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Sarcopenia, the age-related decline in muscle mass and function, is a significant contributor to increased frailty and mortality in the elderly. Currently, no FDA-approved treatment exists for sarcopenia. Here, we identified norharmane (NR), a β-carboline alkaloid, as a potential therapeutic agent for mitigating muscle aging. We aimed to determine the ability of NR to delay muscle aging in Caenorhabditis elegans (C. elegans), mouse, and muscle cells in mice and humans. NR treatment improved swimming ability and increased the maximum velocity in aged C. elegans. Transcriptomic analysis revealed that NR upregulated detoxification genes in C. elegans, including cytochrome P450, UGT, and GST enzymes. NR-induced benefits were dependent on the SKN-1/Nrf2 stress response pathway. In mammalian models, NR delayed cellular senescence in human skeletal muscle myoblasts and enhanced myogenesis in C2C12 cells and primary aged myoblasts. NR supplementation in aged mice prevented muscle loss, improved muscle function, and reduced markers of cellular senescence. We found that the p38 MAPK pathway mediated NR activation of Nrf2 by disrupting the Nrf2-Keap1 interaction. NR also improved oxygen consumption rates and promoted mitochondrial biogenesis. These findings suggest that NR is a promising candidate for preventing sarcopenia and improving muscle health.

Abstract Skeletal muscle atrophy occurs in several pathological conditions. Among other reasons, high-dose or long-term administration of glucocorticoids increases circulating glucocorticoid levels and causes muscle atrophy. The purpose of this study was to investigate whether Lithospermum erythrorhizon and Lonicera japonica complex extract (LELJ) has a beneficial effect on dexamethasone (Dexa)-induced muscle atrophy. In Dexa-induced myotube atrophy, treatment with LELJ increased myotube diameter, decreased the expression of muscle atrophy markers, and increased the expression of myosin heavy chain (MHC) isoforms. Supplementation with LELJ improved muscle function and performance in mice with Dexa-induced muscle atrophy as demonstrated by grip strength and running tests. Additionally, it increased skeletal muscle mass, size, and expression of MHC isoforms and protein synthesis-related markers. Furthermore, it reduced the upregulated protein levels of skeletal muscle atrophy markers in Dexa-treated mice. Supplementation with LELJ reversed Dexa-induced translocation of the glucocorticoid receptor and forkhead box O3 from the cytosol to the nucleus in skeletal muscles. LELJ also ameliorated age-related muscle loss by extending lifespan and increasing locomotor capacity in Caenorhabditis elegans. We identified loganin and lithospermic acid as bioactive compounds of LELJ and found that treatment with these agents increased myotube diameter, MHC isoform, and puromycin protein levels, and decreased atrophy markers in Dexa-treated myotubes. The current findings underscore how LELJ can prevent Dexa-induced skeletal muscle atrophy, attributing the effects to loganin and lithospermic acid.

The use of insects as a food source is not a new idea, but it has gained momentum in recent years due to the need for sustainable protein source in livestock feedstuffs and for more environmentally friendly organic waste treatment. In the case of black soldier fly larvae, Hermetia illucens, research has focused on their ability to convert organic waste into usable nutrients and their potential as a protein source for animal and human consumption. In this study, black soldier fly larvae were reared on raw food waste (FW) mixed with garlic peel waste (G) and hydronic growth media waste (H) and the proximate composition and bioactive potential of black soldier fly larvae extract (SFL) were compared. Analysis showed that protein content of SFL fed with G was 4.21% higher and lipid content was 9.93% lower than FW. Similar results were obtained for SFL fed with H. Antioxidant activity of SFL-G was higher than that of SFL-FW and SFL-H. SFL-G treatment exhibited enhanced anti-inflammatory and anti-adipogenesis activities as well compared to SFL-FW. Current results suggested that feeding black soldier fly larvae with food waste added with garlic peel and hydroponic growth media waste resulted in increased nutritional value, polyphenol content and bioactivity for SFLs. In this context, garlic peel waste-added food waste was suggested a promising substrate for black soldier fly larvae to obtain high-quality protein source with enhanced antioxidant, anti-inflammatory and anti-adipogenic potential.

Abstract Background Deep neural networks (DNNs) have the potential to revolutionize our understanding and treatment of genetic diseases. An inherent limitation of deep neural networks, however, is their high demand for data during training. To overcome this challenge, other fields, such as computer vision, use various data augmentation techniques to artificially increase the available training data for DNNs. Unfortunately, most data augmentation techniques used in other domains do not transfer well to genomic data. Results Most genomic data possesses peculiar properties and data augmentations may significantly alter the intrinsic properties of the data. In this work, we propose a novel data augmentation technique for genomic data inspired by biology: point mutations. By employing point mutations as substitutes for codons, we demonstrate that our newly proposed data augmentation technique enhances the performance of DNNs across various genomic tasks that involve coding regions, such as translation initiation and splice site detection. Conclusion Silent and missense mutations are found to positively influence effectiveness, while nonsense mutations and random mutations in non-coding regions generally lead to degradation. Overall, point mutation-based augmentations in genomic datasets present valuable opportunities for improving the accuracy and reliability of predictive models for DNA sequences.

Abstract Electrochemical nitrogen reduction reaction (NRR) is a sustainable alternative to the Haber‒Bosch process for ammonia (NH3) production. However, the significant uphill energy in the multistep NRR pathway is a bottleneck for favorable serial reactions. To overcome this challenge, we designed a vanadium oxide/nitride (V2O3/VN) hybrid electrocatalyst in which V2O3 and VN coexist coherently at the heterogeneous interface. Since single‐phase V2O3 and VN exhibit different surface catalytic kinetics for NRR, the V2O3/VN hybrid electrocatalyst can provide alternating reaction pathways, selecting a lower energy pathway for each material in the serial NRR pathway. As a result, the ammonia yield of the V2O3/VN hybrid electrocatalyst was 219.6 µg h−1 cm−2, and the Faradaic efficiency was 18.9%, which is much higher than that of single‐phase VN, V2O3, and VNxOy solid solution catalysts without heterointerfaces. Density functional theory calculations confirmed that the composition of these hybrid electrocatalysts allows NRR to proceed from a multistep reduction reaction to a low‐energy reaction pathway through the migration and adsorption of intermediate species. Therefore, the design of metal oxide/nitride hybrids with coherent heterointerfaces provides a novel strategy for synthesizing highly efficient electrochemical catalysts that induce steps favorable for the efficient low‐energy progression of NRR.

Enterprises typically install firewalls at communication points to their internal networks with the primary objective of protecting their core assets from external cyber attackers. This ensures unauthorized access is controlled and prevented. However, overly permissive policies and services with vulnerabilities can be exploited by attackers, providing them with pathways into internal systems. Therefore, firewall policies must be meticulously applied and managed. Given the significant ramifications of firewall policies, they must be continuously managed with high importance. As the number of policies increases and the amount of information to be processed grows, the process becomes complex, and there are limitations to managing policies from a human cognitive perspective. An increase in unmanaged misuse policies can inadvertently introduce security risks through unintended allowance policies. In the case of large-scale network networks operating multiple firewalls, a different form of misuse policy check and management is required compared to managing a single firewall policy. The proposed tool, HSViz-II, not only visualizes misuse of a single firewall policy but also visualizes four misuse cases in a distributed firewall environment, providing a detailed breakdown based on Octets. It displays the distribution of anomalous policies by dividing the Source IP into Octet Layers. For the four anomalous policy cases, it offers five views based on dividing the Source IP into Octet Layers and three overall views for upstream firewall, downstream firewall, and both, totaling 60 views. The processing speed for each function was measured using four sets of actual upstream and downstream firewall policies, comprising eight different firewall policies in total. Firewall operators can use this tool to grasp the distribution status of misuse policies in single and multiple firewalls and check the status of misuse policies by Octet. By offering a method for firewall operators to accurately find meaningful information, this paper proposes a firewall misuse policy visualization system in a distributed firewall environment to help reduce the risk of asset exposure to cyber threats for enterprises. HSViz-II tool can be found on the web site: https://youtu.be/jvR8ZY2uapQ

Abstract Background Muscle atrophy is characterized by decreased muscle mass, function, and strength. Synthetic glucocorticoids, including dexamethasone (Dexa), are commonly used to treat autoimmune diseases. However, prolonged exposure of Dexa with high dose exerts severe side effects, including muscle atrophy. The purpose of this study was to investigate whether Gromwell root extract (GW) can prevent Dexa-induced muscle atrophy in C2C12 cells and mice and to characterize the composition of GW to identify bioactive compounds. Methods For in vitro experiments, GW (0.5 and 1 µg/mL) or lithospermic acid (LA, 5 and 10 µM) was added to C2C12 myotubes on day 4 of differentiation and incubated for 24 h, along with 50 µM Dexa. For in vivo experiment, four-week-old male C57BL/6 mice were randomly divided into the four following groups (n = 7/group): Con group, Dexa group, GW0.1 group, and GW0.2 group. Mice were fed experimental diets of AIN-93 M with or without 0.1 or 0.2% GW for 4 weeks. Subsequently, muscle atrophy was induced by administering an intraperitoneal injection of Dexa at a dose of 15 mg/kg/day for 38 days, in conjunction with dietary intake. Results In Dexa-induced myotube atrophy, treatment with GW increased myotube diameter, reduced the expression of muscle atrophy markers, and enhanced the expression of myosin heavy chain (MHC) isoforms in C2C12 cells. Supplementation with the GW improved muscle function and performance in mice with Dexa-induced muscle atrophy, evidenced in the grip strength and running tests. The GW group showed increased lean body mass, skeletal muscle mass, size, and myosin heavy chain isoform expression, along with reduced skeletal muscle atrophy markers in Dexa-injected mice. Supplementation with GW increased protein synthesis and decreased protein degradation through the Akt/mammalian target of rapamycin and glucocorticoid receptor/forkhead box O3 signaling pathways, respectively. We identified LA as a potential bioactive component of the GW. LA treatment increased myotube diameter and decreased the expression of muscle atrophy markers in Dexa-induced C2C12 cells. Conclusions These findings underscore the potential of the GW in preventing Dexa-induced skeletal muscle atrophy and highlight the contribution of LA to its effects.

Summary: Background: The current pipeline for new antibiotics fails to fully address the significant threat posed by drug-resistant Gram-negative bacteria that have been identified by the World Health Organization (WHO) as a global health priority. New antibacterials acting through novel mechanisms of action are urgently needed. We aimed to identify new chemical entities (NCEs) with activity against Klebsiella pneumoniae and Acinetobacter baumannii that could be developed into a new treatment for drug-resistant infections. Methods: We developed a high-throughput phenotypic screen and selection cascade for generation of hit compounds active against multidrug-resistant (MDR) strains of K. pneumoniae and A. baumannii. We screened compound libraries selected from the proprietary collections of three pharmaceutical companies that had exited antibacterial drug discovery but continued to accumulate new compounds to their collection. Compounds from two out of three libraries were selected using “eNTRy rules” criteria associated with increased likelihood of intracellular accumulation in Escherichia coli. Findings: We identified 72 compounds with confirmed activity against K. pneumoniae and/or drug-resistant A. baumannii. Two new chemical series with activity against XDR A. baumannii were identified meeting our criteria of potency (EC50 ≤50 μM) and absence of cytotoxicity (HepG2 CC50 ≥100 μM and red blood cell lysis HC50 ≥100 μM). The activity of close analogues of the two chemical series was also determined against A. baumannii clinical isolates. Interpretation: This work provides proof of principle for the screening strategy developed to identify NCEs with antibacterial activity against multidrug-resistant critical priority pathogens such as K. pneumoniae and A. baumannii. The screening and hit selection cascade established here provide an excellent foundation for further screening of new compound libraries to identify high quality starting points for new antibacterial lead generation projects. Funding: BMBF and GARDP.

Abstract 2D materials are regarded as promising electrocatalysts for water splitting because of their advances in providing ample active sites and improving electrochemical reaction kinetics. 2D MoSe2 has a greater intrinsic electrical conductivity and lower Gibbs free energy for reactant adsorption. However, there is still room for improvement in the electrocatalytic performance of MoSe2 for high‐performance electrochemical water splitting devices. Herein, the in situ preparation of heterostructure made of covalently bonded MoSe2 and rGO is reported. The obtained electrocatalyst contains the aggregated 3D structured MoSe2 over rGO, which is covalently bonded together with more edge sites. The active edge sites of MoSe2/rGO are dynamically involved in the electrocatalytic activity while facilitating electron transfer. Hence, the MoSe2/rGO heterostructure requires a low cell voltage of 1.64 V to reach 100 mA cm−2 in water splitting with high reaction kinetics. The aggregated MoSe2 over rGO with more edge sites exposed by the 3D structure of MoSe2 and the interfacial covalent bond in between them provides a favorable electronic structure for the HER and OER with low overpotentials and high current densities and enhances the stability of the electrocatalyst. This work presents an attractive and cost‐effective electrocatalyst suitable for industrial‐scale hydrogen fuel production.

Objective: To explore the anti-melanogenic potential of Cyrtomium falcatum. Methods: The effects of Cyrtomium falcatum crude extract and its solvent fractions on tyrosinase activity, melanin content, and the expressions of melanogenesis-related genes and proteins were analyzed in α-melanocyte-stimulating hormone (α-MSH)-stimulated B16F10 cells. Results: α-MSH treatment significantly increased tyrosinase activity, and extracellular and intracellular melanin content, as well as the expression levels of tyrosinase, microphthalmia-associated transcription factor (MITF), tyrosinase-related protein (TRP)-1, and TRP-2 in B16F10 cells. Treatment with Cyrtomium falcatum crude extract and its solvent fractions reduced tyrosinase activity and extracellular and intracellular melanin content and downregulated the expression levels of tyrosinase, MITF, TRP-1, and TRP-2 in a dose-dependent manner. Conclusions: Cyrtomium falcatum has potential anti-melanogenesis effects and can be used as a potential source material in cosmeceutical industry for the research and development of novel lead molecules with whitening properties.

Red paprika (RP) is rich in carotenoids and capsanthin (CS) is its main carotenoid. We determined whether whole RP and CS can ameliorate obesogenic sarcopenia.C2C12 myotubes were co-treated with 500 μM of palmitic acid (PA) and 1 and 5 μg/mL RP or 0.5 and 1.0 μM CS for 24 h. Both RP and CS effectively attenuated PA-induced myotube atrophy. Male obese C57BL/6 mice (n = 40) were fed high-fat diets containing 5 and 10% RP or 0.025% CS for 10 weeks. Supplementation with RP and CS increased lean body mass, muscle performance, mtDNA content, and mitochondrial oxidative phosphorylation, while it decreased intracellular lipid accumulation in muscle tissue. Moreover, both RP and CS increased myosin heavy chains and decreased atrogens expression, which are associated with the activation of mTORC1 signaling. These results demonstrated that RP and CS protect against obesogenic sarcopenia by improving mitochondrial function.

Abstract The colloidal dispersion in a nonpolar medium is an essential material for electrophoretic displays (EPD) with low‐power consumption. A uniform‐sized superparamagnetic iron oxide nanoparticle (SPION) is a promising candidate for EPD, which exhibits tunable structural color by Bragg diffraction. In this study, the surface of SPION is charged in a nonpolar medium by inverse micelles of Solsperse‐17k, an oil‐soluble polymeric surfactant. A photonic ink of SPION dispersion exhibits simultaneous magnetochromism and electrochromism. The photonic ink is encapsulated via a complex coacervation process, in which double layers of gelatin/gum Arabic form a stable shell for µ‐capsule. The µ‐capsules show tunable structural colors, which depends upon the size of SPION in photonic ink. The increased surfactant content in photonic ink brings about a decrease in µ‐capsule size due to a reduced surface tension. A lowered gelatin concentration during coacervation results in a smaller µ‐capsule, which exhibits an electrical color tunability. Optical characterization using a confocal microscopy enables 3D visualization of the inner structure of µ‐capsules and the formation of particle chain structure of SPION in H‐field. The encapsulated photonic ink exhibits magnetochromism for 1 year, illuminating the long‐term stability of µ‐capsules developed in this study.

Machine learning techniques are extensively employed in drug discovery, with a significant focus on developing QSAR models that interpret the structural information of potential drugs. In this study, the pre-trained natural language processing (NLP) model, ChemBERTa, was utilized in the drug discovery process. We proposed and evaluated four core model architectures as follows: deep neural network (DNN), encoder, concatenation (concat), and pipe. The DNN model processes physicochemical properties as input, while the encoder model leverages the simplified molecular input line entry system (SMILES) along with NLP techniques. The latter two models, concat and pipe, incorporate both SMILES and physicochemical properties, operating in parallel and with sequential manners, respectively. We collected 5238 entries from DrugBank, including their physicochemical properties and absorption, distribution, metabolism, excretion, and toxicity (ADMET) features. The models’ performance was assessed by the area under the receiver operating characteristic curve (AUROC), with the DNN, encoder, concat, and pipe models achieved 62.4%, 76.0%, 74.9%, and 68.2%, respectively. In a separate test with 84 experimental microsomal stability datasets, the AUROC scores for external data were 78% for DNN, 44% for the encoder, and 50% for concat, indicating that the DNN model had superior predictive capabilities for new data. This suggests that models based on structural information may require further optimization or alternative tokenization strategies. The application of natural language processing techniques to pharmaceutical challenges has demonstrated promising results, highlighting the need for more extensive data to enhance model generalization.

Background: To investigate rural?urban differences in hospital-based care utilization among women of reproductive age (18?44 years). Methods: Rural?urban differences were estimated for hospital outpatient visits, emergency department (ED) visits, hospitalizations, and associated expenditures both overall and by insurance status, by analyzing a nationally representative sample of women of reproductive age from the Medical Expenditure Panel Survey (2006?2015). Results: The study sample consisted of 48,114 women of reproductive age. Unadjusted results showed that rural women reported higher likelihood of hospital outpatient visits (rural vs. urban: 17.10% vs. 13.34%) although, among those using such care, fewer average visits (rural vs. urban: 2.00 vs. 2.56 visits). Rural women reported higher likelihood of ED visits (rural vs. urban: 18.13% vs. 15.11%) and more hospital stays (rural vs. urban: 0.13 vs. 0.11 stays). Adjusted results showed rural women had higher likelihood of outpatient care use (+2.5 percentage points; 95% confidence interval [CI]?=?0.002?0.049) but fewer visits (?0.314 visits, 95% CI?=??0.566 to ?0.062). For the privately insured, rural women had greater likelihood of outpatient care (+3.1 percentage points, 95% CI?=?0.001?0.060) and fewer ED visits (?0.031 visits, 95% CI?=??0.061 to ?0.003); for the publicly insured, rural women had more hospital stays (+0.045 stays, 95% CI?=?0.009?0.083); for the uninsured, rural women had fewer outpatient visits among those using such care (?1.118 visits, 95% CI?=??1.865 to ?0.372) and shorter hospital stays overall (?0.093 nights, 95% CI?=??0.181 to ?0.005). Rural?urban expenditure differences were not significant between any insurance grouping. Conclusions: Rural?urban differences in hospital-based care utilization were observed, although somewhat heterogeneous by insurance status. Strengthening outpatient and preventive service access, particularly for publicly insured and uninsured rural women of reproductive age, is important for shifting care to lower cost settings and improving population health.

Hydrogen has become an indispensable aspect of sustainable energy resources due to depleting fossil fuels and increasing pollution. Since hydrogen storage and transport is a major hindrance to expanding its applicability, green ammonia produced by electrochemical method is sourced as an efficient hydrogen carrier. Several heterostructured electrocatalysts are designed to achieve significantly higher electrocatalytic nitrogen reduction (NRR) activity for electrochemical ammonia production. In this study, we controlled the nitrogen reduction performances of Mo2C-Mo2N heterostructure electrocatalyst prepared by a simple one pot synthesis method. The prepared Mo2C-Mo2N0.92 heterostructure nanocomposites show clear phase formation for Mo2C and Mo2N0.92, respectively. The prepared Mo2C-Mo2N0.92 electrocatalysts deliver a maximum ammonia yield of about 9.6 μg h-1 cm-2 and a Faradaic efficiency (FE) of about 10.15%. The study reveals the improved nitrogen reduction performances of Mo2C-Mo2N0.92 electrocatalysts due to the combined activity of the Mo2C and Mo2N0.92 phases. In addition, the ammonia production from Mo2C-Mo2N0.92 electrocatalysts is intended by the associative nitrogen reduction mechanism on Mo2C phase and by Mars-van-Krevelen mechanism on Mo2N0.92 phase, respectively. This study suggests the importance of precisely tuning the electrocatalyst by heterostructure strategy to substantially achieve higher nitrogen reduction electrocatalytic activity.

Abstract Background Although mounting evidence indicates that insulin resistance (IR) co‐occurs with mitochondrial dysfunction in skeletal muscle, there is no clear causal link between mitochondrial dysfunction and IR pathogenesis. In this study, the exact role of mitochondria in IR development was determined. Methods Six‐week‐old C57BL/6 mice were fed a high‐fat diet for 2 weeks to induce acute IR or for 24 weeks to induce chronic IR (n = 8 per group). To characterize mitochondrial function, we measured citrate synthase activity, ATP content, mitochondrial DNA (mtDNA) content, and oxygen consumption rate in gastrocnemius and liver tissues. We intraperitoneally administered mitochondrial division inhibitor 1 (mdivi‐1) to mice with acute IR and measured mitochondrial adaptive responses such as mitophagy, mitochondrial unfolded protein response (UPRmt), and oxidative stress (n = 6 per group). Results Acute IR occurred coincidently with impaired mitochondrial function, including reduced citrate synthase activity (−37.8%, P

Background: The COVID-19 pandemic has had a substantial adverse impact on the health and well-being of populations in the United States (US) and globally. Although COVID-19 vaccine disparities among US adults aged ≥18 years are well documented, COVID-19 vaccination inequalities among US children are not well studied. Using the recent nationally representative data, we examine disparities in COVID-19 vaccination among US children aged 5-17 years by a wide range of social determinants and parental characteristics. Methods: Using the US Census Bureau’s Household Pulse Survey from December 1, 2021 to April 11, 2022 (N=86,335), disparities in child vaccination rates by race/ethnicity, socioeconomic status, health insurance, parental vaccination status, parental COVID-19 diagnosis, and metropolitan area were modeled by multivariate logistic regression. Results: During December 2021–April 2022, an estimated 40.1 million or 57.2% of US children aged 5-17 received COVID-19 vaccination. Vaccination rates were lowest among children of parents aged 25-34 (34.9%) and highest among children of parents aged 45-54 (69.2%). Children of non-Hispanic Black parents, divorced/separated and single individuals, parents with lower education and household income levels, renters, not-employed parents, the uninsured, and parents without COVID-19 vaccination or with COVID-19 diagnoses had significantly lower rates of vaccination. Controlling for covariates, Asian and Hispanic children aged 5-17 had 134% and 47% higher odds of receiving vaccination than their non-Hispanic White counterparts. Children of parents with a high school education had 47% lower adjusted odds of receiving vaccination than children of parents with a master’s degree or higher. Children with annual household income

Background: Adolescents and young adults in the United States (US) have experienced a significant increase in drug overdose mortality rates in the last two decades. During the Coronavirus disease 2019 (COVID-19) pandemic, they experienced a lack of access to substance use disorder treatment, stay-home orders, school closure, social isolation, increased psychological distress, and financial strain. Few studies have examined the impact of the pandemic on monthly trends in drug-overdose mortality among youth by race/ethnicity. This study estimates differential changes in monthly drug overdose mortality among youth in the US by age, sex, and race/ethnicity. Methods: Monthly deaths from the final 2018-2020 national mortality data and the 2021 provisional mortality data were used, and monthly population estimates were obtained from the Census Bureau. We calculated age-specific monthly drug overdose deaths per one million population and used log-linear regression models to estimate monthly percent increases in mortality rates from January 2018 through October 2021. Results: Drug-overdose deaths among individuals aged 15-34 increased by 36.5% from 2019 (21,152 deaths) to 2020 (28,879 deaths). From February 2020 to May 2020, the drug-overdose mortality rate increased by 62% for males, 53% for females, 79% for Blacks, 62% for American Indians/Alaska Natives (AIANs), 57% for Hispanics, 56% for non-Hispanic Whites, and 47% for Asians. From January 2018 to October 2021, the average monthly drug-overdose mortality rate increased by 2.69% per month for Blacks, 2.54% for AIANs, 2.27% for Hispanics, 1.37% for Asians, and 0.81% for non-Hispanic Whites. Increases in drug-overdose mortality were more rapid among males than females and among youth aged 15-24 than youth aged 25-34. Conclusion and Global Health Implications: During the peak months in 2020 and 2021, the COVID-19 pandemic had a disproportionate impact by race/ethnicity on trends in drug overdose mortality among the youth. Drug overdose mortality rates increased faster among Blacks, Hispanics, AIANs, and Asians compared to non-Hispanic Whites. Copyright © 2022 Lee and Singh. Published by Global Health and Education Projects, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution License CC BY 4.0.

Mass transit systems, including subways and buses, are useful environments for studying the urban microbiome, as the vast majority of populations in urban areas use public transportation. Microbial communities in urban environments include both human- and environment-associated bacteria that play roles in health and pathogen transmission. In this study, we used shotgun metagenomic sequencing to profile microbial communities sampled from various surfaces found in subway stations and bus stops within the Seoul mass transit system. The metagenomic approach and network analysis were used to investigate broad-spectrum antibiotic resistance genes (ARGs) and their co-occurrence patterns. We uncovered 598 bacterial species in 76 samples collected from various surfaces within the Seoul mass transit system. All samples were dominated by the potential human pathogen Salmonella enterica (40 %) and the human skin bacterium Cutibacterium acnes (19 %). Significantly abundant biomarkers detected in subway station samples were associated with bacteria typically found in the human oral cavity and respiratory tract, whereas biomarkers detected in bus stop samples were associated with bacteria commonly found in soil, water, and plants. Temperature and location had significant effects on microbial community structure and diversity. In total, 41 unique ARG subtypes were identified, associated with single-drug or multidrug resistance to clinically important and extensively used antibiotics, including aminoglycosides, carbapenem, glycopeptide, and sulfonamides. We revealed that Seoul subway stations and bus stops possess unique microbiomes containing potential human pathogens and ARGs. These findings provide insights for refining location-specific responses to reduce exposure to potentially causative agents of infectious diseases, improving public health.

Skeletal muscle atrophy is characterized by reduced muscle function and size. Oxidative stress contributes to muscle atrophy but can be treated with antioxidants. This study investigated the antioxidant activity of a castor oil plant leaf (Ricinus communis L.) extract (RC) and its effects on muscle atrophy. Rutin was identified as the major compound among the thirty compounds identified in RC via LC-MS/MS and was found to inhibit dexamethasone (DEX)-induced muscle atrophy and mitochondrial oxidative stress. Rutin-rich RC showed DPPH and ABTS radical scavenging activities and efficiently reduced the DEX-induced myotube atrophy and mitochondrial oxidative damage in C2C12 cells. RC supplementation prevented the loss of muscle function and muscle mass in DEX-administered mice and ameliorated DEX-induced oxidative stress via Nrf2 signaling. Taken together, both RC and rutin ameliorated muscle atrophy and helped in maintaining redox homeostasis; hence, rutin-rich RC could be a promising functional food that is beneficial for muscle health.

Abstract Vertical sleeve gastrectomy (VSG) is the most commonly performed bariatric/metabolic surgery, exhibiting a high rate of diabetes remission in humans. To elucidate the molecular mechanisms of VSG, we performed transcriptomic analysis of the liver, fat, and muscle in VSG mice. C57BL/6 mice fed a high-fat diet were randomly assigned to sham or VSG surgery. The sham-operated mice were fed ad libitum (sham group) or pair-fed (sham-PF group) matching their food intake to the VSG-operated mice. Comparative transcriptomic analysis of the liver, fat, and muscle using RNA sequencing was performed. VSG reduced body weight and improved glucose tolerance compared to the sham group, but not more than the sham-PF group. Improvement in fatty liver and adipose tissue inflammation was comparable between VSG and sham-PF. However, global gene expression profiles showed distinctive changes in the liver, fat, and muscle of the VSG group compared to both the sham or sham-PF groups. The liver showed the most prominent gene expression changes. Immune response-related pathways were commonly upregulated in the three organs of the VSG group compared to the sham or sham-PF. VSG induces organ-specific gene expression changes in the liver, fat, and muscle, which may play critical roles in metabolic improvements after VSG.

Background & Aims: The development of nonalcoholic fatty liver disease (NAFLD) can be modulated by microRNAs (miRNA). Dietary polyphenols modulate the expression of miRNA such as miR-467b-3p in the liver. In addition, 6-gingerol (6-G), the functional polyphenol of ginger, has been reported to ameliorate hepatic steatosis; however, the exact mechanism involved and the role of miRNA remain elusive. In this study, we assessed the role of miR-467b-3p in the pathogenesis of hepatic steatosis and the regulation of miR-467b-3p by 6-G through the hepatocyte nuclear factor 4α (HNF4α). Methods: miR-467b-3p expression was measured in free fatty acid (FFA)-treated hepatocytes or liver from high-fat diet (HFD)-fed mice. Gain- or loss-of-function of miR-467b-3p was induced using miR-467b-3p–specific miRNA mimic or miRNA inhibitor, respectively. 6-G was exposed to FFA-treated cells and HFD-fed mice. The HNF4α/miR-467b-3p/GPAT1 axis was measured in mouse and human fatty liver tissues. Results: We found that miR-467b-3p was down-regulated in liver tissues from HFD-fed mice and in FFA-treated Hepa1-6 cells. Overexpression of miR-467b-3p decreased intracellular lipid accumulation in FFA-treated hepatocytes and mitigated hepatic steatosis in HFD-fed mice via negative regulation of glycerol-3-phosphate acyltransferase-1 (GPAT1). In addition, miR-467b-3p up-regulation by 6-G was observed. 6-G inhibited FFA-induced lipid accumulation and mitigated hepatic steatosis. Moreover, it increased the transcriptional activity of HNF4α, resulting in the increase of miR-467b-3p and subsequent decrease of GPAT1. HNF4α/miR-467b-3p/GPAT1 signaling also was observed in human samples with hepatic steatosis. Conclusions: Our findings establish a novel mechanism by which 6-G improves NAFLD. This suggests that targeting of the HNF4α/miR-467b-3p/GPAT1 cascade may be used as a potential therapeutic strategy to control NAFLD.

Most of the companies have firewalls in order to protect their internal networks and assets from the attacker of the cyber space. Firewall policies should be maintained and organized with high importance. However, considering the length of time needed in analyzing the highly complex policies and the risks of disabling firewall that may arise in case of a false policy setting. It is extremely hard to securely optimize the performance of firewalls. This paper is to suggest a visualization tool that shows the status and the types of policies applied throughout the firewalls so that such difficulties related to the maintenance of firewall policies can be resolved. The proposed tool is designed in six different angles; (1) Hierarchy-view, (2) Anomaly-view, (3) Distributed-view, (4) ANYPolicy-view, (5) SearchResult-view, and (6) Top and Bottom Used-view. The core of the overall function is to facilitate the easy identification of the policy interrelationships. The visualization tool has been tested by being applied across approximately 24 different firewall policies. The processing speed of each function and abuse detection rate were all reviewed positively. By the help of the tool, identifying the services, performance improvement, and visibility of the policy relations, which thereby will lead to better safety in preserving the assets intact. A video of the proposed visualization tool can be found on the web site: https://youtu.be/43OfHN8dteU

Background: Previous research has shown a significant association between psychological distress (PD) and all-cause mortality. However, there is a dearth of studies quantifying the contributions of sociodemographic and behavioral characteristics to group differences in mortality. In this study, we identify factors of mortality differences by PD. Methods: The Blinder-Oaxaca decomposition analysis was used to quantify the contributions of individual sociodemographic and behavioral characteristics to the observed mortality differences between United States (US) adults with no PD and those with serious psychological distress (SPD), using the pooled data from the 1997-2014 National Health Interview Survey prospectively linked to the 1997-2015 National Death Index (N = 263,825). Results: Low educational level, low household income, and high proportions of current smokers, renters, former drinkers, and adults experiencing marital dissolution contributed to high all-cause mortality among adults with SPD. The relative percentage of all-cause mortality disparity explained by socioeconomic and demographic factors was 38.86%. Approximately 47% of the mortality disparity was attributed to both sociodemographic and behavioral risk factors. Lower educational level (21.13%) was the top contributor to higher all-cause mortality among adults with SPD, followed by smoking status (13.51%), poverty status (11.77%), housing tenure (5.11%), alcohol consumption (4.82%), marital status (3.61%), and nativity/immigrant status (1.95%). Age, sex, and body mass index alleviated all-cause mortality risk among adults with SPD. Conclusions and Global Health Implications: Improved education and higher income levels, and reduced smoking among US adults with SPD might eliminate around half of the all-cause mortality disparity by SPD. Such a policy strategy might lead to reductions in mental health disparities and adverse health impacts both in the US and globally. Copyright © 2022 Lee et al. Published by Global Health and Education Projects, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution License CC BY 4.0.

Electrochromic technologies that exhibit low power consumption have been spotlighted recently. In particular, with the recent increase in demand for paper-like panel displays, faster coloration time has been focused on in researching electrochromic devices. Tungsten trioxide (WO3) has been widely used as an electrochromic material that exhibits excellent electrochromic performance with high thermal and mechanical stability. However, in a solid film-type WO3 layer, the coloration time was long due to its limited surface area and long diffusion paths of lithium ions (Li-ions). In this study, we attempted to fabricate a fibrous structure of WO3@poly(ethylene oxide) (PEO) composites through electrospinning. The fibrous and porous layer showed a faster coloration time due to a short Li-ion diffusion path. Additionally, PEO in fibers supports Li-ions being quickly transported into the WO3 particles through their high ionic conductivity. The optimized WO3@PEO fibrous structure showed 61.3 cm2/C of high coloration efficiency, 1.6s fast coloration time, and good cycle stability. Lastly, the electrochromic device was successfully fabricated on fabric using gel electrolytes and a conductive knitted fabric as a substrate and showed a comparable color change through a voltage change from −2.5 V to 1.5 V.

Determining the number of factors in exploratory factor analysis (EFA) is crucial because it affects the rest of the analysis and the conclusions of the study. Researchers have developed various methods for deciding the number of factors to retain in EFA, but this remains one of the most difficult decisions in the EFA. The purpose of this study is to compare the parallel analysis with the performance of fit indices that researchers have started using as another strategy for determining the optimal number of factors in EFA. The Monte Carlo simulation was conducted with ordered categorical items because there are mixed results in previous simulation studies, and ordered categorical items are common in behavioral science. The results of this study indicate that the parallel analysis and the root mean square error of approximation (RMSEA) performed well in most conditions, followed by the Tucker-Lewis index (TLI) and then by the comparative fit index (CFI). The robust corrections of CFI, TLI, and RMSEA performed better in detecting misfit underfactored models than the original fit indices. However, they did not produce satisfactory results in dichotomous data with a small sample size. Implications, limitations of this study, and future research directions are discussed.

Abstract Objectives This study evaluated the incidence of colorectal cancer (CRC) according to the number of metabolic syndrome (MetS) components. Methods Using health checkup and insurance claims data of 6,365,409 subjects, the occurrence of CRC according to stage of MetS by sex was determined from the date of the health checkup in 2009 until December 31, 2018. Results Cumulative incidence rates (CIR) of CRC in men and women was 3.9 and 2.8 per 1000 (p < 0.001), respectively. CIR of CRC for the normal, pre-MetS, and MetS groups in men was 2.6, 3.9, and 5.5 per 1000 (p < 0.001) and CIR in women was 2.1, 2.9, and 4.5 per 1000 (p < 0.001), respectively. Compared with the normal group, the hazard ratio (HR) of CRC for the pre-MetS group was 1.25 (95% CI 1.17–1.33) in men and 1.09 (95% CI 1.02–1.17) in women, and the HR of CRC for the MetS group was 1.54 (95% CI 1.43–1.65) in men and 1.39 (95% CI 1.26–1.53) in women after adjustment. Conclusions We found that MetS is a risk factor for CRC in this study. Therefore, the prevention and active management of MetS would contribute to the prevention of CRC.

Melanin protects the skin against UV damage, whereas excessive melanin accumulation causes abnormal pigmentation and even melanoma. It has been reported that Rosa rugosa exhibits antioxidant, anti-bacterial, anti-tumor, and anti-inflammation activities. The current study evaluated the melanogenesis-suppressing effect of R. rugosa extract and its solvent fractions (H2O, n-BuOH, 85% aq. MeOH, and n-hexane). The effect of R. rugosa on the extra/intra-cellular melanin and intracellular active tyrosinase levels, melanogenesis-related gene and protein expression, and PKA/CREB signaling pathway activation was investigated in α-MSH-induced B16F10 cells. The results showed that R. rugosa effectively suppressed melanin secretion and tyrosinase activity at non-cytotoxic concentrations. R. rugosa extract down-regulated the melanogenesis-related expression of genes and proteins of tyrosinase, microphthalmia-associated transcription factor (MITF), tyrosinase-related protein (TRP)-1, and TRP-2. Furthermore, R. rugosa effectively inhibited the phosphorylation of the PKA/CREB proteins. Finally, the total polyphenol content of R. rugosa crude extract and its H2O, n-BuOH, 85% aq. MeOH, and n-hexane solvent fractions were 1383.9 ± 44.5, 2004.7 ± 43.4, 7270.3 ± 54.5, 2064.1 ± 34.8, and 1091.1 ± 26.2 mg gallic acid equivalent/100 g extract, respectively. The anti-melanogenesis effect of R. rugosa was suggested to be exhibited by downregulating the PKA/CREB signaling pathway potentially due to a high content of polyphenols. Overall, R. rugosa crude extract and its solvent fractions could be considered sources of bioactive ingredients that can be used against hyperpigmentation.

With the increasing market share of ready-to-cook foods, accurate determination of the food freshness and thus food safety has emerged as a concern. To commercialize and popularize food sensing technologies, food sensors with diverse functionalities, low cost, and facile use must be developed. This paper proposes printable sensors based on a hydrogel-containing pH indicator to detect ammonia gas. The sensors were composed of biocompatible polymers such as 2-hydroxyethyl methacrylate (HEMA) and [2-(methacryloyloxy)ethyl] trimethylammonium chloride (MAETC). The p(HEMA-MAETC) hydrogel sensor with bromothymol blue (BTB) demonstrated visible color change as a function of ammonia concentration during food spoilage. Furthermore, polyacrylonitrile (PAN) was added to improve transport speed of ammonium ions as the matrix in the sensors and optimized the viscosity to enable successful printing. The color changed within 3 min at ammonia concentration of 300 ppb and 1 ppm, respectively. The sensor exhibited reproducibility over 10 cycles and selective exposure to various gases generated during the food spoilage process. In an experiment involving pork spoilage, the color change was significant before and after exposure to ammonia gas within 8 h in ambient conditions. The proposed sensor can be integrated in bar codes and QR codes that are easily mass produced.

Studies in rats, monkeys, and humans have found action-value signals in multiple regions of the brain. These findings suggest that action-value signals encoded in these brain structures bias choices toward higher expected rewards. However, previous estimates of action-value signals might have been inflated by serial correlations in neural activity and also by activity related to other decision variables. Here, we applied several statistical tests based on permutation and surrogate data to analyze neural activity recorded from the striatum, frontal cortex, and hippocampus. The results show that previously identified action-value signals in these brain areas cannot be entirely accounted for by concurrent serial correlations in neural activity and action value. We also found that neural activity related to action value is intermixed with signals related to other decision variables. Our findings provide strong evidence for broadly distributed neural signals related to action value throughout the brain.

The identification of optimal drug candidates is very important in drug discovery. Researchers in biology and computational sciences have sought to use machine learning (ML) to efficiently predict drug–target interactions (DTIs). In recent years, according to the emerging usefulness of pretrained models in natural language process (NLPs), pretrained models are being developed for chemical compounds and target proteins. This study sought to improve DTI predictive models using a Bidirectional Encoder Representations from the Transformers (BERT)-pretrained model, ChemBERTa, for chemical compounds. Pretraining features the use of a simplified molecular-input line-entry system (SMILES). We also employ the pretrained ProBERT for target proteins (pretraining employed the amino acid sequences). The BIOSNAP, DAVIS, and BindingDB databases (DBs) were used (alone or together) for learning. The final model, taught by both ChemBERTa and ProtBert and the integrated DBs, afforded the best DTI predictive performance to date based on the receiver operating characteristic area under the curve (AUC) and precision-recall-AUC values compared with previous models. The performance of the final model was verified using a specific case study on 13 pairs of subtrates and the metabolic enzyme cytochrome P450 (CYP). The final model afforded excellent DTI prediction. As the real-world interactions between drugs and target proteins are expected to exhibit specific patterns, pretraining with ChemBERTa and ProtBert could teach such patterns. Learning the patterns of such interactions would enhance DTI accuracy if learning employs large, well-balanced datasets that cover all relationships between drugs and target proteins.

Since 2014, 32 states implemented Medicaid expansion by removing the categorical criteria for childless adults and by expanding income eligibility to 138% of the federal poverty level (FPL) for all non-elderly adults. Previous studies found that the Affordable Care Act (ACA) Medicaid expansion improved rates of being insured, unmet needs for care due to cost, number of physician visits, and health status among low-income adults. However, a few recent studies focused on the expansion’s effect on racial/ethnic disparities and used the National Academy of Medicine (NAM) disparity approach with a limited set of access measures. This quasi-experimental study examined the effect of Medicaid expansion on racial/ethnic disparities in access to health care for U.S. citizens aged 19 to 64 with income below 138% of the federal poverty line. The difference-in-differences model compared changes over time in 2 measures of insurance coverage and 8 measures of access to health care, using National Health Interview Survey (NHIS) data from 2010 to 2016. Analyses used the NAM definition of disparities. Medicaid expansion was associated with significant decreases in uninsured rates and increases in Medicaid coverage among all racial/ethnic groups. There were differences across racial/ethnic groups regarding which specific access measures improved. For delayed care and unmet need for care, decreases in racial/ethnic disparities were observed. After the ACA Medicaid expansion, most access outcomes improved for disadvantaged groups, but also for others, with the result that disparities were not significantly reduced.

Background: This study examines trends and inequalities in US maternal mortality from indirect obstetric causes (ICD-10 codes: O98-O99) and specific chronic conditions by maternal race/ethnicity, socioeconomic status, nativity/immigrant status, marital status, place and region of residence, and cause of death. Methods: National vital statistics data from 1999 to 2017 were used to compute maternal mortality rates by sociodemographic factors. Rate ratios and log-linear regression were used to model mortality trends and differentials. Results: During 1999-2017, maternal mortality from indirect causes showed an upward trend; the annual rates increased by 11.2% for the overall population, 12.9% for non-Hispanic Whites, and 9.4% for non-Hispanic Blacks. The proportion of all maternal deaths due to indirect causes increased from 12.0% in 1999 to 26.9% in 2017. Maternal mortality from CVD increased sharply over time, from 0.40/100,000 live births in 1999 to 1.82 in 2017. During 2013-2017, compared to non-Hispanic Whites, non-Hispanic Blacks had 83% higher, Hispanics 51% lower, and Asian/Pacific Islanders 55% lower mortality from indirect causes. Non-Hispanic White women with

Objectives: Socioeconomic disparities in life expectancy in the United States (US) are marked and have widened over time. However, there is limited research using individual-level socioeconomic variables as such information is generally lacking or unreliable in vital records used for life table construction. Using longitudinal cohort data, we computed life expectancy for US adults by social determinants such as education, income/poverty level, occupation, and housing tenure. Methods: We analyzed the 1997-2014 National Health Interview Survey prospectively linked to mortality records in the National Death Index (N=1,146,271). Standard life table methodologies were used to compute life expectancy and other life table functions at various ages according to socioeconomic variables stratified by sex and race/ethnicity. Results: Adults with at least a Master’s degree had 14.7 years higher life expectancy at age 18 than those with less than a high school education and 8.3 years higher life expectancy than those with a high school education. Poverty was inversely related to life expectancy. Individuals living in poverty had 10.5 years lower life expectancy at age 18 than those with incomes ≥400% of the poverty threshold. Laborers and those employed in craft and repair occupations had, respectively, 10.9 years and 8.6 years lower life expectancy at age 18 than those with professional and managerial occupations. Male and female renters had, respectively, 4.0 years and 4.6 years lower life expectancy at age 18 than homeowners. Women in the most advantaged socioeconomic group outlived men in the most disadvantaged group by 23.5 years at age 18. Conclusions and Global Health Implications: Marked socioeconomic gradients in US life expectancy were found across all sex and racial/ethnic groups. Adults with lower education, higher poverty levels, in manual occupations, and with rental housing had substantially lower life expectancy compared to their counterparts with higher socioeconomic position. Copyright © 2021 Singh and Lee. Published by Global Health and Education Projects, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in this journal, is properly cited.

Background: Despite having one of the highest Gross Domestic Product (GDP) per capita levels, United States (US) ranks lower in subjective well-being, including happiness and life satisfaction, compared with European countries. Studies of the impact of happiness and life satisfaction on life expectancy and mortality in the US are limited or non-existent. Using a national longitudinal dataset, we examined the association between levels of happiness/life satisfaction and US life expectancy and all-cause mortality. Methods: We analyzed the 2001 National Health Interview Survey (NHIS) prospectively linked to 2001-2014 mortality records in the National Death Index (NDI) (N=30,377). Cox proportional hazards regression was used to model survival time as a function of happiness, life satisfaction, and sociodemographic and behavioral covariates. Results: Life expectancies at age 18 among adults with high levels of happiness and life satisfaction were, respectively, 7.5 and 8.9 years higher compared to those with low levels of happiness and life satisfaction. In Cox models with 14 years of mortality follow-up, all-cause mortality risk was 82% higher (hazard ratio [HR]=1.82; 95% CI=1.59,2.08) in adults with little or no happiness, controlling for age, and 36% higher (HR=1.36; 95% CI=1.17,1.57) in adults with little/no happiness, controlling for sociodemographic, behavioral and health characteristics, when compared with adults reporting happiness all of the time. Mortality risk was 107% higher (HR=2.07; 95% CI=1.80,2.38) in adults who were very dissatisfied with their life, controlling for age, and 39% higher (HR=1.39; 95% CI=1.20,1.60) in adults who were very dissatisfied, controlling for all covariates, when compared with adults who were very satisfied. Conclusions and Global Health Implications: Adults with higher happiness and life satisfaction levels had significantly higher life expectancy and lower all-cause mortality risks than those with lower happiness and satisfaction levels. These findings underscore the significance of addressing subjective well-being in the population as a strategy for reducing all-cause mortality. Key words: • Inequalities • Disparities • Happiness • Life satisfaction • Life expectancy • Mortality • Longitudinal • Social determinants Copyright © 2020 Lee and Singh. Published by Global Health and Education Projects, Inc. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work, first published in this journal, is properly cited.

Objective: Despite the long-term decline, heart disease has remained the leading cause of death in the United States (US) over the past eight decades, accounting for 23% of all deaths in 2017. Although psychological distress has been associated with cardiovascular disease mortality, the relationship between different psychological distress levels and heart disease mortality in the US has not been analyzed in detail. Using a national longitudinal dataset, we examined the association between levels of psychological distress and US heart disease mortality. Methods: We analyzed the Kessler 6-item psychological distress scale as a risk factor for heart disease mortality using the pooled 1997-2014 data from the National Health Interview Survey (NHIS) linked to National Death Index (NDI) (N=513,081). Cox proportional hazards regression was used to model survival time as a function of psychological distress and sociodemographic and behavioral covariates. Results: In Cox models with 18 years of mortality follow-up, the heart disease mortality risk was 121% higher (hazard ratio [HR]=2.21; 95% CI=1.99,2.45) in adults with serious psychological distress (SPD) (p

Tuberous sclerosis complex–associated renal cell carcinoma (TSC-RCC) has distinct clinical and histopathologic features and is considered a specific subtype of RCC. The genetic alterations of TSC1 or TSC2 are responsible for the development of TSC. In this study, we assessed the mTOR pathway activation and aimed to evaluate molecular characteristics and pathogenic pathways of TSC-RCC. Two cases of TSC-RCC, one from a 31-year-old female and the other from an 8-year-old male, were assessed. The mTOR pathway activation was determined by immunohistochemistry. The mutational spectrum of both TSC-RCCs was evaluated by whole exome sequencing (WES), and pathogenic pathways were analyzed. Differentially expressed genes were analyzed by NanoString Technologies nCounter platform. The mTOR pathway activation and the germline mutations of TSC2 were identified in both TSC-RCC cases. The WES revealed several cancer gene alterations. In Case 1, genetic alterations of CHD8, CRISPLD1, EPB41L4A, GNA11, NOTCH3, PBRM1, PTPRU, RGS12, SETBP1, SMARCA4, STMN1, and ZNRF3 were identified. In Case 2, genetic alterations of IWS1 and TSC2 were identified. Further, putative pathogenic pathways included chromatin remodeling, G protein–coupled receptor, Notch signaling, Wnt/β-catenin, PP2A and the microtubule dynamics pathway in Case 1, and mRNA processing and the PI3K/AKT/mTOR pathway in Case 2. Additionally, the ALK and CRLF2 mRNA expression was upregulated and CDH1, MAP3K1, RUNX1, SETBP1, and TSC1 mRNA expression was downregulated in both TSC-RCCs. We present mTOR pathway activation and molecular characteristics with pathogenic pathways in TSC-RCCs, which will advance our understanding of the pathogenesis of TSC-RCC.

The randomized control trial (RCT) is the primary experimental design in education research due to its strong internal validity for causal inference. However, in situations where RCTs are not feasible or ethical, quasi-experiments are alternatives to establish causal inference. This paper serves as an introduction to several quasi-experimental designs: regression discontinuity design, difference-in-differences analysis, interrupted time series design, instrumental variable analysis, and propensity score analysis with examples in education research.

The continuous rise of antimicrobial resistance urgently demands new therapeutic agents for human health. Drug repurposing is an attractive strategy that could significantly save time delivering new antibiotics to clinics. We screened 182 US Food and Drug Administration (FDA)-approved drugs to identify potential antibiotic candidates against Staphylococcus aureus, a major pathogenic bacterium. This screening revealed the significant antibacterial activity of three small molecule drugs against S. aureus: (1) LDK378 (Ceritinib), an anaplastic lymphoma kinase (ALK) inhibitor for the treatment of lung cancer, (2) dronedarone HCl, an antiarrhythmic drug for the treatment of atrial fibrillation, and (3) eltrombopag, a thrombopoietin receptor agonist for the treatment of thrombocytopenia. Among these, eltrombopag showed the highest potency against not only a drug-sensitive S. aureus strain but also 55 clinical isolates including 35 methicillin-resistant S. aureus (Minimum inhibitory concentration, MIC, to inhibit 50% growth [MIC50] = 1.4–3.2 mg/L). Furthermore, we showed that eltrombopag inhibited bacterial growth in a cell infection model and reduced bacterial loads in infected mice, demonstrating its potential as a new antibiotic agent against S. aureus that can overcome current antibiotic resistance.

Purpose The dose of drug and the size of instrument are determined based on children’s weight. We aimed to validate the finger counting method (FCM) for weight estimation in Korean children using the Monte Carlo simulation. Methods We estimated the weight of Korean children aged 1 to 9 years by the FCM. These measurements were compared with the weight extracted by the Monte Carlo simulation applied to the “2007 Korean Children and Adolescents Growth Standard.” Pearson correlation coefficients (r) were measured to assess the correlation between the weight extracted by the simulation and that estimated by FCM. Bland-Altman analyses were performed to assess the agreement between the weight extracted by the simulation and that estimated by FCM and 2 other well-known pediatric weight estimation formulas (the Advanced Pediatric Life Support and Luscombe formulas). Results Data regarding 9,000 children’s weight selected by age and gender was randomly extracted using the simulation. We found a positive correlation between the weight estimated by the FCM and the weight extracted (in boys, r = 0.896, P < 0.001; in girls, r = 0.899, P < 0.001). The FCM tended to underestimate weight in the children aged 7 years or old. Conclusion This article suggests the usefulness of FCM in weight estimation, particularly in children younger than 7 years. With appreciation of the limitation in older children, the FCM could be applied to emergency practice.

BackgroundRural health disparities and access gaps may contribute to higher maternal and infant morbidity and mortality. Understanding and addressing access barriers for specialty women's health services is important in mitigating risks for adverse childbirth events. The objective of this study was to investigate rural-urban differences in health care access for women of reproductive age by examining differences in past-year provider visit rates by provider type, and quantifying the contributing factors to these findings.Methods and findingsUsing a nationally-representative sample of reproductive age women (n = 37,026) from the Medical Expenditure Panel Survey (2010-2015) linked to the Area Health Resource File, rural-urban differences in past-year office visit rates with health care providers were examined. Blinder-Oaxaca decomposition analysis quantified the portion of disparities explained by individual- and county-level sociodemographic and provider supply characteristics. Overall, there were no rural-urban differences in past-year visits with women's health providers collectively (65.0% vs 62.4%), however differences were observed by provider type. Rural women had lower past-year obstetrician-gynecologist (OB-GYN) visit rates than urban women (23.3% vs. 26.6%), and higher visit rates with family medicine physicians (24.3% vs. 20.9%) and nurse practitioners/physician assistants (NPs/PAs) (24.6% vs. 16.1%). Lower OB-GYN availability in rural versus urban counties (6.1 vs. 13.7 providers/100,000 population) explained most of the rural disadvantage in OB-GYN visit rates (83.8%), and much of the higher family physician (80.9%) and NP/PA (50.1%) visit rates. Other individual- and county-level characteristics had smaller effects on rural-urban differences.ConclusionAlthough there were no overall rural-urban differences in past-year visit rates, the lower OB-GYN availability in rural areas appears to affect the types of health care providers seen by women. Whether rural women are receiving adequate specialized women's health care services, while seeing a different cadre of providers, warrants further investigation and has particular relevance for women experiencing high-risk pregnancies and deliveries.

The primary cause of colorectal cancer (CRC) recurrence is increased distant metastasis after radiotherapy, so there is a need for targeted therapeutic approaches to reduce the metastatic-relapse risk. Dysregulation of the cell-surface glycoprotein podocalyxin-like protein (PODXL) plays an important role in promoting cancer-cell motility and is associated with poor prognoses for many malignancy types. We found that CRC cells exposed to radiation demonstrated increased TGFβ and PODXL expressions, resulting in increased migration and invasiveness due to increased extracellular matrix deposition. In addition, both TGFβ and PODXL were highly expressed in tissue samples from radiotherapy-treated CRC patients compared to those from patients without this treatment. However, it is unclear whether TGFβ and PODXL interactions are involved in cancer-progression resistance after radiation exposure in CRC. Here, using CRC cells, we showed that silencing PODXL blocked radiation-induced cell migration and invasiveness. Cell treatment with galunisertib (a TGFβ-pathway inhibitor) also led to reduced viability and migration, suggesting that its clinical use may enhance the cytotoxic effects of radiation and lead to the effective inhibition of CRC progression. Overall, the results demonstrate that downregulation of TGFβ and its-mediated PODXL may provide potential therapeutic targets for patients with radiotherapy-resistant CRC.

This study aims to identify and synthesize recent literature on the effect and strategies of flipped learning in the health professions education. Participant–intervention-comparator-outcome (PICO) strategies were used to identify articles from published peer-reviewed papers from January 2017 to March 2020 in Korea Med, Korean Citation Index, National Digital Science Library, and Korean Studies Information Service System. Of the 83 screened articles, 10 published articles met all the inclusion criteria. Most of articles targeted nursing students and focused on practicum classes. The effects of flipped learning were measured based on satisfaction, self-motivated learning, information literacy, and critical thinking disposition. Further, pre-class, in-class, and post-class activities were analyzed. The findings revealed that flipped learning improved class performance, overall evaluation, self-motivated learning, self-efficacy, and problem-solving abilities. The study suggests implementing a tailored flipped learning design based on class characteristics and appropriate post-class activities for enhancing students’ learning abilities.

BackgroundPatients with atrial fibrillation are known to have a high risk of mortality. There is a paucity of population-based studies about the impact of atrial fibrillation on the mortality risk stratified by age, sex, and detailed causes of death.MethodsA total of 15,411 patients with atrial fibrillation from the Korean National Health Insurance Service-National Sample Cohort were enrolled, and causes of death were identified according to codes of the 10th revision of the International Classification of Diseases.ResultsFrom 2002 to 2013, a total of 4,479 (29%) deaths were confirmed, and the crude mortality rate for all-cause death was 63.3 per 1,000 patient-years. Patients with atrial fibrillation had a 3.7-fold increased risk of all-cause death compared with the general population. The standardized mortality ratio for all-cause death was the highest in young patients and decreased with increasing age (standardized mortality ratio 21.93, 95% confidence interval 7.60-26.26 in patients aged ConclusionsPatients with atrial fibrillation had a 4 times increased risk of mortality compared with the general population. However, the impact of atrial fibrillation on mortality decreased with age and in men. Cerebral infarction was the most common cause of death, and more attention should be paid to reducing the risk of stroke.

An analytical method to measure solubilized orthophosphate ions (HPO42− and PO43− ) from the water-insoluble food additives calcium phosphate dibasic (DCP) and calcium phosphate tribasic (TCP) in processed foods was optimized by comparing ion chromatography (IC) coupled with DS6 conductivity detector (Cond.) and high-performance liquid chromatography (HPLC) with Evaporative light scattering detector (ELSD) methods. The ion-pairing HPLC method could analyze calcium and phosphate ions successively. However, this method exhibited low reproducibility after approximately 48 hours of measurements. The IC method was established as an effective method of measuring orthophosphate ions with high reproducibility using distilled water and KOH solution as the mobile phase with a Dionex column. Matrix-based limit of detections (LOD) and limit of quantifications (LOQ) for snacks and cereals were estimated in the range of 0.01−0.91 µg/mL and 0.21−2.74 µg/mL, respectively. In inter-day and intra-day tests, the calculated precision (%RSD) and accuracy (recovery %) ranged from 0.5% to 6.6% and 82% to 117%, respectively, in both food samples. The levels of DCP or TCP could be analyzed in various positive food samples, and the developed IC method demonstrated good applicability in the analysis of DCP and TCP in collected processed foods.

This study concerns the role of short- and long-wave radiant flux densities from different directions in complex urban settings for human thermal comfort on clear-sky summer days. The aims of the investigation are to quantify the importance of the sky view factor as an urban design-dependent variable for the 3-D radiant flux densities absorbed by the standardized human-biometeorological reference person and to analyze the varying impact of the absorbed 3-D short- and long-wave radiant flux densities on the mean radiant temperature (Tmrt$T_{\text{mrt}}$), near-surface air temperature (Ta$T_{\text{a}}$) and physiologically equivalent temperature (PET).The results obtained by measuring campaigns and numerical simulations point to the different importance of the absorbed 3-D radiant flux densities for human thermal comfort characterized by Ta$T_{\text{a}}$, Tmrt$T_{\text{mrt}}$ and PET. The magnitude of Tmrt$T_{\text{mrt}}$ is mainly determined by the total of the absorbed 3-D long-wave radiant flux densities. However, the fluctuations of Tmrt$T_{\text{mrt}}$ are mainly governed by the total of the absorbed 3-D short-wave radiant flux densities. Their variance can be well explained by the variance of the sky view factor related to the southern part of the upper half space. Taking account of the different impact of the 3-D radiant flux densities, Tmrt$T_{\text{mrt}}$ can be quite well estimated by a multiple regression using the total of the absorbed 3-D short-wave radiant flux densities and the absorbed long-wave radiant flux density from the lower half space as independent variables. PET can be well estimated by a multiple regression showing Tmrt$T_{\text{mrt}}$ and Ta$T_{\text{a}}$ as independent variables. On a hot summer day, the increase of the albedo of vertical building walls within a simple E-W oriented street canyon leads to a decrease of the surface temperature of the S-facing wall, but to an increase of Tmrt$T_{\text{mrt}}$ and PET at the S-facing sidewalk.

BackgroundCystoscopic procedure is a very common practice in the field of urology due to its ability to survey the bladder for a variety of indications. However, patients who undergo cystoscopy feel intense pain and discomfort. This study investigated the half maximal effective concentration (EC50) of remifentanil in preventing cystoscope insertion pain under sedation using dexmedetomidine.MethodsThe study was prospectively conducted on 18 male patients, aged 18 to 65. Remifentail infusion was initiated together with dexmedetomidine, and started at a dose of 2.4 ng/ml on the first patient. The effect-site concentration (Ce) of remifentanil for each subsequent patient was determined by the previous patient's response using Dixon's up-and-down method with an interval of 0.3 ng/ml. Patients received a loading dose of 1.0 µg/kg dexmedetomidine over 10 minutes, followed by a maintenance dose of 0.6 µg/kg/hr. After the patient's OAA/S score (Observer's Assessment of Alertness/Sedation scale) reached 3-4, and the Ce of remifentanil reached target concentration, the urologist was allowed to insert the cystoscope and the pain responses were observed.ResultsThe effect-site concentration of remifentanil required to prevent cystoscope insertion pain in 50% of patients under sedation using dexmedetomidine was 1.30 ± 0.12 ng/ml by Dixon's up-and-down method. The logistic regression curve of the probability of response showed that the EC50 and EC95 values (95% confidence limits) of remifentanil were 1.33 ng/ml (1.12-1.52 ng/ml) and 1.58 ng/ml (1.44-2.48 ng/ml), respectively.ConclusionsCystoscopic procedure can be carried out successfully without any pain or adverse effects by optimal remifentanil effect-site concentration (EC50, 1.33 ng/ml; EC95, 1.58 ng/ ml) combined with sedation using dexmedetomidine.

Abstract Sirtuin 1 (SIRT1) plays a critical role in the maintenance of metabolic homeostasis and promotes fat mobilization in white adipose tissue. However, regulation of SIRT1 during adipogenesis, particularly through microRNAs, remains unclear. We observed that miR‐146b expression was markedly increased during adipogenesis in 3T3‐L1 cells. Differentiation of 3T3‐L1 was induced by overexpression of miR‐146b. Conversely, inhibition of miR‐146b decreased adipocyte differentiation. Bioinformatics‐based studies suggested that SIRT1 is a target of miR‐146b. Further analysis confirmed that SIRT1 was negatively regulated by miR‐146b. We also observed that miR‐146b bound directly to the 3′‐untranslated region of SIRT1 and inhibited adipogenesis through SIRT1 downregulation. The miR‐146b/SIRT1 axis mediates adipogenesis through increased acetylation of forkhead box O1 (FOXO1). Expression of miR‐146b was increased and SIRT1 mRNA subsequently decreased in the adipose tissues of diet‐induced and genetically obese mice. Furthermore, in vivo knockdown of miR‐146b by a locked nucleic acid miR‐146b antagomir significantly reduced body weight and fat volume in accordance with upregulation of SIRT1 and subsequent acetylation of FOXO1. Therefore, the miR‐146b/SIRT1 pathway could be a potential target for obesity prevention and treatment.

BackgroundAlthough cisatracurium has many advantages in anesthetic practices, the best choice of a nondepolarizing neuromuscular blocking agent that can replace succinylcholine is rocuronium. However, it is reported that remifentanil with propofol might provide reliable intubating condition, even without a neuromuscular blocking agent; therefore, it might improve the intubating condition with cisatracurium. This study examined intubating conditions after administering rocuronium or cisatracurium in a rapid sequence induction with remifentanil-propofol.MethodsFifty two ASA physical status 1 or 2 adult patients scheduled for an elective surgery were enrolled in a randomized double-blinded trial. Anesthesia was induced in all patients with propofol 2.0 mg/kg and remifentanil 0.5 µg/kg, administered over 60 seconds. Rocuronium 0.9 mg/kg (3 × ED95, R group, n = 23) or cisatracurium 0.15 mg/kg (3 × ED95, C group, n = 29) was administered after the induction sequence. Laryngoscopy was attempted when the anesthesiologist thought it was 90 seconds after drug administration and appropriate time for intubation. The examiner, another anesthesiologist, recorded the exact time to intubation and suppression of maximal T1 on TOF. The intubating condition was assessed by the first anesthesiologist, as excellent, good, poor or not possible.ResultsThe best time to laryngoscopy was predicted by measuring TOF and was found to be significantly longer in the C group (197 ± 53 s) than in the R group (102 ± 49 s) (P value < 0.05). However, time to larygoscopy, intubating condition during the laryngoscopy, and hemodynamic changes after intubation was similar in both groups.ConclusionsDespite fundamentally slower onset time, cisatracurium can provide quite good intubating conditions, which were comparable to those achieved with equipotent doses of rocuronium, which is more expensive in anesthesia inducted with remifentanil and propofol.

We demonstrate a fast response colorimetric humidity sensor using a crosslinked poly(2-hydroxyethyl methacrylate) (PHEMA) in the form of inverse opal photonic gel (IOPG) soaked in 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM+][BF4−]), a non-volatile hydrophilic room temperature ionic liquid (IL). An evaporative colloidal assembly enabled the fabrication of highly crystalline opal template, and a subsequent photopolymerization of PHEMA followed by solvent-etching and final soaking in IL produced a humidity-responsive IOPG showing highly reflective structural color by Bragg diffraction. Three IOPG sensors with different crosslinking density were fabricated on a single chip, where a lightly crosslinked IOPG exhibited the color change response over entire visible spectrum with respect to the humidity changes from 0 to 80% RH. As the water content increased in IL, thermodynamic interactions between PHEMA and [BMIM+][BF4−] became more favorable, to show a red-shifted structural color owing to a longitudinal swelling of IOPG. Highly porous IO structure enabled fast humidity-sensing kinetics with the response times of ~1 min for both swelling and deswelling. Temperature-dependent swelling of PHEMA in [BMIM+][BF4−] revealed that the current system follows an upper critical solution temperature (UCST) behavior with the diffraction wavelength change as small as 1% at the temperature changes from 10 °C to 30 °C.