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CNS Drug discovery has been challenging due to the lack of clarity on CNS diseases' basic biological and pathological mechanisms. Despite the difficulty, some CNS drugs have been developed based on phenotypic effects. Herein, we propose a phenotype-structure relationship model, which predicts an anti-neuroinflammatory potency based on 3D molecular structures of the phenotype-active or inactive compounds without specifying targets. For this chemo-centric study, a predictive model of the nitric oxide (NO) inhibitory potency in hyper-activated microglia is built from the 548 agents, which were collected from 95 research articles (28 substructures consisting of natural products and synthetic scaffolds) and doubly externally validated by the agents of 9 research articles as third set. 3D Structures (multi-conformer ensemble) of every agent were encoded into the E3FP molecular fingerprint of the Keiser group as a 3D molecular representation. The location information of the molecular fingerprints could be learned and validated to classify the inhibitory potency of compounds (IC50 cut-off between the active and inactive: 37.1 µM): (1) multi-layer perceptron (MLP) (AUC-CV: 0.997, AUC-Test: 0.992), (2) recurrent neural network (RNN) (AUC-CV: 0.999, AUC-Test: 0.995), and (3) convolutional neural network (CNN) (AUC-CV: 0.998, AUC-Test: 0.994). The high performance of these models was compared with that of four classical machine classification models (Logistic, Ridge, Lasso, and Naïve Bayes). We named the binary classification models NO-Classifier. Independent test set validation and decision region analysis of the independent test set doubly demonstrated NO-Classifier effectively discerned the anti-inflammatory potency of testing compounds in inflammatory cell phenotype with the webserver in https://no-classifier.onrender.com. [ABSTRACT FROM AUTHOR]

Purpose: Invasive mucinous adenocarcinoma (IMA) of the lungs is a rare subtype of lung adenocarcinoma with a limited understanding of its prognosis, particularly in advanced stages. This study aimed to assess the prognosis of patients with advanced IMA by focusing on treatment modalities. Methods: This single-center retrospective study evaluated 33 patients with IMAs diagnosed with advanced-stage disease or disease progression after curative treatment between 2011 and 2021. The primary outcome was overall survival (OS), and the secondary outcome was progression-free survival (PFS). OS and PFS were calculated from the date of the diagnosis of advanced IMA. Results: The study cohort included 13 patients at the initial advanced stage and 20 patients who progressed after curative treatment. Treatment modalities included conventional chemotherapy in 24 patients (72.7%), targeted therapy in seven (21.2%), immunotherapy in 13 (39.4%), and local ablative therapy (LAT) in 13 (39.4%). The median OS was 32 months (95% confidence interval [CI], 2.9–61.0), with LAT significantly associated with improved OS compared to non-LAT treatment (not reached vs. 11.3 months, p = 0.001). However, there was no significant difference in OS based on conventional chemotherapy (p = 0.396), targeted therapy (p = 0.655), or immunotherapy (p = 0.992). In multivariate analysis, LAT remained an independent prognostic factor for OS (hazard ratio, 0.125; 95% CI, 0.026–0.608; p = 0.01). PFS was 8.6 months (95% CI, 3.6–13.7), with no significant differences observed among the treatment modalities. Conclusion: Our findings suggest that LAT may provide favorable survival outcomes in patients with advanced IMA. [ABSTRACT FROM AUTHOR]

Purpose: Gadolinium (Gd)-based contrast agents are primarily used for contrast-enhanced magnetic resonance lymphangiography (MRL). However, overcoming venous contamination issues remains challenging. This study aims to assess the MRL efficacy of the newly developed iron-based contrast agent (INV-001) that is specially designed to mitigate venous contamination issues. The study further explores the optimal dosage, including both injection volume and concentration, required to achieve successful visualization of the popliteal lymph nodes and surrounding lymphatic vessels. Procedures. All animals utilized in this study were male Sprague–Dawley (SD) rats weighing between 250 and 300 g. The contrast agents prepared were injected intradermally in the fourth phalanx of both hind limbs using a 30-gauge syringe in SD rats. MRL was performed every 16 min on a coronal 3D time-of-flight sequence with saturation bands using a 9.4-T animal machine. Results: Contrary to Gd-DOTA, which exhibited venous contamination in most animals irrespective of injection dosages and conditions, INV-001 showed no venous contamination. For Gd-DOTA, the popliteal lymph nodes and lymphatic vessels reached peak enhancement 16 min after injection from the injection site and then rapidly washed out. However, with INV-001, they reached peak enhancement between 16 and 32 min after injection, with prolonged visualization of the popliteal lymph node and lymphatic vessels. INV-001 at 0.45 μmol (15 mM, 30 μL) and 0.75 μmol (15 mM, 50 μL) achieved high scores for qualitative image analysis, providing good visualization of the popliteal lymph nodes and lymphatic vessels without issues of venous contamination, interstitial space enhancement, or lymph node enlargement. Conclusion: In MRL, INV-001, a novel T1 contrast agent based on iron, enables prolonged enhancement of popliteal lymph nodes and lymphatic vessels without venous contamination. [ABSTRACT FROM AUTHOR]

Objectives: Polo-like kinase 1 (Plk1) is an important mitotic protein. In particular, this protein is highly overexpressed in many types of tumors and has been identified as a potential biomarker for the treatment and diagnosis of tumors. Plk1 is composed of two domains, an N-terminal kinase domain and a C-terminal polo-box domain (PBD). Presently, inhibitors with improved selectivity and specificity for Plk1 are unavailable. Therefore, we aimed to develop an inhibitor targeting the C-terminal PBD present only in Plk1. Methods & results: In this study, three derivatives targeting PBD for Plk1 were designed by protein–protein interactions, which showed high levels of selectivity and specificity for Plk1 PBD, and were evaluated to inhibit tumor cell proliferation through an apoptotic process during tumor cell division. The investigation of the in vitro and in vivo antitumor effects of these inhibitors demonstrated that one of the new small molecules, 1, is a promising anticancer agent. Conclusion: Our findings can provide new insights for the design of novel Plk1 peptide inhibitors in the future. [ABSTRACT FROM AUTHOR]

Objectives: To determine the concordance of dynamic contrast-enhanced (DCE) imaging findings with clinico-pathologic characteristics and their prognostic impact for predicting biochemical recurrence (BCR) in patients who underwent radical prostatectomy (RP) for prostate cancer. Methods: This retrospective study included patients who underwent MRI within 1 year after RP between November 2019 and October 2020. DCE findings and their concordance with the presence and location of positive surgical margin (PSM) were assessed using RP specimens. Kaplan–Meier and logistic regression analyses were used to evaluate the prognostic impact of DCE findings for BCR. Results: Among the 272 men (mean age ± standard deviation, 66.6 ± 7.4 years), focal nodular enhancement was more frequently observed in those with PSM compared to those with negative margin (85.4% versus 14.6%; p < 0.001). The sites of focal nodular enhancement were 72.9% (35/48) concordant with the PSM locations. Focal nodular enhancement was associated with a higher Gleason score, higher preoperative PSA (≥ 10 ng/mL), higher Gleason grade at the surgical margin, and non-limited margin involvement (p = 0.002, 0.006, 0.032, and 0.001, respectively). In patients without BCR at the time of MRI, focal nodular enhancement was associated with a shorter time to BCR (p < 0.001) and a significant factor predicting 1-year BCR in both univariate (odds ratio = 8.4 [95% CI: 2.5–28.3]; p = 0.001) and multivariate (odds ratio = 5.49 [1.56–19.3]; p = 0.008) analyses. Conclusions: Focal nodular enhancement on post-prostatectomy MRI was associated with adverse clinico-pathologic characteristics of high risk for recurrence and can be a predictor for 1-year BCR in patients undergoing RP. Key Points: • Focal nodular enhancement (PI-RR DCE score ≥ 4) was 72.9% (35/48) concordant with the site of positive resection margin by radiologic-histologic correlation. • Focal nodular enhancement (PI-RR DCE score ≥ 4) was associated with higher Gleason score (≥ 8), preoperative PSA (> 10 ng/mL), and Gleason grade 4 or 5 at the surgical margin and non-limited margin involvement (p ≤ 0.032). • In patients without BCR at the time of MRI, focal nodular enhancement was a significant factor predicting 1-year BCR (odds ratio = 5.49; 95% CI: 1.56–19.3; p = 0.008). [ABSTRACT FROM AUTHOR]

Lung cancer is the second most commonly reported type of cancer worldwide. Approximately 80–85% of lung cancer occurrences are accounted by non-small cell lung cancer (NSCLC). Polo-like kinase-1 (Plk1) plays multiple roles in cell cycle progression and its overexpression is observed in majority of malignancies, including NSCLC. A combination of frontline drugs and inhibitors targeting the Plk kinase domain (KD) has been used to overcome drug resistance in NSCLC. Plk1 KD inhibitors are highly prone to cross-reactivity with similar kinases, eventually leading to undesirable side effects. Moreover, there have been no reports of Plk1 PBD inhibitors showing antitumorigenic effects on NSCLC cells or animal models so far. To address this issue herein, for the first time, our recently reported Plk1 PBD inhibitor KBJK557 was evaluated for the anticancer potential against NSCLC cells. KBJK557 displayed notable cytotoxic effects in A549, PC9, and H1975 cells. Mechanistic investigations revealed that KBJK557-treated cells underwent G2/M cell cycle arrest, triggering subsequent apoptosis. In vivo antitumorigenic activity in xenograft mice model demonstrates that KBJK557-treated mice showed a considerable decrease in tumor size, proving the significances of Plk1 in lung cancer. Collectively, this study demonstrates that KBJK557 can serve as a promising drug candidate for treating the lung cancer through Plk1 PBD inhibition. [ABSTRACT FROM AUTHOR]

Molecular insights into chemical safety are very important for sustainable development as well as risk assessment. This study considers how to manage future upcoming harmful agents, especially potentially cholinergic chemical warfare agents (CWAs). For this purpose, the structures of known cholinergic agents were encoded by molecular descriptors. And then each drug target interaction (DTI) was learned from the encoded structures and their cholinergic activities to build DTI classification models for five cholinergic targets with reliable statistical validation (ensemble-AUC: up to 0.790, MCC: up to 0.991, accuracy: up to 0.995). The collected classifiers were transformed into 2D or 3D array type meta-predictors for multi-task: (1) cholinergic prediction and (2) CWA detection. The detection ability of the array classifiers was verified under the imbalanced dataset between CWAs and none CWAs (area under the precision-recall curve: up to 0.997, MCC: up to 0.638, F1-score of none CWAs: up to 0.991, F1-score of CWAs: up to 0.585). [ABSTRACT FROM AUTHOR]

Virtual screening has significantly improved the success rate of early stage drug discovery. Recent virtual screening methods have improved owing to advances in machine learning and chemical information. Among these advances, the creative extraction of drug features is important for predicting drug–target interaction (DTI), which is a large-scale virtual screening of known drugs. Herein, we report Kullbeck–Leibler divergence (KLD) as a DTI feature and the feature-driven classification model applicable to DTI prediction. For the purpose, E3FP three-dimensional (3D) molecular fingerprints of drugs as a molecular representation allow the computation of 3D similarities between ligands within each target (Q–Q matrix) to identify the uniqueness of pharmacological targets and those between a query and a ligand (Q–L vector) in DTIs. The 3D similarity matrices are transformed into probability density functions via kernel density estimation as a nonparametric estimation. Each density model can exploit the characteristics of each pharmacological target and measure the quasi-distance between the ligands. Furthermore, we developed a random forest model from the KLD feature vectors to successfully predict DTIs for representative 17 targets (mean accuracy: 0.882, out-of-bag score estimate: 0.876, ROC AUC: 0.990). The method is applicable for 2D chemical similarity. [ABSTRACT FROM AUTHOR]

Accumulating evidence shows that nut consumption beneficially affects health outcomes. The purpose of this study was to investigate the association between the intake of nuts, focusing on their mineral contents, and the risk of hypertension in nationally representative samples in Korea. A cross-sectional study was conducted among 12,113 subjects (4762 men and 7351 women) aged 19–64 years using raw data from KNHANES 2016–2019. Daily intake of 20 nuts and 9 minerals from nuts was assessed using the 24-h recall method. The risk of hypertension according to the median mineral intake from nuts and nuts themselves was assessed using logistic regression analysis with adjustment for potential confounders. The average daily nut intake was 4.34 g for females and 3.78 g males. Among nut intake, chestnuts represented the highest value at 0.95 g/day, followed by peanuts (0.72 g/day), almonds (0.62 g/day), sesame seeds (0.62 g/day), perilla seeds (0.33 g/day), and walnuts (0.32 g/day). The daily intake of minerals from nuts was significantly higher in the nut-overmedian (OM) group than in the nut-undermedian (UM) group. Regarding mineral intake from nuts, each mineral-UM group showed higher odds of hypertension than the mineral-OM group in women, but not in men. After adjustment for potential confounders, an inverse association between nut consumption, including minerals obtained from nuts, and hypertension prevalence, especially in women, was observed. Based on our results, it is suggested that incorporation of nuts into a daily diet may yield beneficial effects and lower the risk of hypertension in adult Korean women. [ABSTRACT FROM AUTHOR]

This study aims to demonstrate the need for learner-corpus-informed applications and proposes methods of application that promote the proper use of Korean topic and nominative markers. This study extracted 3004 pieces of error from the error-annotated corpus of the Korean Learners' Corpus, the largest Korean learner corpus to date. A detailed examination of the above data was conducted to subdivide the types of substitution errors related to the topic and nominative markers, and to analyze the error rate according to the type of error and level of proficiency. The statistical data revealed no consistent correlation between the error rate and proficiency level. Furthermore, based on the proportion of error types by proficiency level, this study proposes the use of common mistake boxes with real errors; these errors are generally committed by learners of all proficiency levels and are not presumed problematic by grammarians or intuition-based teachers. These boxes can, therefore, be utilized as a practical tool for inclusion in pedagogical materials, such as learner's dictionaries and textbooks. [ABSTRACT FROM AUTHOR]

Objectives: To develop a simplified MRI-based model to predict the risk for positive surgical margins (PSMs) after radical prostatectomy (RP) in patients with prostate cancer (PCa).Methods: Consecutive patients who underwent RP for PCa were retrospectively identified from a tertiary referral hospital. Patients who underwent RP between January 2014 and June 2014 were assigned as derivation cohort (n = 330) and those between January 2018 and February 2018 were assigned as validation cohort (n = 100). MRI-based predictors associated with PSM were assessed: tumor size, tumor-capsule contact length, the Prostate Imaging Reporting and Data System (PI-RADS) category, tumor location (tumor contact to the apex or posterolateral side near the neurovascular bundle), apical depth, and prostate volume. A prediction model was developed by using multivariable logistic regression, and then it was transformed into a scoring system. The prediction and calibration performance of this scoring system was evaluated using the C statistics and Hosmer-Lemeshow goodness-of-fit test.Results: A total of 121 (36.7%) and 32 (32.0%) of patients in the derivation and validation cohorts had PSMs after RP. The scoring system consisted of the following variables: tumor-capsule contact length, PI-RADS category, tumor located at the apex and/or posterolateral side. This scoring system provided good prediction performance for PSM in the derivation (C statistics, 0.80 [95% CI: 0.76, 0.85]) and validation (C statistics, 0.77 [95% CI: 0.68, 0.87]) cohorts, and also showed good calibration in both cohorts (p = 0.83 and 0.86, respectively).Conclusions: An MRI-based scoring system can help estimate the risk of PSM after RP.Key Points: • An MRI-based scoring system served as a tool to estimate the risk of positive surgical margin (C statistics, 0.80 and 0.77 in the derivation and validation cohorts, respectively) after radical prostatectomy. • Tumor with contact to the apex or posterolateral aspect, the tumor contact length to capsule, and higher PI-RADS category were independent predictors for the presence of positive resection margins after radical prostatectomy in men with prostate cancer. • High-risk patients as determined by the scoring system demonstrated adverse post-surgical outcomes compared with low- or intermediate-risk patients, in regard to longer length (mean length, 13.0 mm versus 3.9 mm in low risk or 6.2 mm in intermediate risk; p ≤ 0.001) and higher Gleason grade at the margin (grades 4 and 5 in 69.4% and 20.4% versus 16.7% and 16.7% in low risk or 46.7% and 5.4% in intermediate risk; p < 0.001). [ABSTRACT FROM AUTHOR]

In drug discovery, rapid and accurate prediction of protein–ligand binding affinities is a pivotal task for lead optimization with acceptable on-target potency as well as pharmacological efficacy. Furthermore, researchers hope for a high correlation between docking score and pose with key interactive residues, although scoring functions as free energy surrogates of protein–ligand complexes have failed to provide collinearity. Recently, various machine learning or deep learning methods have been proposed to overcome the drawbacks of scoring functions. Despite being highly accurate, their featurization process is complex and the meaning of the embedded features cannot directly be interpreted by human recognition without an additional feature analysis. Here, we propose SMPLIP-Score (Substructural Molecular and Protein–Ligand Interaction Pattern Score), a direct interpretable predictor of absolute binding affinity. Our simple featurization embeds the interaction fingerprint pattern on the ligand-binding site environment and molecular fragments of ligands into an input vectorized matrix for learning layers (random forest or deep neural network). Despite their less complex features than other state-of-the-art models, SMPLIP-Score achieved comparable performance, a Pearson's correlation coefficient up to 0.80, and a root mean square error up to 1.18 in pK units with several benchmark datasets (PDBbind v.2015, Astex Diverse Set, CSAR NRC HiQ, FEP, PDBbind NMR, and CASF-2016). For this model, generality, predictive power, ranking power, and robustness were examined using direct interpretation of feature matrices for specific targets. [ABSTRACT FROM AUTHOR]

Silicon (Si) is important for the growth and development of bone and connective tissues. This study aimed to evaluate the effect of Si supplementation on the balance of calcium (Ca), Si, magnesium (Mg), and bone status in growing female rats fed diets with different Ca levels. Sixty 6-week-old female Wistar rats were divided into 6 groups and fed diets with different levels of Ca (0.1, 0.5, 1.5%) and Si (5, 500 ppm) for 10 weeks. Experimental groups were as follows: Low-Ca group (LCa; 0.1% Ca), Low-Ca with Si supplementation group (LCaSi), adequate-Ca group (ACa; 0.5% Ca), adequate-Ca with Si supplementation group (ACaSi), high-Ca group (HCa; 1.5% Ca), and high-Ca with Si supplementation group (HCaSi). Si retention significantly increased by Si supplementation and significantly decreased by high-Ca diet (1.5%). Mg retention significantly decreased by high-Ca diet. Serum Ca and Si contents were not significantly different among the 6 groups. Low-Ca diet significantly increased serum osteoclain and C-telopeptide cross-link of type 1 collagen (CTx) levels, and Si supplementation significantly decreased CTx levels in the low-Ca diet group. Bone mineral density was significantly increased along with Ca increase in the diet, but was decreased by Si supplementation in the high-Ca diet. Rats in the adequate-Ca diet group had a significant increase in strength of tibia after Si supplementation. These findings indicate that the effect of Si supplementation on bone metabolism may differ according to the Ca-intake level in growing females. Although further research is needed, when supplementing Si to improve bone health in growing females, Ca-intake level should be considered. [ABSTRACT FROM AUTHOR]

In-house 1,5-oxaza spiroquinone 1, with spiro[5.5]undeca ring system, was announced as an unprecedented anti-inflammatory scaffold through chemistry-oriented synthesis (ChOS), a chemocentric approach. Herein, we studied how to best position the spiro[5.5]undeca ring system in kinase inhibitor space. Notably, late-stage modification of the scaffold 1 into compounds 2a-r enhanced kinase-likeness of the scaffold 1. The improvement could be depicted with (1) selectivity with target shift (from JNK-1 into GSK-3) and (2) potency (> 20-fold). In addition, ATP independent IC50 of compound 2j suggested a unique binding mode of this scaffold between ATP site and substrate site, which was explained by docking based optimal site selection and molecular dynamic simulations of the optimal binding site. Despite the shift of kinase profiling, the anti-inflammatory activity of compounds 2a-r could be retained in hyperactivated microglial cells. [ABSTRACT FROM AUTHOR]

Purpose: To investigate whether the detection of clinically significant prostate cancer (csPCa) and the added value of focal saturation biopsy and systematic biopsy (SBx) differ according to index lesion size, and to compare the current guidelines for csPCa detection. Methods: This retrospective study included consecutive men who underwent MRI and subsequent SBx and MRI-targeted biopsy (TBx) for a suspicious lesion between April 2019 and February 2020. Lesion visibility on transrectal ultrasound (US) and added value of focal saturation biopsy and SBx were compared according to index lesion size using chi-square and McNemar tests. csPCa detection rates and the proportion of biopsy-indicated men were compared among four biopsy strategies based on current guidelines. Results: Of 313 men evaluated (median age, 65; interquartile range 60‒71), csPCa was detected in 110 (35%). In lesions < 10 mm, greater US invisibility (42.7% of lesions < 10 mm versus 20.0% of lesions ≥ 10 mm; p < 0.001) and higher added value of focal saturation biopsy and SBx (11.1% and 17.1% in lesions < 10 mm versus 4.2% and 6.3% in lesions ≥ 10 mm) were observed, compared with lesions ≥ 10 mm. Consideration of prostate-specific antigen (PSA) density > 0.15 ng/mL/mL as a cutoff in unsuspicious MRI led to a 14% reduction (44/313) in men who needed biopsy. Conclusion: Determination of the biopsy strategy in terms of the need for focal saturation biopsy or SBx should be made considering lesion size. The use of PSA density in non-suspicious MRI can lead to a reduction in biopsy-indicated men. [ABSTRACT FROM AUTHOR]

Malignant melanoma is considered to be a heterogeneous disease that arises from altered genes and transformed melanocytes. In this study, special softjet cold atmospheric plasma was used to treat three different human melanoma cells using air and N2 gases to check the anti-melanoma activity. The physical effects by plasma revealed an increase in the temperature with the gradual reduction in pH at 60 sec, 180 sec and 300 sec air and N2 plasma treatment. Cellular toxicity revealed a decreased in cell survival (~50% cell survival using air gas and <~60% cell survival using N2 gas at 60 sec plasma treatment in G-361 cells). Gene analysis by q-PCR revealed that 3 min and 5 min air and N2 plasma treatment activated apoptotic pathways by triggering apoptotic genes in all three melanoma cell lines. The apoptosis was confirmed by DAPI staining and its related pathways were further explored according to protein-protein docking, and their probable activation mechanism was revealed. The pathways highlighted that activation of apoptosis which leads to cellular cascades and hence stimulation ASK1 (docking method) revealed that softjet plasma can be an effective modality for human melanoma treatment. [ABSTRACT FROM AUTHOR]

Keywords: Confounder; Nuts; Hypertension; Body mass index EN Confounder Nuts Hypertension Body mass index 2123 2124 2 03/21/23 20230501 NES 230501 Dear Editor, We appreciate Ren and colleagues for their interest and comments about our recent paper [[1]] in I Biological Trace Element Research i regarding a relationship between dietary mineral intake from nuts and hypertension among Korean adults. Adjust 2: Adjusted for body mass index in addition to Adjust 1 In conclusion, as reported in our study [[1]], body mass index was not a confounding variable in the relationship between nut intake and hypertension. Finally, we analyzed the odds ratio of hypertension risk according to nut intake, adding body mass index to the confounding variables (age, household income, education level, current smoking, etc.). [Extracted from the article]

Previous studies have reported that silicon (Si) has a positive effect on bone health, immune response, and cognitive health. However, basic and important studies on evaluating dietary intake and urinary excretion of Si are limited. The aim of this study was to evaluate dietary Si intake and urinary excretion according to gender and age in healthy and free-living Korean adults and to investigate the relationship between them with gender. In this cross-sectional study, anthropometric measurements, dietary assessment using a food record, and a 24-h urine collection were conducted in 80 healthy Korean adults (40 males and 40 females; groups of 8 subjects representing each decade of life [20s to 60s]) with self-selected diet. The dietary assessment and 24-h urine collection were performed twice at intervals of 3 days. Daily intake of Si was estimated using a Si database of food composition. Urinary excretion of Si was analyzed using ICP-OES. The mean dietary Si intake was 22.8 mg/day for men and 19.3 mg/day for women without significant difference according to their gender and age. Si intake was the highest from vegetables both in men and women, followed by grains, beverages, and fruits in men and by grains, fruits, and milks in women. Urinary Si excretion was significantly higher in men (9.8 mg/day) than women (9.3 mg/day), and significantly increased with age only in women. Regarding the relationship between dietary Si intake and urinary Si excretion, a significantly positive correlation was found in men, but not in women. Longitudinal and balance studies to elucidate gender differences in Si nutrition are needed. [ABSTRACT FROM AUTHOR]

Abstract: The Gaussian-based 3D-QSAR studies for 58 selective COX-2 (cyclooxygenase-2) inhibitors belonging to benzopyran chemical class were performed. Partial least squares analysis produced statistically significant model with (Rtraining2 = 0.866) and predictability (Qtraining2 = 0.66, Qtest2 = 0.846). The 3D-QSAR model includes steric, electrostatic, hydrophobic, and hydrogen bond acceptor field indicators, whereas the potential field contributions indicate that the steric and hydrophobic features of the molecules play an important role in governing their biological activity. A molecular docking simulation and protein-ligand interaction pattern analysis reveal the importance of Tyr-361 and Ser-516 of the COX-2 active site for X-ray crystal structures and this class of molecules. Thus the combined approach of ligand-based and structure-based models provided an improved understanding in the interaction between benzopyran chemical class and COX-2 inhibition, which will guide the future identification of more potent anti-inflammatory drugs.Graphical Abstract: [ABSTRACT FROM AUTHOR]

Non-enzymatic lipid peroxidation of the skin-lipid bilayer causes perturbations that affect the biomembrane structure, function, and permeability of reactive oxygen species (ROS). In the present study, we employed molecular dynamics simulations to study the effect of lipid peroxidation on the bilayer structural properties and permeability of various ROS. The oxidized skin-lipid bilayer was composed of ceramide, cholesterol, free fatty acid, and 5α-hydroperoxycholesterol (5α-CH). The simulation showed that, upon oxidation, the oxidized group (−OOH) of 5α-CH migrates towards the aqueous phase and the backbone of 5α-CH tilts, which causes the membrane to expand laterally. Measurements of the permeability of all ROS along the oxidized skin-lipid bilayer revealed a decreased breaching barrier for all the species as the degree of peroxidation increased, with a resulting easy passage across the membrane. The insights from the simulations indicate that lipid peroxidation might perturb the membrane barrier, thereby inflicting oxidative stress that leads to apoptosis. This study helps to understand oxidative stress at the atomic level. To our knowledge, this is the first reported molecular dynamics simulation study on oxidized skin-lipid bilayer and permeability of ROS. [ABSTRACT FROM AUTHOR]

The interaction between calcium and magnesium as a risk modifier for cardiovascular disease (CVD) has been largely overlooked in previous studies, for the strict regulatory system in blood has been thought to keep such homeostatic interactions under tight control. This study aimed to investigate the association between calcium-magnesium ratio in hair and subclinical coronary artery calcification. Using multiple linear regression analysis, we examined the associations between calcium-magnesium ratio in hair and the coronary calcium score (CCS) in 216 Koreans aged 40 years and above (122 men and 94 women). We found that the calcium-to-magnesium ratio in hair was independently and positively associated with CCS after adjusting for age and sex (regression coefficient 6.051 ± 2.329, P = 0.010). When we assessed the association between the calcium-magnesium ratio and CCS after adjusting for potential cardiovascular risk factors and vascular function modifying drugs, we found that the strength of association with CCS was comparable to before (regression coefficient 5.434 ± 2.523, P = 0.032). Our findings suggest that among middle-aged and elderly Koreans without clinical CVD, the association between coronary artery calcification and hair calcium-magnesium ratio is stronger in those with a higher calcium-magnesium ratio in hair than in those with a lower ratio. [ABSTRACT FROM AUTHOR]

Background: The accuracy of any 3D-QSAR, Pharmacophore and 3D-similarity based chemometric target fishing models are highly dependent on a reasonable sample of active conformations. Since a number of diverse conformational sampling algorithm exist, which exhaustively generate enough conformers, however model building methods relies on explicit number of common conformers. Results: In this work, we have attempted to make clustering algorithms, which could find reasonable number of representative conformer ensembles automatically with asymmetric dissimilarity matrix generated from openeye tool kit. RMSD was the important descriptor (variable) of each column of the N × N matrix considered as N variables describing the relationship (network) between the conformer (in a row) and the other N conformers. This approach used to evaluate the performance of the well-known clustering algorithms by comparison in terms of generating representative conformer ensembles and test them over different matrix transformation functions considering the stability. In the network, the representative conformer group could be resampled for four kinds of algorithms with implicit parameters. The directed dissimilarity matrix becomes the only input to the clustering algorithms. Conclusions: Dunn index, Davies-Bouldin index, Eta-squared values and omega-squared values were used to evaluate the clustering algorithms with respect to the compactness and the explanatory power. The evaluation includes the reduction (abstraction) rate of the data, correlation between the sizes of the population and the samples, the computational complexity and the memory usage as well. Every algorithm could find representative conformers automatically without any user intervention, and they reduced the data to 14-19% of the original values within 1.13 s per sample at the most. The clustering methods are simple and practical as they are fast and do not ask for any explicit parameters. RCDTC presented the maximum Dunn and omega-squared values of the four algorithms in addition to consistent reduction rate between the population size and the sample size. The performance of the clustering algorithms was consistent over different transformation functions. Moreover, the clustering method can also be applied to molecular dynamics sampling simulation results. [ABSTRACT FROM AUTHOR]

Accumulated data suggests a positive effect of silicon on bone health; however, limited research exists on the silicon content of foods. To further the understanding of the relationship between dietary silicon intake and bone health, a food composition database of commonly consumed foods in Korea is required. For quantitative data on the intake levels of silicon, we analyzed the silicon content of 365 food items commonly consumed in Korea using inductively coupled plasma-atomic emission spectrometry following microwave-assisted digestion. To investigate the dietary silicon intake status and to examine the potential role of dietary silicon intake in the bone status of men, a total of 400 healthy Korean adult males aged 19-25 were observed for their diet intake and calcaneus bone density using the 24-h recall method and quantitative ultrasound, respectively. Clinical markers reflecting bone metabolism such as serum total alkaline phosphatase, N-mid osteocalcin, and type 1 collagen C-terminal telopeptide concentrations were also analyzed. Silicon intake of the subjects was estimated as 37.5 ± 22.2 mg/day. Major food sources of dietary silicon in the Korean male were cereal and cereal products (25.6 % of total silicon intake), vegetables (22.7 %), beverages and liquors (21.2 %), and milk and milk products (7.0 %). Silicon intake correlated positively with age, weight, energy intake, protein intake, calcium intake, and alcohol intake. After adjusted for age, weight, energy intake, protein intake, calcium intake, alcohol intake, smoking cigarettes, and regular exercise status, daily total silicon intake had no correlation with calcaneus bone density and the bone metabolism markers, but silicon intake from vegetables had a positive correlation with serum total alkaline phosphatase activity, a bone formation maker. These findings show the possible positive relationship between dietary silicon intake from vegetables and the bone formation of young adult males. Further investigation in a larger (Korean) population and correcting for additional nutritional confounders is required to confirm these findings. [ABSTRACT FROM AUTHOR]

Objectives: The aim of our study was to assess the value of diffusion-weighted imaging with reverse phase-encoding polarity (R-DWI) in addition to conventional DWI using forward phase-encoding polarity (F-DWI) in differentiating acute brainstem infarctions from hyperintense artefacts.Methods: Seventy-six patients with 38 hyperintense brainstem artefacts and 38 acute brainstem infarctions that had undergone F-DWI and R-DWI were retrospectively selected based on the clinicoradiological diagnosis. Four radiologists independently rated their confidence in diagnosing acute infarctions and ruling out brainstem artefacts in a blind manner, and then compared the diagnostic performance and confidence between F-DWI alone and F-DWI with R-DWI.Results: The areas under the curve determined for F-DWI with R-DWI in diagnosing infarctions were significantly higher than F-DWI alone for all readers (resident 1, 0.908 vs 0.776; resident 2, 0.908 vs 0.789; neuroradiologist, 0.961 vs 0.868; emergency radiologist, 0.934 vs 0.855, all p < 0.05). All readers were more confident using F-DWI with R-DWI than F-DWI alone (all p < 0.05) for diagnosing acute brainstem infarction, and three readers (readers except the neuroradiologist) were more confident using F-DWI with R-DWI for ruling out brainstem artefacts (p ≤ 0.001).Conclusion: The addition of R-DWI to F-DWI is a valuable method for differentiating acute brainstem infarctions from hyperintense artefacts.Key Points: • Hyperintense brainstem artefacts can be confused with acute infarctions on DWI. • Additional R-DWI to F-DWI reduces inter-reader variability in diagnosing brainstem infarctions. • Additional R-DWI improves performance and confidence for discriminating infarctions from artefacts. [ABSTRACT FROM AUTHOR]

Previous studies have suggested that silicon (Si) had positive effects on bone, but such benefits from Si may be dependent on calcium status. Also, several biochemical roles of Si in osteoblastic mineralization, the regulation of gene expression related to bone matrix synthesis, and the decrease in reactive oxygen species and pro-inflammatory mediators were reported, but these effects were mostly shown in cell culture studies. Hence, we tested the effect of Si supplementation on bone status and the gene expression related to bone metabolism and inflammatory mediators in young estrogen-deficient rats under calcium-replete condition (0.5 % diet). Results showed that 15-week supplementation of both high and very high doses of Si (0.025 and 0.075 % diet, respectively) could not restore the ovariectomy (OVX)-induced decrease of bone mineral density (BMD) of vertebrae, femur, and tibia. Also, several bone biochemical markers (ALP, osteocalcin, CTx) and mRNA expression of COL-I, RANKL, IL-6, and TNF-α in femur metaphysis were not significantly changed by Si in OVX rats. However, a very high dose (0.075 %) of Si supplementation significantly increased OPG expression and decreased the ratio of RANKL/OPG in mRNA expression comparable to that of sham-control animals. Taken together, Si supplementation did not increase BMD under calcium-replete condition but the decrease in the ratio of RANKL/OPG expression to the normal level suggests the possibility of a bone health benefit of Si in estrogen deficiency-induced bone loss. [ABSTRACT FROM AUTHOR]

The original article can be found online at https://doi.org/10.1186/s13321-022-00644-1. Random-forest model for drug-target interaction prediction via Kullback-Leibler divergence. Correction: Random-forest model for drug-target interaction prediction via Kullback-Leibler divergence. [Extracted from the article]

The STAT/JAK3 pathway is a well-known therapeutic target in various diseases (ex. rheumatoid arthritis and psoriasis). The therapeutic advantage of JAK3 inhibition motivated to find new scaffolds with desired DMPK. For the purpose, in silico high-throughput sieves method is developed consisting of a receptor-guided three-dimensional quantitative structure-activity relationship study and shape-based virtual screening. We developed robust and predictive comparative molecular field analysis ( q = 0.760, r = 0.915) and comparative molecular similarity index analysis ( q = 0.817, r = 0.981) models and validated these using a test set, which produced satisfactory predictions of 0.925 and 0.838, respectively. Graphical Abstract: [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

Purpose: Based on experimental results, various authors have advocated a size 4 ProSeal™ laryngeal mask airway (PLMA) in preference to a size 3 PLMA for women given a neuromuscular blocking agent because the larger size provided a better airway seal. However, spontaneously breathing patients may be ventilated adequately with a lower seal pressure than that needed for mechanical ventilation. Therefore, a smaller size might be preferable as its reduced bulk possibly induces less mucosal damage in non-paralyzed patients. Methods: A total of 152 females undergoing general anesthesia for short outpatient gynecological surgeries were randomly allocated in equal numbers to insertion of a size 3 or 4 PLMA. The insertion time, success rate, seal pressure, hemodynamic variables, and complications, such as blood staining and sore throat, were evaluated. Results: The incidence of blood staining was lower with the size 3 PLMA compared to the size 4 PLMA (18 vs. 36 %; P = 0.028). Compared with the size 3 LMA, the size 4 PLMA resulted in higher fluctuations in both blood pressure ( P = 0.003) and heart rate ( P = 0.01). The insertion time was shorter with the size 3 PLMA (9 vs. 16 s; P < 0.001). The airway seal pressure with the size 3 PLMA, although lower than that of the size 4 PLMA (23 vs. 28 cmHO; P = 0.001), was sufficient for spontaneous ventilation. Conclusions: Due to the reduced incidence of mucosal injury and greater hemodynamic stability, the size 3 PLMA may be preferable to the size 4 PLMA for non-paralyzed females. [ABSTRACT FROM AUTHOR]

Wild vegetables, those edible among naturally grown vegetables, have been reported to contain many bioactive substances, dietary fibers, vitamins, and minerals. The purpose of this study is to examine the six elements of the wild vegetables frequently consumed by Koreans and assess the element intakes through them. Contents of six kinds of elements (Ca, Mg, Fe, Zn, Cu, and Mn) in 11 wild vegetables were analyzed by inductively coupled plasma optical emission spectroscopy. Using these analysis data, the 6-element intakes from the wild vegetables were evaluated in healthy Korean adults aged 19-64 years from the Korea National Health and Nutrition Examination Survey (2010-2011). Sedum and shepherd's purse contained over 100 mg of Ca in 100 g of their edible portion. The Mg content per 100 g of the 11 wild vegetables ranged from 12.1 mg to 43.4 mg. The wild vegetable with the highest mineral content per 100 g was sedum for Ca, spinach for Mg, shepherd's purse for Fe, spinach for Zn, bracken for Cu, and fragrant edible wild aster for Mn. The element intakes from the 11 wild vegetables compared with dietary reference intakes in the healthy Koreans were 1.0 % for Ca, 2.1 % for Mg, 5.3 % for Fe, 1.4 % for Zn, 0.3 % for Cu, and 1.8 % for Mn. Considering the low intake ratio (1.2 %) of the wild vegetable to total food intake, wild vegetables may contribute to some element intakes. Our results show the nutritional value of the wild vegetables in the aspect of mineral nutrition; however, further research is needed to evaluate the bioavailability of various elements in wild vegetables. [ABSTRACT FROM AUTHOR]

Purpose: This study was conducted to evaluate feasibility of sunitinib-CLIO conjugate as a vascular endothelial growth factor receptor/platelet-derived growth factor receptor (VEGFR/PDGFR)-specific magnetic resonance (MR) probe.Procedure: VEGFR/PDGFR-targeting MR probe was synthesized by conjugating cross-linked iron-oxide (CLIO) with tyrosine-kinase inhibitor (sunitinib). In VEGFR/PDGFR-positive (U118MG) and VEGFR/PDGFR-negative (HT29) cells and tumor models, conjugate-driven ΔR 2 was estimated, while CLIO was used as control. Prussian-blue staining was performed for quantifying the amount of tumor-binding conjugates.Results: ΔR 2 between sunitinib-CLIO-treated and non-treated cells was greater in U118MG (mean, 2.1/s) than in HT29 cells (1.0/s). In in vivo study, conjugate induced a greater ΔR 2 in U118MG (11.2/s) than HT29 tumors (5.9/s). Conjugate-induced R 2 changes were not correlated with degree of Gd-DTPA enhancement, demonstrating that tumor binding of sunitinib-CLIO was independent of enhanced permeability and retention effect. % area of Prussian-blue staining was greater in U118MG (8.5 %) than in HT29 (1.4 %).Conclusions: Sunitinib-CLIO conjugate can be used as an active MR probe for quantifying VEGFR/PDGFR. [ABSTRACT FROM AUTHOR]

Silicon (Si) is important for the growth and development of bone and connective tissues. Several studies have reported that Si supplementation improved bone mineral density (BMD) in female ovarectomized rats. However, few studies have investigated the effects of Si supplementation on bone status and bone metabolism in male animals. The purpose of this study was to investigate the effects of Si supplementation on BMD and balance of calcium (Ca) and magnesium (Mg) in adult male mice. Si was administrated orally through demineralized water containing different contents of Si as a form of sodium metasilicate (0 %, control; 0.025 %, Si50; 0.050 %, Si100; and 0.075 %, Si150) to 9-week-old male mice for 4 weeks. Si supplementation did not alter weight gain or BMD of femur and tibia in male mice. However, a high level of Si (0.05 and 0.075 %) supplementation significantly decreased Mg retention without changing Ca retention. Serum alkaline phosphatase of Si-supplemented groups significantly decreased compared with that of the control. According to these results, short-term Si supplementation did not affect BMD but showed a possible effect on increasing the need for Mg in adult male mice. [ABSTRACT FROM AUTHOR]

Previous studies have revealed that magnesium (Mg) plays a significant role in bone health; however, few studies have investigated the effects of Mg supplementation in diets with different calcium (Ca) levels on the bone status and bone metabolism in a growing stage. In this present study, we tested the effects of Mg supplementation on bone status in growing female rats, relative to Ca intake levels. A total of 40 Sprague-Dawley female rats aged 6 weeks were divided into the following four groups and fed for 12 weeks as indicated: (1) LCaAMg: low Ca (Ca, 0.1 % of total diet) and adequate Mg (Mg, 0.05 % of total diet), (2) LCaHMg: low Ca and high Mg ( Mg, 0.1 % of total diet), (3) ACaAMg: adequate Ca (Ca, 0.5 % of total diet) and adequate Mg, and (4) ACaHMg: adequate Ca and high Mg. Our results showed that Mg supplementation with the adequate Ca diet significantly increased the bone mineral contents, bone size (bone area and bone thickness), and bone mineral density of femur or tibia by improving bone metabolism without changing Ca absorption. Mg supplementation significantly increased the serum osteocalcin in the adequate-Ca-diet group ( p < 0.05), while the Mg supplementation significantly decreased the serum level of C-telopeptide cross-links of type I collagen in the adequate-Ca-diet group ( p < 0.001). This study suggests that Mg supplementation with adequate Ca intake in the growing stage may increase the bone mineral density and bone size by improving bone metabolism. [ABSTRACT FROM AUTHOR]

The purpose of this study is to evaluate the dietary intakes of calcium (Ca), phosphorus (P), magnesium (Mg), iron (Fe), zinc (Zn), copper (Cu), and manganese (Mn) and investigate their correlation with blood pressure and blood lipids. Targeting 258 healthy men and women, blood pressure was measured, and blood samples were collected to analyze serum lipids, and then the intakes of seven minerals were assessed through a food intake survey for 3 days using a 24-h recall method. The average age of the men and women was 49.55 and 49.19, respectively. The daily energy intake of the men was 1,830.57 kcal, which was significantly higher than that of women, 1,476.23 kcal ( p < 0.001). The mineral intake of the subjects was as follows: 450.95 mg/day for Ca, 915.24 mg/day for P, 279.23 mg/day for Mg, 12.60 mg/day for Fe, 8.25 mg/day for Zn, 1.23 mg/day for Cu, and 4.22 mg/day for Mn. These accounted for 63.83, 130.76, 90.74, 129.75, 97.50, 154.49, and 113.50 % of adequate intake or the recommended intake of each mineral, respectively. Subjects who did not satisfy the estimated average requirement were 74.00 % for Ca, 63.18 % for Mg, and 41.86 % for Zn. After adjusting for age, sex, BMI, and energy intake, Mg intake had a negative correlation with systolic blood pressure (SBP), and Cu intake had a significant negative correlation with SBP and diastolic blood pressure (DBP). Also, Mn intake was negatively correlated with DBP, serum total cholesterol, and triglycerides. Thus, it is concluded that the dietary intakes of Mg, Cu, and Mn may play an important role in controlling blood pressure and lipids in Korean adults. [ABSTRACT FROM AUTHOR]

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The present study was conducted to compare the serum ferritin status between the postmenopausal vegetarians and non-vegetarians and to identify the relation of serum ferritin with metabolic syndrome (MetS) risk factors in postmenopausal women. The two study groups consisted of postmenopausal vegetarians ( n = 59) who maintained a vegetarian diet for over 20 years and age-matched non-vegetarian controls ( n = 48). Anthropometric measurements, dietary intakes, serum metabolic syndrome-related parameters, and serum ferritin level between the two groups were compared. The vegetarians exhibited significantly lower weight ( p < 0.01), body mass index (BMI) ( p < 0.001), percentage of body fat ( p < 0.001), waist circumference ( p < 0.01), SBP ( p < 0.001), DBP ( p < 0.001), and fasting glucose ( p < 0.05). According to the National Cholesterol Education Program (NCEP)-Adult Treatment Panel III criteria for MetS applying Korean guidelines for waist circumference, the prevalence of MetS was lower in vegetarians (33.9 %) than in non-vegetarians (47.9 %). Vegetarians had significantly lower serum level of ferritin ( p < 0.01) than non-vegetarians. In the correlation analysis, serum ferritin was positively related to fasting glucose ( r = 0.264, p < 0.01), triglycerides ( r = 0.232, p < 0.05), and the NCEP score ( r = 0.214, p < 0.05) and negatively related to high-density lipoprotein-cholesterol ( r = −0.225, p < 0.05) after adjusting for BMI, lifestyle, and dietary factors (animal protein, animal fat, and dietary fiber intake). In conclusion, postmenopausal vegetarians had lower MetS presence and a lower serum ferritin level compared to non-vegetarians. Furthermore, vegetarians' low serum ferritin level may reduce the risk of MetS in postmenopausal women. [ABSTRACT FROM AUTHOR]

Many studies have reported magnesium's role in nutrition as a vital factor involved in bone health. However, not enough studies have evaluated magnesium (Mg) intakes in young women. In this study, we evaluated Mg intake in healthy adults and its relation with bone quality. A total of 484 healthy young women in their early 20s were enrolled into the study. Anthropometric measurements, dietary intake survey using 3-day dietary records, and the bone quality of the calcaneus using quantitative ultrasounds were obtained and analyzed. Average age, height, and weight of the subjects were respectively 20.20 years, 161.37 cm, and 54.09 kg, respectively. Also, the average broadband ultrasound attenuation, speed of sound (SOS), stiffness index (SI), and calcaneus T scores were 114.32 dB/MHz, 1,568.45 m/s, 95.23, and 0.36 g/cm, respectively. The subject's average intake of energy was 1,543.19 kcal, and the average Mg intake was 185.87 mg/day. Mg intake per 1,000 kcal of consumed energy in our subjects was 119.85 mg. Subjects consumed 63.11% of the recommended intake for Mg. Food groups consumed with high Mg content in our subjects included cereals (38.62 mg), vegetables (36.97 mg), milk (16.82 mg), legumes (16.72 mg), and fish (16.50 mg). The level of Mg intake per 1,000 kcal showed significant correlation to the SOS in the calcaneus ( r = 0.110, p < 0.05) after adjustment for age, BMI, and percent body fat. In addition, the intakes of Mg from potatoes ( p < 0.001), legumes ( p < 0.05), and fungi and mushrooms ( p < 0.05) positively correlated with the SOS of the calcaneus. In conclusion, the magnesium intake status of young Korean women aged 19-25 years is unsatisfactory. Improving dietary intake of Mg may positively impact bone quality in this population. [ABSTRACT FROM AUTHOR]

Commercially available seaweed calcium extract can supply high amounts of calcium as well as significant amounts of magnesium and other microminerals. The purpose of this study was to investigate the degree to which the high levels of magnesium in seaweed calcium extract affects the calcium balance and the bone status in ovariectomized rats in comparison to rats supplemented with calcium carbonate and magnesium oxide. A total of 40 Sprague-Dawley female rats (7 weeks) were divided into four groups and bred for 12 weeks: sham-operated group (Sham), ovariectomized group (OVX), ovariectomized with inorganic calcium and magnesium supplementation group (OVX-Mg), and ovariectomized with seaweed calcium and magnesium supplementation group (OVX-SCa). All experimental diets contained 0.5% calcium. The magnesium content in the experimental diet was 0.05% of the diet in the Sham and OVX groups and 0.1% of the diet in the OVX-Mg and OVX-SCa groups. In the calcium balance study, the OVX-Mg and OVX-SCa groups were not significantly different in calcium absorption compared to the OVX group. However, the femoral bone mineral density and strength of the OVX-SCa group were higher than those of the OVX-Mg and OVX groups. Seaweed calcium with magnesium supplementation or magnesium supplementation alone did not affect the serum ALP and CTx levels in ovariectomized rats. In summary, consumption of seaweed calcium extract or inorganic calcium carbonate with magnesium oxide demonstrated the same degree of intestinal calcium absorption, but only the consumption of seaweed calcium extract resulted in increased femoral bone mineral density and strength in ovariectomized rats. Our results suggest that seaweed calcium extract is an effective calcium and magnesium source for improving bone health compared to synthetic calcium and magnesium supplementation. [ABSTRACT FROM AUTHOR]

For wide application of a dendritic cell (DC) vaccination in myeloma patients, easily available tumor antigens should be developed. We investigated the feasibility of cellular immunotherapy using autologous alpha-type 1-polarized dendritic cells (αDC1s) loaded with apoptotic allogeneic myeloma cells, which could generate myeloma-specific cytotoxic T lymphocytes (CTLs) against autologous myeloma cells in myeloma patients. Monocyte-derived DCs were matured by adding the αDC1-polarizing cocktail (TNFα/IL-1β/IFN-α/IFN-γ/poly-I:C) and loaded with apoptotic allogeneic CD138 myeloma cells from other patients with matched monoclonal immunoglobulins as a tumor antigen. There were no differences in the phenotypic expression between αDC1s loaded with apoptotic autologous and allogeneic myeloma cells. Autologous αDC1s effectively took up apoptotic allogeneic myeloma cells from other patients with matched subtype. Myeloma-specific CTLs against autologous target cells were successfully induced by αDC1s loaded with allogeneic tumor antigen. The cross-presentation of apoptotic allogeneic myeloma cells to αDC1s could generate CTL responses between myeloma patients with individual matched monoclonal immunoglobulins. There was no difference in CTL responses between αDC1s loaded with autologous tumor antigen and allogeneic tumor antigen against targeting patient's myeloma cells. Our data indicate that autologous DCs loaded with allogeneic myeloma cells with matched immunoglobulin can generate potent myeloma-specific CTL responses against autologous myeloma cells and can be a highly feasible and effective method for cellular immunotherapy in myeloma patients. [ABSTRACT FROM AUTHOR]

Streptococcus mutans is the primary etiological agent responsible for dental caries. Microfluidic devices have been used to provide a level of control over bacterial microenvironments under laminar flow conditions. In this study, we used a microfluidic device packed with glass beads to simulate the interproximal space, which is the space between the teeth. In the device, the effects of environmental factors, such as sucrose and metal ions, on S. mutans attachment and biofilm formation were quantitatively measured using confocal laser scanning microscopy and atomic force microscopy. We determined that sucrose was required for both bacterial attachment and exopolysaccharide (EPS) production in S. mutans. These results suggest that the in vivo condition between the teeth was successfully mimicked and that the device is highly suitable for in situ monitoring of oral biofilms. [ABSTRACT FROM AUTHOR]

The magnesium (Mg) and manganese (Mn) were evaluated for its effectiveness as an immunomodulator in rats. The treatments were as follows: Group 1, AIN-93M diet (0.05% Mg, 0.001% Mn); Group 2, high-dose Mg (0.1% Mg, 0.001% Mn); and Group 3, high dose Mn (0.05% Mg, 0.01% Mn) (n-12/group). After 12 weeks of supplementation, rats were sacrificed to assess the effect on a range of innate responses (tumoricidal activity, oxidative burst and nitric oxide) and the mitogen-stimulated lymphoproliferative response. Immune function was significantly affected in both the high dose Mg and the Mn group. Lymphocyte proliferative responses and NK cell activity were measured in pooled spleen from each group. The mitogen response of lymphocytes to LPS in the spleen was significantly reduced in high dose Mg-treated groups, whereas the response to ConA was not affected in both high dose minerals-treated groups. The reactive oxygen species level of macrophages was decreased in both groups. These effects were more pronounced in high dose Mg-treated group. Nitric oxide production was also decreased in high dose minerals-treated group. In addition, tumoricidal activities of splenic NK cell and peritoneal macrophage in mineral exposed rats were significantly increased. Moreover, percent death of macrophage was reduced in two groups receiving high dose mineral supplements. Taken together, the present data suggest that high dose trace min-erals exert a differential effect on the function of immune cells. [ABSTRACT FROM AUTHOR]

In this research, in order to improve the mechanical strength and oxidation resistance of a catalyst support, we studied the formation of SiC layer on the pore surfaces of activated carbons by permeating and depositing SiC from a reaction between hydrogen and dichlorodimethylsilane (DDS). The porous structure should be kept during deposition. A fluidized bed reactor and activated carbons of size of 20-40 mesh were used. By studying characteristics of deposits under various deposition conditions, we confirmed that the best conditions of manufacturing catalyst support are a lower pressure and a lower concentration. In this work, at the conditions of 5 torr of total pressure and 3% of DDS concentration, during the 10 hr processing time, deposition occurred on the pore walls before plugging pores. The results from the mathematical modeling were compared with the experimental results. [ABSTRACT FROM AUTHOR]

In drug repurposing approaches, the chemically diverse and potentially safe molecules can be explored as therapeutic potential beyond those originally targeted indications. However, accessible information on a limited number of drug pipelines can lead to competitive over-heating issues, and intellectual property rights also restrict the free investigation in chemical space. As a complementary approach to the drawbacks, ring systems of approved drugs (instead of clinical drugs) can be optimized and used for repurposing purposes. In this study, bi-directional target (T) and ring system (R) dual screening (TR screening) was developed for the repurposing of their rarely used ring systems from FDA approved drugs. The TR screening suggested RAR β and cyproheptadine as the best pair of target and ring system to escape a saddle point. The selected ring system was virtually grown and elaborated with the defined criteria: synthesizability, drug-likeness, and docking pose showing the top scores. The achieved compounds were synthesized and biologically tested with an acceptable ADME/T profile. [ABSTRACT FROM AUTHOR]

Although obesity is associated with numerous diseases, the risks of disease may depend on metabolic health. Associations between the gut microbiota, obesity, and metabolic syndrome have been reported, but differences in microbiomes according to metabolic health in the obese population have not been explored in previous studies. Here, we investigated the composition of gut microbiota according to metabolic health status in obese and overweight subjects. A total of 747 overweight or obese adults were categorized by metabolic health status, and their fecal microbiota were profiled using 16S ribosomal RNA gene sequencing. We classified these adults into a metabolically healthy group (MH, N = 317) without any components of metabolic syndrome or a metabolically unhealthy group (MU, N = 430) defined as having at least one metabolic abnormality. The phylogenetic and non-phylogenetic alpha diversity for gut microbiota were lower in the MU group than the MH group, and there were significant differences in gut microbiota bacterial composition between the two groups. We found that the genus Oscillospira and the family Coriobacteriaceae were associated with good metabolic health in the overweight and obese populations. This is the first report to describe gut microbial diversity and composition in metabolically healthy and unhealthy overweight and obese individuals. Modulation of the gut microbiome may help prevent metabolic abnormalities in the obese population. [ABSTRACT FROM AUTHOR]

Lipid peroxidation by reactive oxygen species (ROS) during oxidative stress is non-enzymatic damage that affects the integrity of biological membrane, and alters the fluidity and permeability. We conducted molecular dynamic simulation studies to evaluate the structural properties of the bilayer after lipid peroxidation and to measure the permeability of distinct ROS. The oxidized membrane contains free fatty acid, ceramide, cholesterol, and 5α-hydroperoxycholesterol (5α-CH). The result of unconstrained molecular dynamic simulations revealed that lipid peroxidation causes area-per-lipid of the bilayer to increase and bilayer thickness to decrease. The simulations also revealed that the oxidized group of 5α-CH (-OOH) moves towards the aqueous layer and its backbone tilts causing lateral expansion of the bilayer membrane. These changes are detrimental to structural and functional properties of the membrane. The measured free energy profile for different ROS (H2O2, HO2, HO, and O2) across the peroxidized lipid bilayer showed that the increase in lipid peroxidation resulted in breaching barrier decrease for all species, allowing easy traversal of the membrane. Thus, lipid peroxidation perturbs the membrane barrier and imposes oxidative stress resulting into apoptosis. The collective insights increase the understanding of oxidation stress at the atomic level. [ABSTRACT FROM AUTHOR]

In this study, pharmacophore based 3D QSAR models for human acetylcholinesterase (AChE) inhibitors were generated, with good significance, statistical values (r2training = 0.73) and predictability (q2training = 0.67). It was further validated by three methods (Fischer’s test, decoy set and Güner-Henry scoring method) to show that the models can be used to predict the biological activities of compounds without costly and time-consuming synthesis. The criteria for virtual screening were also validated by testing the selective AChE inhibitors. Virtual screening experiments and subsequent in vitro evaluation of promising hits revealed a novel and selective AChE inhibitor. Thus, the findings reported herein may provide a new strategy for the discovery of selective AChE inhibitors. The IC50 value of compounds 5c and 6a presented selective inhibition of AChE without inhibiting butyrylcholinesterase (BChE) at uM level. Molecular docking studies were performed to explain the potent AChE inhibition of the target compounds studies to explain high affinity. [ABSTRACT FROM AUTHOR]

The anti-cancer activity of the benzo[h]quinolines was evaluated on cultured human skin cancer (G361), lung cancer (H460), breast cancer (MCF7) and colon cancer (HCT116) cell lines. The inhibitory effect of these compounds on the cell growth was determined by the MTT assay. The compounds 3e, 3f, 3h and 3j showed potential cytotoxicity against these human cancer cell lines. Effect of active compounds on DNA oxidation and expression of apoptosis related gene was studied. We also developed a quantitative method to measure the activity of cyclin-dependent kinases-2 (CDK2) by western blotting in the presence of active compound. In addition, molecular docking revealed that benzo[h]quinolines can correctly dock into the hydrophobic pocket of the targets receptor protein aromatase and CDK2, while their bioavailability/drug-likeness was predicted to be acceptable but requires future optimization. These findings reveal that benzo[h]quinolines act as anti-cancer agents by inducing oxidative stress-mediated DNA damage. [ABSTRACT FROM AUTHOR]