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Insulin receptor (IR) signaling defects cause a variety of metabolic diseases including diabetes. Moreover, inherited mutations of the IR cause severe insulin resistance, leading to early morbidity and mortality with limited therapeutic options. A previously reported selective IR agonist without sequence homology to insulin, S597, activates IR and mimics insulin's action on glycemic control. To elucidate the mechanism of IR activation by S597, we determine cryo-EM structures of the mouse IR/S597 complex. Unlike the compact T-shaped active IR resulting from the binding of four insulins to two distinct sites, two S597 molecules induce and stabilize an extended T-shaped IR through the simultaneous binding to both the L1 domain of one protomer and the FnIII-1 domain of another. Importantly, S597 fully activates IR mutants that disrupt insulin binding or destabilize the insulin-induced compact T-shape, thus eliciting insulin-like signaling. S597 also selectively activates IR signaling among different tissues and triggers IR endocytosis in the liver. Overall, our structural and functional studies guide future efforts to develop insulin mimetics targeting insulin resistance caused by defects in insulin binding and stabilization of insulin-activated state of IR, demonstrating the potential of structure-based drug design for insulin-resistant diseases., (© 2022. The Author(s).)

Background: Previous studies have shown a close relationship between skipping breakfast and nutritional deficiency. However, the impact of regular eating, including lunch and dinner, has not been studied well. We explored the correlation between regularity and frequency of daily meals and nutritional status., Methods: We analyzed Korea National Health and Nutrition Examination Surveys between 2016 and 2018. A total of 7,725 adults aged 19-49 years were classified into four groups according to the regularity of meal intake: three-meal regular diet (3MRD), two-meal regular diet, one-meal regular diet, and irregular diet (IRD). Food and nutrient intake was assessed using the 24-hour recall method and estimated by a generalized linear model in complex sample weight variables., Results: In IRD, there were relatively more females who were not married, lived alone, or reported low levels of education. As subjects ate more meals, more people felt thinner and healthier by themselves. Dietary intake of cereal, vegetables, seaweed, and fiber was directly proportional to the number of regular meals as well as essential components such as water, carbohydrates, protein, fat, and micronutrients. Contrarily, alcohol and beverage consumption was inversely proportional to the number of regular meals. Intake level of legumes, fish, fruits, seasonings, milk, oils, sugars, and cholesterol was consistent regardless of meal frequency., Conclusion: Our findings suggest that 3MRD showed nutrient adequacy and a healthier profile on body weight, body mass index, waist circumference, blood pressure, serum fasting glucose, total cholesterol, and triglyceride.

We aim to investigate common diagnoses and risk factors for emergency department (ED) visits as well as those for hospitalization and death after ED visits. This study describes the clinical course of ED visits by using the 2014-2015 population data retrieved from the National Health Insurance Service. Sociodemographic, medical, and behavioral factors were analyzed through multiple logistic regression. Older people were more likely to be hospitalized or to die after an ED visit, but younger people showed a higher risk for ED visits. Females were at a higher risk for ED visits, but males were at a higher risk for ED-associated hospitalization and death. Individuals in the highest quartile of income had a lower risk of ED death relative to lowest income level individuals. Disabilities, comorbidities, and medical issues, including previous ED visits or prior hospitalizations, were risk factors for all ED-related outcomes. Unhealthy behaviors, including current smoking, heavy alcohol consumption, and not engaging in regular exercise, were also significantly associated with ED visits, hospitalization, and death. Common diagnoses and risk factors for ED visits and post-visit hospitalization and death found in this study provide a perspective from which to establish health polices for the emergency medical care system.

The assembly of metal nanoparticles and targets to be detected in a small light probe volume is essential for achieving sensitive in-solution surface-enhanced Raman spectroscopy (SERS). Such assemblies generally require either chemical linkers or templates to overcome the random diffusion of the colloids unless the aqueous sample is dried. Here, a facile method is reported to produce 3D multiscale assemblies of various colloids ranging from molecules and nanoparticles to microparticles for sensitive in-solution SERS detection without chemical linkers and templates by exploiting photothermally driven convective flow. The simulations suggest that colloids sub 100 nm in diameter can be assembled by photothermally driven convective flow regardless of density; the assembly of larger colloids up to several micrometers by convective flow is significant only if their density is close to that of water. Consistent with the simulation results, the authors confirm that the photothermally driven convective flow is mainly responsible for the observed coassembly of plasmonic gold nanorods with either smaller molecules or larger microparticles. It is further found that the coassembly with the plasmonic nanoantennae leads to dramatic Raman enhancements of molecules, microplastics, and microbes by up to fivefold of magnitude compared to those measured in solution without the coassembly., (© 2022 Wiley-VCH GmbH.)

Reactive oxygen species (ROS) regulate various physiological and pathological conditions in cells by interacting with signaling molecules and inducing oxidative stress. Therefore, sensitive monitoring of ROS levels in living cells is important to track cellular state and study the complex role of ROS in the development of various pathologies. Herein, we present an optically tunable plasmonic interface covered with graphene to monitor cellular ROS levels with superior sensitivity and cellular comfortability. As a sensing principle, we employed plasmon resonance energy transfer (PRET)-based spectral quenching dips modulated by redox-active cytochrome c for real-time monitoring. By transferring graphene layers to plasmonic nanoparticles immobilized on a glass substrate, the scattering profiles of the nanoprobes were adjusted in terms of the position, width, and intensity of the peaks to determine the optimal conditions for measuring the PRET signal. Using the optimized graphene-covered plasmonic nanoprobe, we obtained calibration curves over a wide concentration range from femtomoles to millimoles for hydrogen peroxide based on the change in the PRET signal. Before monitoring cellular ROS, we confirmed that a high density of cells adhered well to the graphene-covered plasmonic interface by observing immunofluorescence images of the cytoskeleton of the immobilized cells. Finally, we monitored the real-time ROS generated by the cells under oxidative stress conditions by directly measuring the spectral changes of the probes around the cells. We believe that the proposed graphene-covered tunable plasmonic interface has versatile applicability for investigating cellular stress and disease progression by monitoring ROS levels under various cellular conditions., (© 2022. The Author(s).)

Insulin receptor (IR) signaling controls multiple facets of animal physiology. Maximally four insulins bind to IR at two distinct sites, termed site-1 and site-2. However, the precise functional roles of each binding event during IR activation remain unresolved. Here, we showed that IR incompletely saturated with insulin predominantly forms an asymmetric conformation and exhibits partial activation. IR with one insulin bound adopts a Γ-shaped conformation. IR with two insulins bound assumes a Ƭ-shaped conformation. One insulin binds at site-1 and another simultaneously contacts both site-1 and site-2 in the Ƭ-shaped IR dimer. We further show that concurrent binding of four insulins to sites-1 and -2 prevents the formation of asymmetric IR and promotes the T-shaped symmetric, fully active state. Collectively, our results demonstrate how the synergistic binding of multiple insulins promotes optimal IR activation., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

The adsorptive removal of acetaldehyde is more compatible for real-world applications. However, it must be upgraded from simple adsorption to a high efficiency process with value added products. This study develops a modified zeolite with Mg 2+ ions that possesses acid-base sites for the removal of acetaldehyde at room temperature. Through a modified procedure, MgO is coated on commercial zeolite (13x), achieving a porosity of 501 m 2  g -1 with MgO particles of 100 nm and pore diameter of 2.6 nm, and high breakthrough capacity of 50.00 mg/g. The initial pH and concentration of Mg 2+ ion 12.5 and 0.2 M, respectively, with a maximum breakthrough capacity of 12.72 mg/g at 10% humidity. Significant variations in breakthrough capacity with respect to humidity in the presence of H 2 S and NH 3 demonstrate the effects of water and gases on adsorption efficiency. Desorptive oxidation of adsorbed acetaldehyde at 250 °C yielded a high molecular weight intermediate ethylene oxide formation. The oxidation is followed by aldol condensation and hydrogenation. The higher breakthrough capacity and the intermediate product yielded using the developed MgO-zeolite proves the acid-base reaction sites involved in acetaldehyde removal follows chemisorption and possible process scale-up., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Dynamics of release and cellular uptake of aqueous CO from CO-releasing molecules (CORMs) significantly affect signaling and cell viability. So far, it has been mainly observed by IR, UV-visible, and fluorescence techniques, which suffer from poor sensitivity and slow response time. Here, we show how to directly probe the mass transfer of aqueous CO from CORMs to cells using a fluidic chamber integrated with live cells and Raman reporters of large-area Au@Pd core-shell nanoparticle assembly to emulate a physiologically relevant microenvironment. We sensitively and directly detect CO release from trace CORMs of as low as 100 nM by measuring the Raman transitions of CO via rapid chemisorption onto the surface of the Au@Pd nanoparticles. By using our method, we successfully observe the dynamics of CO release from CORM-2 despite its very short half-life. We also reveal that the initial rate of CO release from CORM-3 is dramatically decreased by tens to hundreds of times when exposed to physiologically relevant pH variations from 7.4 to 2.5, which can be attributed to the acid hydrolysis of the CO ligand. CORM-2 tends to quickly release CO regardless of pH, probably because of its rapid cleavage into two monomeric Ru complexes by the co-solvent. The decrease in the initial rate at lower temperatures is more significant for CORM-3 than for CORM-2. Finally, we observe that the cellular uptake of aqueous CO from CORM-3 by lung cancer cells is approximately 2 times higher than that of normal lung cells.

Background: The present study aimed to translate the Fear of COVID-19 Scale (FCV-19S) into the Korean language and test the validity and reliability of the translated Korean version., Methods: An online questionnaire survey was conducted with 300 adults (aged ≥19 years) living in South Korea. The data collection period was 1 June to 15 October 2020. The Korean version of the FCV-19S (KFCV-19S) was tested in terms of content validity, construct validity, criterion validity, item response theory, and reliability., Results: When the content and construct validity of the FCV-19S was tested, the results showed that all items could be retained in the Korean version. When the criterion validity was tested based on correlation analysis between the KFCV-19S and the State-Trait Anxiety Inventory, the results showed a positive correlation (r = 0.53, p < 0.001). Item suitability test results showed that all items were within the reference value of 0.5-1.5. Internal consistency reliability test results showed a Cronbach's alpha of 0.81., Conclusion: The applicability of the KFCV-19S for identifying the level of fear Korean people experience regarding COVID-19 was verified. This tool is recommended for use in future assessments of Korean populations regarding levels of fear and anxiety regarding COVID-19.

Oral squamous cell carcinoma (OSCC) frequently invades the maxillary or mandibular bone, and this bone invasion is closely associated with poor prognosis and survival. Here, we show that CCL28 functions as a negative regulator of OSCC bone invasion. CCL28 inhibited invasion and epithelial-mesenchymal transition (EMT), and its inhibition of EMT was characterized by induced E-cadherin expression and reduced nuclear localization of β-catenin in OSCC cells with detectable RUNX3 expression levels. CCL28 signaling via CCR10 increased retinoic acid receptor-β (RARβ) expression by reducing the interaction between RARα and HDAC1. In addition, CCL28 reduced RANKL production in OSCC and osteoblastic cells and blocked RANKL-induced osteoclastogenesis in osteoclast precursors. Intraperitoneally administered CCL28 inhibited tumor growth and osteolysis in mouse calvaria and tibia inoculated with OSCC cells. RARβ expression was also increased in tumor tissues. In patients with OSCC, low CCL28, CCR10, and RARβ expression levels were highly correlated with bone invasion. Patients with OSCC who had higher expression of CCL28, CCR10, or RARβ had significantly better overall survival. These findings suggest that CCL28, CCR10, and RARβ are useful markers for the prediction and treatment of OSCC bone invasion. Furthermore, CCL28 upregulation in OSCC cells or CCL28 treatment can be a therapeutic strategy for OSCC bone invasion.

Introduction: Previous occasional successes after delayed replantation suggest that the presence of viable cells may not be the only factor for successful periodontal regeneration in delayed replantation. Various other factors such as proteins or the extracellular matrix (ECM) may play a role in this process. The purpose of this study was to characterize changes in the proteome components of periodontal ligament (PDL) tissue after hypothermic preservation of the tooth., Methods: Extracted teeth were divided into 4 groups: immediate sampling, sampling after 1 week of preservation at 4°C, sampling after 2 weeks of preservation at 4°C, and sampling after 1 week of dry storage at room temperature as a negative control. PDL tissues were collected from the root and stored immediately in liquid nitrogen. The tissues were subjected to 2-dimensional gel electrophoresis, and spot selection was executed. Selected spots that maintained the protein volume were then processed with matrix-assisted laser desorption and ionization time-of-flight mass spectrometry to identify the nature of the proteins., Results: Thirty-five selected spots were analyzed. Sixteen spots were identified as vimentin, and 3 spots were type VI collagen. The size of the 16 vimentin spots decreased gradually with increasing storage time, from 0 to 2 weeks, and decreased rapidly after dry storage. However, only the dry storage group differed significantly from the immediately sampled group., Conclusions: Vimentin was the most prominent protein followed by type VI collagen in volumetrically maintained protein spots. Although these proteins are known to be closely related with ECM integrity, the role of these proteins in delayed replantation is beyond the scope of this study. Further studies are needed to elucidate the possible role of these proteins for periodontal healing of delayed replantation., (Copyright © 2017 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

High recurrence and lower survival rates in patients with oral squamous cell carcinoma (OSCC) are associated with its bone invasion. We identified the oncogenic role of RUNX3 during bone invasion by OSCC. Tumor growth and the generation of osteolytic lesions were significantly inhibited in mice that were subcutaneously inoculated with RUNX3-knockdown human OSCC cells. RUNX3 knockdown enhanced TGF-β-induced growth arrest and inhibited OSCC cell migration and invasion in the absence or presence of transforming growth factor-β (TGF-β), a major growth factor abundant in the bone microenvironment. RUNX3 knockdown induced cell cycle arrest at the G1 and G2 phases and promoted G2 arrest by TGF-β in Ca9.22 OSCC cells. RUNX3 knockdown also inhibited both the basal and TGF-β-induced epithelial-to-mesenchymal transition by increasing E-cadherin expression and suppressing the nuclear translocation of β-catenin. In addition, the expression and TGF-β-mediated induction of parathyroid hormone-related protein (PTHrP), one of key osteolytic factors, was blocked in RUNX3-knockdown OSCC cells. Furthermore, treating human osteoblastic cells with conditioned medium derived from RUNX3-knockdown OSCC cells reduced the receptor activator of nuclear factor-kappaB ligand (RANKL)/osteoprotegerin ratio compared with treatment with conditioned medium from RUNX3-expressing cells. These findings indicate that RUNX3 expression in OSCC cells contributes to their bone invasion and the resulting osteolysis by inducing their malignant behaviors and production of osteolytic factors. RUNX3 alone or in combination with TGF-β and PTHrP may be a useful predictive biomarker and therapeutic target for bone invasion by oral cancer.

Non-small cell lung cancer (NSCLC) frequently metastasizes to bone, which is associated with significant morbidity and a dismal prognosis. RUNX3 functions as a tumour suppressor in lung cancer and loss of expression occurs more frequently in invasive lung adenocarcinoma than in pre-invasive lesions. Here, we show that RUNX3 and RUNX3-regulated chemokines are linked to NSCLC-mediated bone resorption. Notably, the receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) ratio, an index of osteoclastogenic stimulation, was significantly increased in human osteoblastic cells treated with conditioned media derived from RUNX3-knockdown NSCLC cells. We aimed to identify RUNX3-regulated factors that modify the osteoblastic RANKL/OPG ratio and found that RUNX3 knockdown led to CCL5 up-regulation and down-regulation of CCL19 and CXCL11 in NSCLC cells. Tumour size was noticeably increased and more severe osteolytic lesions were induced in the calvaria and tibiae of mice that received RUNX3-knockdown cells. In response to RUNX3 knockdown, serum and tissue levels of CCL5 increased, whereas CCL19 and CXCL11 decreased. Furthermore, CCL5 increased the proliferation, migration, and invasion of lung cancer cells in a dose-dependent manner; however, CCL19 and CXCL11 did not show any significant effects. The RANKL/OPG ratio in osteoblastic cells was increased by CCL5 but reduced by CCL19 and CXCL11. CCL5 promoted osteoclast differentiation, but CCL19 and CXCL11 reduced osteoclastogenesis in RANKL-treated bone marrow macrophages. These findings suggest that RUNX3 and related chemokines are useful markers for the prediction and/or treatment of NSCLC-induced bone destruction., (© 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.)