-linking. Further bioinformatic analysis uncovered 252 homologous gene clusters, including that of tryptorubins, which possess a distinct Trp-Trp linkage. Cihunamides do not display the non-canonical atropisomerism shown in tryptorubins, which are the founding members of the "atropitide" family. Therefore, we propose to use a new RiPP family name, "bitryptides", for cihunamides, tryptorubins, and their congeners, wherein the Trp-Trp linkages define the structural class rather than non-canonical atropisomerism.

Association of the etiology and peak level of markedly elevated aminotransferases with mortality: a multicenter study.

BACKGROUND: Markedly elevated aminotransferase levels are commonly encountered among hospitalized patients. However, data regarding the trajectory of enzyme elevation and disease-specific prognosis are limited. METHODS: This study included 3237 patients with at least one episode of aspartate aminotransferase or alanine aminotransferase level being higher than 400 U/L between January 2010 and December 2019 at 2 centers. Patients were classified into 5 groups comprising 13 diseases according to etiology. Factors associated with 30-day mortality were evaluated using a logistic regression analysis. RESULTS: The most common disease leading to markedly elevated aminotransferase level was ischemic hepatitis (33.7%), followed by pancreatobiliary disease (19.9%), DILI (12.0%), malignancy (10.8%), and viral hepatitis (7.0%). The 30-day all-cause mortality rate was 21.6%. The mortality rate for patients from the pancreatobiliary, hepatocellular, extrahepatic, malignancy, and ischemic hepatitis groups was 1.7%, 3.2%, 13.8%, 39.9%, and 44.2%, respectively. Age, etiology, and peak aminotransferase levels were independently associated with 30-day mortality. CONCLUSIONS: In patients with markedly elevated liver enzymes, the etiology and peak AST level are significantly associated with mortality.

Deep-Learning Algorithm and Concomitant Biomarker Identification for NSCLC Prediction Using Multi-Omics Data Integration.

Early diagnosis of lung cancer to increase the survival rate, which is currently at a low range of mid-30%, remains a critical need. Despite this, multi-omics data have rarely been applied to non-small-cell lung cancer (NSCLC) diagnosis. We developed a multi-omics data-affinitive artificial intelligence algorithm based on the graph convolutional network that integrates mRNA expression, DNA methylation, and DNA sequencing data. This NSCLC prediction model achieved a 93.7% macro F1-score, indicating that values for false positives and negatives were substantially low, which is desirable for accurate classification. Gene ontology enrichment and pathway analysis of features revealed that two major subtypes of NSCLC, lung adenocarcinoma and lung squamous cell carcinoma, have both specific and common GO biological processes. Numerous biomarkers (i.e., microRNA, long non-coding RNA, differentially methylated regions) were newly identified, whereas some biomarkers were consistent with previous findings in NSCLC (e.g., SPRR1B). Thus, using multi-omics data integration, we developed a promising cancer prediction algorithm.

Clinical Features of Hepatitis C Virus-related Acute-on-chronic Liver Failure in a Korean Population.

Background/Aims: Acute-on-chronic liver failure (ACLF) is a widely recognized concept in which acute decompensation (AD) in patients with cirrhosis results in organ failure and high short-term mortality. On the other hand, few studies reflecting the various etiologies of cirrhosis are available. This study examined the clinical features of patients with hepatitis C virus (HCV)-related ACLF. Methods: Between January 2005 and December 2018, 109 HCV-related cirrhosis patients hospitalized for AD (ascites, hepatic encephalopathy, gastrointestinal hemorrhage, and bacterial infection) were enrolled for ACLF defined by the European Association for the Study of the Liver (EASL). Results: ACLF developed in 35 patients (32.1%) on admission. Eight, eight, and 19 patients had ACLF grades 1, 2, and 3, respectively. The 28-day and 90-day mortality rates were very low (2.7% and 5.4%, respectively) in patients without ACLF and very high (60.0% and 74.3%, respectively) in those with ACLF. In patients with HCV-related ACLF, compared to previous studies on hepatitis B virus-related ACLF and alcohol-related ACLF, the prevalence of liver failure was very low (17.1%), whereas that of kidney failure was very high (71.4%). Compared with all other prognostic scores, the Chronic liver failure Consortium Organ Failure score predicted the 90-day mortality most accurately, with an area under the receiver operator characteristic of 0.921. Conclusions: HCV-related ACLF has unique clinical characteristics distinct from hepatitis B virus-related and alcohol-related ACLF. ACLF defined by EASL can be useful for predicting the short-term mortality in HCV-related cirrhosis.

Leveraging Building Material as Part of the In-Plane Robotic Kinematic System for Collective Construction.

Although collective robotic construction systems are beginning to showcase how multi-robot systems can contribute to building construction by efficiently building low-cost, sustainable structures, the majority of research utilizes non-structural or highly customized materials. A modular collective robotic construction system based on a robotic actuator, which leverages timber struts for the assembly of architectural artifacts as well as part of the robot body for locomotion is presented. The system is co-designed for in-plane assembly from an architectural, robotic, and computer science perspective in order to integrate the various hardware and software constraints into a single workflow. The system is tested using five representative physical scenarios. These proof-of-concept demonstrations showcase three tasks required for construction assembly: the ability of the system to locomote, dynamically change the topology of connecting robotic actuators and timber struts, and collaborate to transport timber struts. As such, the groundwork for a future autonomous collective robotic construction system that could address collective construction assembly and even further increase the flexibility of on-site construction robots through its modularity is laid.

Markedly Elevated Aspartate Aminotransferase from Non-Hepatic Causes.

There have been no reports on mortality in patients with markedly elevated aspartate aminotransferase (AST) levels from non-hepatic causes to date. This study aimed to determine the etiologies of markedly elevated AST levels > 400 U/L due to non-hepatic causes and to investigate the factors associated with mortality in these cases. This retrospective study included 430 patients with AST levels > 400 U/L unrelated to liver disease at two centers between January 2010 and December 2021. Patients were classified into three groups according to etiology: skeletal muscle damage, cardiac muscle damage, and hematologic disorder. Binary logistic regression analysis was performed to evaluate the factors associated with 30-day mortality. The most common etiology for markedly elevated AST levels was skeletal muscle damage (54.2%), followed by cardiac muscle damage (39.1%) and hematologic disorder (6.7%). The 30-day mortality rates for the skeletal muscle damage, cardiac muscle damage, and hematologic disorder groups were 14.2%, 19.5%, and 65.5%, respectively. The magnitude of the peak AST level significantly correlated with 30-day mortality, with rates of 12.8%, 26.7%, and 50.0% for peak AST levels < 1000 U/L, <3000 U/L, and ≥3000 U/L, respectively. In the multivariate analysis, cardiac muscle damage (odds ratio [OR] = 2.76, 95% confidence interval [CI] = 1.31−5.80), hematologic disorder (OR = 9.47, 95% CI = 2.95−30.39), peak AST < 3000 U/L (OR = 2.94, 95% CI = 1.36−6.35), and peak AST ≥ 3000 U/L (OR = 9.61, 95% CI = 3.54−26.08) were associated with increased 30-day mortality. Our study revealed three etiologies of markedly elevated AST unrelated to liver disease and showed that etiology and peak AST level significantly affected the survival rate.

Analyzing climate change impacts on health, energy, water resources, and biodiversity sectors for effective climate change policy in South Korea.

This study analyzes how climate change affects the economy, society, and environment in South Korea. Then, the study explores the ways to strengthen capabilities that can alleviate climate change impacts. To find them, the study employs a system dynamics simulation method and builds a model with several sectors including the urban, rural, population, and social-environmental sectors. The study compares the size of climate change damages in rural and urban areas. The results with representative concentration path (RCP) 8.5 show that the size of climate change damage will continue to increase by 2050. The projected damages from the reduced industrial outputs in urban areas will be larger than that in rural areas. The results also show that the service sector will face stronger impacts from climate change than the manufacturing and agricultural sectors. However, the total size of damage in the rural areas will be bigger than that of the urban areas. It is because the size of reduced industrial outputs per capita in the rural areas is twice bigger than that of the urban areas. The climate change damage in the social and environmental sectors (including a loss of biodiversity and an increase in health costs) account for the largest part of the total damage. The study finally provides suggestions and policies that can improve the capabilities to reduce the climate change damages. One of the major suggestions of this study is that the increase in the climate change budget corresponding to the GDP growth can minimize the size of climate change impacts.

Publisher Correction: Distinct handedness of spin wave across the compensation temperatures of ferrimagnets.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Distinct handedness of spin wave across the compensation temperatures of ferrimagnets.

Antiferromagnetic spin waves have been predicted to offer substantial functionalities for magnonic applications due to the existence of two distinct polarizations, the right-handed and left-handed modes, as well as their ultrafast dynamics. However, experimental investigations have been hampered by the field-immunity of antiferromagnets. Ferrimagnets have been shown to be an alternative platform to study antiferromagnetic spin dynamics. Here we investigate thermally excited spin waves in ferrimagnets across the magnetization compensation and angular momentum compensation temperatures using Brillouin light scattering. Our results show that right-handed and left-handed modes intersect at the angular momentum compensation temperature where pure antiferromagnetic spin waves are expected. A field-induced shift of the mode-crossing point from the angular momentum compensation temperature and the gyromagnetic reversal reveal hitherto unrecognized properties of ferrimagnetic dynamics. We also provide a theoretical understanding of our experimental results. Our work demonstrates important aspects of the physics of ferrimagnetic spin waves and opens up the attractive possibility of ferrimagnet-based magnonic devices.

Risk factors of postoperative major adverse cardiac events after radical cystectomy: implication of diastolic dysfunction.

Radical cystectomy, which is a standard treatment of muscle invasive and high-grade non-invasive bladder tumour, is accompanied with high rates of postoperative complications including major adverse cardiac events (MACE). Diastolic dysfunction is associated with postoperative complications. We evaluated perioperative risk factors including diastolic dysfunction related with MACE within 6 months after radical cystectomy. The 546 patients who underwent elective radical cystectomy were included. Diastolic dysfunction was defined as early transmitral flow velocity (E)/early diastolic mitral annulus velocity (e') > 15. Logistic regression analysis, Kaplan-Meier survival analysis and log-rank test were performed. MACE within 6 months after radical cystectomy developed in 43 (7.9%) patients. MACE was related with female (odds ratio 2.546, 95% confidence interval 1.166-5.557, P = 0.019) and diastolic dysfunction (odds ratio 3.077, 95% confidence interval 1.147-8.252, P = 0.026). The 6-month mortality were significantly higher in the MACE group, and hospital stay and intensive care unit stay were significantly longer in the MACE group compared to the non-MACE group. Accordingly, preoperative diastolic dysfunction (E/e' > 15) was related with postoperative MACE and MACE was related with 6-month survival after radical cystectomy. These results suggest that preoperative diastolic dysfunction can provide useful information on postoperative complications.

Combined Treatment with Low Concentrations of Aqueous and Gaseous Chlorine Dioxide Inactivates Escherichia coli O157:H7 and Salmonella Typhimurium Inoculated on Paprika.

Combined treatment with gaseous and aqueous chlorine dioxide (ClO2) was performed to improve the microbiological safety and quality of paprika. A single treatment of 50 ppmv ClO2 gas for 30 min decreased the populations of Escherichia coli O157:H7 and Salmonella Typhimurium by 2.33 and 2.91 log CFU/g, respectively. In addition, a single treatment of aqueous ClO2 (50 ppm) for 5 min decreased these populations by 1.86 and 1.37, respectively. The most dramatic effects were achieved by combined treatment of 50 ppm aqueous and gaseous ClO2 for 30 min, which decreased populations of E. coli O157:H7 and S. Typhimurium by 4.11 and 3.61 log CFU/g, respectively. With regard to the qualities of paprika, no adverse effects were elicited by the combined treatment. Thus, combined treatment with aqueous and gaseous ClO2 is a suitable approach that can be used to improve the microbial safety and quality of paprika.

Efficiencies of Dye-Sensitized Solar Cells with Hollow SnO2 Nanofiber/TiO2 Nanoparticle Composite Photoanodes.

In this study, we present dye-sensitized solar cells (DSSCs) with improved efficiencies by using SnO2/TiO2 composite photoanodes containing SnO2 at various concentrations. The composites consisted of hollow nanofibers (h-NFs) of SnO2 and TiO2 nanoparticles (NPs). The combination of the large surface area of the NPs and the efficient charge transport in the h-NFs make the use of the SnO2/TiO2 composites advantageous. DSSCs in which composite photoanodes with 50 wt% h-NFs were incorporated showed enhanced efficiencies that were 20% higher than the efficiencies of cells containing TiO2 NP-based photoanodes. These results indicated the improved electron diffusion length and shorter electron transfer time in the composite structures due to the crosslinking between h-NFs and NPs.

HL-217, a new topical anti-angiogenic agent, inhibits retinal vascular leakage and pathogenic subretinal neovascularization in Vldlr⁻/⁻ mice.

HL-217 is a new synthetic angiogenesis inhibitor. Platelet derived growth factor (PDGF) is a vasoactive factor and has been implicated in proliferative retinopathies. In this study, we examined the mechanism of action and efficacy of topical application of HL-217 on subretinal neovascularization in very low-density lipoprotein receptor knockout (Vldlr(-/-)) mice. In three-week-old male Vldlr(-/-) mice, HL-217 (1.5 or 3mg/ml) was administered twice per day for 4 weeks by topical eye drop instillation. Neovascular areas were then measured. We used a protein array to evaluate the expression levels of angiogenic factors. The inhibitory effect of HL-217 on the PDGF-BB/PDGFRß interaction was evaluated in vitro. The neovascular area in the Vldlr(-/-) mice was significantly reduced by HL-217. Additionally, HL-217 decreased the expression levels of PDGF-BB protein and VEGF mRNA. Moreover, HL-217 dose-dependently inhibited the PDGF-BB/PDGFRß interaction (IC50=38.9 ± 0.7 µM). These results suggest that HL-217 is a potent inhibitor of PDGF-BB. HL-217, when applied topically, is an effective inhibitor of subretinal neovascularization due to its ability to inhibit the pro-angiogenic effects of PDGF-BB.

Effects of Ethyl Acetate Extract of Poncirus trifoliata Fruit for Glucocorticoid-Induced Osteoporosis.

Poncirus trifoliata fruit (PTF) affects the digestive and cardiovascular systems, and kidney function. The authors studied the effects of ethyl acetate (EtOAc) extract of PTF on the activities of osteoblasts and in an animal model. The main compounds of the EtOAc extract, naringin and poncirin have been confi rmed by HPLC and NMR analysis. Effects of osteoblastic differentiation were mea-sured by alkaline phosphatase (ALP) activity, osteopontin (OPN) protein expression and osteoprotegerin (OPG) mRNA expression in MC3T3-E1 cells. Also, osteoclast differentiation was measured by multinucleated cells (MNCs) formation through tartrate resistance acid phosphatase (TRAP)-positive staining. Bone mineral density (BMD) was measured before and after treatment with EtOAc extract of PTF in prednisolone-induced osteoporotic mice. Dexamethasone (DEX) decreased OPN and OPG expression level in MC3T3-E1 cells and ALP activity was decreased by DEX dose-dependently. EtOAc extract of PTF recovered the levels of ALP activity, and the expression of OPN and OPG in MC3T3-E1 cells treated with DEX. In osteoclast differentiation, multinucleated TRAP-positive cell formation was significantly suppressed by the EtOAc extract of PTF. Total body BMD was restored by EtOAc extract of PTF in prednisolone-induced osteoporotic mice. In conclusion, EtOAc extract of PTF recovered DEX-mediated deteriorations in osteoblastic and osteoclastic functions, and increased BMD in glucocorticoid-induced osteoporosis.

In vitro and in vivo inhibition of glucocorticoid-induced osteoporosis by the hexane extract of Poncirus trifoliata.

This study was performed to discover a novel herbal therapeutic for effective glucocorticoid-induced osteoporosis (GIO) treatment and further to clarify its molecular mechanism of action. Ethanol or methanol extracts of 68 edible Korean native plants were screened to find effective natural plant sources for the treatment of GIO, and Poncirus trifoliata (L.) (Rutaceae, PT) was selected as a final candidate because of its high inhibitory activity plus its novelty. The hexane extract of PT (PT-H) inhibited apoptotic cell death in dexamethasone-induced osteoblastic cell lines, C3H10T1/2 and MC3T3-E1. In vivo mouse results indicated that PT-H not only had an inhibitory effect on the bone loss caused by glucocorticoid, but also promoted bone formation. The molecular mechanisms behind the effect of PT-H on GIO were further clarified by screening of differentially expressed genes (DEGs) between dexamethasone (Dex)-induced osteoblastic cells with or without PT-H treatment. Finally, it was found that the expression level of AnxA6 in Dex-induced osteoblastic cells and prednisolone (PD)-treated GIO-model mice was significantly decreased by PT-H treatment. These findings suggest that PT-H has a strong in vitro and in vivo inhibitory effect on GIO, and decreased expression of AnxA6 may play a key role in this inhibition.