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HMG-CoA reductase inhibitors (statins) are the most effective pharmacological means of reducing cardiovascular disease risk. The most common side effect of statin use is skeletal muscle myopathy, which may be exacerbated by exercise. Hypercholesterolemia and training status are factors that are rarely considered in the progression of myopathy. The purpose of this study was to determine the extent to which acute and chronic exercise can influence statin-induced myopathy in hypercholesterolemic (ApoE-/-) mice. Mice either received daily injections of saline or simvastatin (20 mg/kg) while: 1) remaining sedentary (Sed), 2) engaging in daily exercise for two weeks (novel, Nov), or 3) engaging in daily exercise for two weeks after a brief period of training (accustomed, Acct) (2x3 design, n = 60). Cholesterol, activity, strength, and indices of myofiber damage and atrophy were assessed. Running wheel activity declined in both exercise groups receiving statins (statin x time interaction, p

Despite its initial positive response to hormone ablation therapy, prostate cancers invariably recur in more aggressive, treatment resistant forms. The lack of our understanding of underlying genetic alterations for the transition from androgen-dependent (AD) to ADI prostate cancer growth hampers our ability to develop target-driven therapeutic strategies for the efficient treatment of ADI prostate cancer.By screening a library of activated human kinases, we have identified TPL2, encoding a serine/threonine kinase, as driving ADI prostate cancer growth. TPL2 activation by over-expressing either wild-type or a constitutively activated form of TPL2 induced ADI growth, whereas the suppression of TPL2 expression and its kinase activity in ADI prostate cancer cells inhibited cell proliferation under androgen-depleted conditions. Most importantly, TPL2 is upregulated in ADI prostate cancers of both the Pten deletion mouse model and the clinical prostate cancer specimens.Together these data suggest that TPL2 kinase plays a critical role in the promotion of ADI prostate cancer progression. Furthermore, the suppression of TPL2 diminishes ADI prostate cancer growth and a high frequency of TPL2 overexpression in human ADI prostate cancer samples validates TPL2 as a target for the treatment of this deadly disease.

Prostate cancer is the second leading cause of cancer-related deaths in men. Activation of MAP kinase signaling pathway has been implicated in advanced and androgen-independent prostate cancers, although formal genetic proof has been lacking. In the course of modeling malignant melanoma in a tyrosinase promoter transgenic system, we developed a genetically-engineered mouse (GEM) model of invasive prostate cancers, whereby an activating mutation of BRAF(V600E)--a mutation found in approximately 10% of human prostate tumors--was targeted to the epithelial compartment of the prostate gland on the background of Ink4a/Arf deficiency. These GEM mice developed prostate gland hyperplasia with progression to rapidly growing invasive adenocarcinoma without evidence of AKT activation, providing genetic proof that activation of MAP kinase signaling is sufficient to drive prostate tumorigenesis. Importantly, genetic extinction of BRAF(V600E) in established prostate tumors did not lead to tumor regression, indicating that while sufficient to initiate development of invasive prostate adenocarcinoma, BRAF(V600E) is not required for its maintenance.

Since the confirmation of African swine fever (ASF) in South Korea in 2019, its spread, predominantly in wild boars, has been a significant concern. A key factor in this situation is the lack of identification of risk factors by surveillance bias. The unique orography, characterized by high mountains, complicates search efforts, leading to overlooked or delayed case detection and posing risks to the swine industry. Additionally, shared rivers with neighboring country present a continual threat of virus entry. This study employs geospatial analysis and statistical methods to 1) identify areas at high risk of ASF occurrence but possibly under-surveilled, and 2) indicate strategic surveillance points for monitoring the risk of ASF virus entry through water bodies and basin influences. Pearson's rho test indicated that elevation (rho = -0.908, p-value < 0.001) and distance from roads (rho = -0.979, p-value < 0.001) may have a significant impact on limiting surveillance activities. A map of potential under-surveilled areas was created considering these results and was validated by a chi-square goodness-of-fit test (X-square = 208.03, df = 1, p-value < 0.001). The strong negative correlation (rho = -0.997, p-value <0.001) between ASF-positive wild boars and distance from water sources emphasizes that areas surrounding rivers are one of the priority areas for monitoring. The subsequent hydrological analyses provided important points for monitoring the risk of virus entry via water from the neighboring country. This research aims to facilitate early detection and prevent further spread of ASF., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Ito et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Photoreceptor cell death can cause progressive and irreversible visual impairments. Still, effective therapies on retinal neuroprotection are not available. Hypoxia-inducible factors (HIFs) are transcriptional factors which strongly regulate angiogenesis, erythropoiesis, intracellular metabolism, and programed cell death under a hypoxic or an abnormal metabolic oxidative stress condition. Therefore, we aimed to unravel that inhibition of HIFs could prevent disease progression in photoreceptor cell death, as recent studies showed that HIFs might be pathologic factors in retinal diseases. Adult male balb/cAJcl (8 weeks old; BALB/c) were used to investigate preventive effects of a novel HIF inhibitor halofuginone (HF) on a murine model of light-induced retinopathy. After intraperitoneal injections of phosphate-buffered saline (PBS) or HF (0.4 mg/kg in PBS) for 5 days, male BALB/c mice were subjected to a dark-adaption to being exposed to a white LED light source at an intensity of 3,000 lux for 1 hour in order to induce light-induced retinal damage. After extensive light exposure, retinal damage was evaluated using electroretinography (ERG), optical coherence tomography (OCT), and TUNEL assay. Light-induced retinal dysfunction was suppressed by HF administration. The amplitudes of scotopic a-wave and b-wave as well as that of photopic b-wave were preserved in the HF-administered retina. Outer retinal thinning after extensive light exposure was suppressed by HF administration. Based on the TUNEL assay, cell death in the outer retina was seen after light exposure. However, its cell death was not detected in the HF-administered retina. Halofuginone was found to exert preventive effects on light-induced outer retinal cell death., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Miwa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Neoantigens are tumor-derived peptides and are biomarkers that can predict prognosis related to immune checkpoint inhibition by estimating their binding to major histocompatibility complex (MHC) proteins. Although deep neural networks have been primarily used for these prediction models, it is difficult to interpret the models reported thus far as accurately representing the interactions between biomolecules. In this study, we propose the GraphMHC model, which utilizes a graph neural network model applied to molecular structure to simulate the binding between MHC proteins and peptide sequences. Amino acid sequences sourced from the immune epitope database (IEDB) undergo conversion into molecular structures. Subsequently, atomic intrinsic informations and inter-atomic connections are extracted and structured as a graph representation. Stacked graph attention and convolution layers comprise the GraphMHC network which classifies bindings. The prediction results from the test set using the GraphMHC model showed a high performance with an area under the receiver operating characteristic curve of 92.2% (91.9-92.5%), surpassing a baseline model. Moreover, by applying the GraphMHC model to melanoma patient data from The Cancer Genome Atlas project, we found a borderline difference (0.061) in overall survival and a significant difference in stromal score between the high and low neoantigen load groups. This distinction was not present in the baseline model. This study presents the first feature-intrinsic method based on biochemical molecular structure for modeling the binding between MHC protein sequences and neoantigen candidate peptide sequences. This model can provide highly accurate responsibility information that can predict the prognosis of immune checkpoint inhibitors to cancer patients who want to apply it., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Jeong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine effectiveness in coronavirus disease (COVID-19) patients with breakthrough infections has not been established in South Korea. To address this, we assessed the impact of vaccination on symptom occurrence and viral load., Methods: We performed a retrospective cohort study of 9,030 COVID-19 patients enrolled between February and November 2021. The impact of vaccination on the incidence of symptoms and viral load as indicated by cycle threshold (Ct) values of RdRp and E genes was evaluated using relative risks (RRs) and 95% confidence intervals (95% CIs)., Results: Compared with unvaccinated patients, fully vaccinated patients were associated with a reduced symptom onset of cough, sputum, and myalgia in COVID-19 patients (RR (95% CI) = 0.86 (0.75-0.99) for cough; RR (95% CI) = 0.74 (0.56-0.98) for sputum; RR (95% CI) = 0.65 (0.53-0.79) for myalgia, respectively). Additionally, lower risk of high viral load, Ct value of RdRp gene <15 or Ct value of E gene <15, was observed especially in fully vaccinated patients younger than 40 years ((RR (95% CI) = 0.69 (0.49-0.96) for RdRp gene; (RR (95% CI) = 0.71 (0.53-0.95) for E gene)., Conclusion: SARS-CoV-2 vaccination was associated with a reduced risk of COVID-19 symptoms as well as decreased viral load, especially in patients younger than 40 years., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Jang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Many studies have reported that hypoalbuminemia could be associated with organ failure after liver transplantation. However, most of them focused on serum albumin levels measured at specific time points and not on the trend of serum albumin change. We investigated whether a cumulative postoperative change in serum albumin level up to postoperative day (POD) 5 is related to organ failure in patients who underwent living-donor liver transplantation (LDLT). Data of adult recipients who underwent LDLT between January 2016 and December 2020 at a single tertiary hospital were reviewed (n = 399). After screening, three patients were excluded because of insufficient data. A cumulative change in serum albumin level was demonstrated using the area under the threshold (AUT, threshold = 3.0 g/dL) of the serum albumin curve up to POD 5. Based on the AUT, the patients were divided into a high-decrease group (n = 156) and a low-decrease group (n = 240). All analyses were conducted using 1:1 propensity score matching. The primary endpoint was the Sequential Organ Failure Assessment (SOFA) score on POD 5. The secondary endpoints were postoperative hospital stay and postoperative 90-day mortality. A total of 162 patients were included. The SOFA score on POD 5 was significantly higher in the High-decrease group compared with the Low-decrease group (5.2 ± 2.6 vs. 4.1 ± 2.3; mean difference: 1.1, 95% CI: 0.3 to 1.8; P = 0.005). However, the length of postoperative hospital stay (P = 0.661) and 90-day mortality (P = 0.497) did not differ between the groups. In conclusion, a cumulative postoperative change in serum albumin level up to POD 5 could help predict postoperative organ failure on POD 5 in patients who underwent LDLT., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Cho et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Recent advances in single-cell sequencing techniques have enabled gene expression profiling of individual cells in tissue samples so that it can accelerate biomedical research to develop novel therapeutic methods and effective drugs for complex disease. The typical first step in the downstream analysis pipeline is classifying cell types through accurate single-cell clustering algorithms. Here, we describe a novel single-cell clustering algorithm, called GRACE (GRaph Autoencoder based single-cell Clustering through Ensemble similarity larning), that can yield highly consistent groups of cells. We construct the cell-to-cell similarity network through the ensemble similarity learning framework, and employ a low-dimensional vector representation for each cell through a graph autoencoder. Through performance assessments using real-world single-cell sequencing datasets, we show that the proposed method can yield accurate single-cell clustering results by achieving higher assessment metric scores., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Ha, Jeong. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Retinoids and vitamin A are essential for multiple biological functions, including vision and immune responses, as well as the development of an embryo during pregnancy. Despite its importance, alterations in retinoid homeostasis during normal human pregnancy are incompletely understood. We aimed to characterize the temporal changes in the systemic retinoid concentrations across pregnancy and postpartum period. Monthly blood samples were collected from twenty healthy pregnant women, and plasma concentrations of retinol, all-trans-retinoic acid (atRA), 13-cis-retinoic acid (13cisRA), and 4-oxo-retinoic acids were measured using liquid chromatography-tandem mass spectrometry. Significant decreases in 13cisRA concentrations over the pregnancy were observed, with rebound increases in retinol and 13cisRA levels after delivery. Of note, atRA concentrations exhibited a unique temporal pattern with levels peaking at mid-pregnancy. While the 4-oxo-atRA concentration was below the limit of quantification, 4-oxo-13cisRA was readily detectable, and its temporal change mimicked that of 13cisRA. The time profiles of atRA and 13cisRA remained similar after correction by albumin levels for plasma volume expansion adjustment. Together, the comprehensive profiling of systemic retinoid concentrations over the course of pregnancy provides insights into pregnancy-mediated changes in retinoid disposition to maintain its homeostasis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Jeong et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Legal age estimation of living individuals is a critically important issue, and radiomics is an emerging research field that extracts quantitative data from medical images. However, no reports have proposed age-related radiomics features of the condylar head or an age classification model using those features. This study aimed to introduce a radiomics approach for various classifications of legal age (18, 19, 20, and 21 years old) based on cone-beam computed tomography (CBCT) images of the mandibular condylar head, and to evaluate the usefulness of the radiomics features selected by machine learning models as imaging biomarkers. CBCT images from 85 subjects were divided into eight age groups for four legal age classifications: ≤17 and ≥18 years old groups (18-year age classification), ≤18 and ≥19 years old groups (19-year age classification), ≤19 and ≥20 years old groups (20-year age classification) and ≤20 and ≥21 years old groups (21-year age classification). The condylar heads were manually segmented by an expert. In total, 127 radiomics features were extracted from the segmented area of each condylar head. The random forest (RF) method was utilized to select features and develop the age classification model for four legal ages. After sorting features in descending order of importance, the top 10 extracted features were used. The 21-year age classification model showed the best performance, with an accuracy of 91.18%, sensitivity of 80%, and specificity of 95.83%. Radiomics features of the condylar head using CBCT showed the possibility of age estimation, and the selected features were useful as imaging biomarkers., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Jeon et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

As automated driving technology continues to develop, studies are being conducted to develop various scenarios for assessing the functional safety, failure safety, and mobility of automated vehicles (AVs). As the commercialization of AVs progresses, it is necessary to develop a set of test scenarios for new car assessment programs (NCAPs), so as to provide information on the safety and reliability of AVs to consumers. To provide valuable information regarding newly emerged AVs to consumers who are willing to purchase them, it is necessary to derive specific and well-defined test scenarios based on the safety-in-use. Accordingly, to apply NCAPs to AVs, this study established test scenarios targeting freeways where AVs were expected to be commercialized. To this end, based on freeway traffic accident data and opinions of traffic safety and AV experts, we derived possible dangerous situations when an AV is maintaining a lane on a freeway. Functional scenarios were defined based on the derived dangerous situations. The priority of the defined functional scenarios was set using the analytic hierarchy process (AHP). Accordingly, this study presents a logical and concrete scenario construction methodology for deriving the ranges and values of test parameters for functional scenarios., Competing Interests: The authors have declared that no competing interests exist.

We examined the potential roles of the athlete's performance passport (APP) for doping detection by analyzing the relationship between weightlifting performance and sanction status. For the present study, performance data of 'not-sanctioned' (26740 datasets) and 'sanctioned' (289 datasets) male athletes were acquired from the website of the International Weightlifting Federation (www.iwf.net). One-way ANOVA, correlation analysis, and t-tests were used to analyze the relationship between athletes' use of doping and their performances across age and body weight. Athletic performance was significantly greater for athletes in the sanctioned group than those of the same age group who were not sanctioned, and this performance difference between the two groups was the greatest in their late thirties at 20.6% (not-sanctioned 292.0kg vs. sanctioned 352.3kg) (p < 0.05). From the age group analysis, out of 289 sanctioned cases, 84 cases, which was the largest proportion, were found within the top 10-25% of their performances. When stratified by body weight, athletic performance was significantly greater for the sanctioned group than the not-sanctioned group, and this performance gap was the greatest in the bodyweight category of 96 at 18.6% (not-sanctioned 310.1kg vs. sanctioned 367.8kg) (p < 0.05). From the body weight category analysis, out of 289 sanctioned cases, 75 cases, which was the largest proportion, were found within the top 10-25% of their performances. Additionally, the mean difference in performance between not-sanctioned and sanctioned groups was the largest in the body weight category of 67kg in the ages of 15-19 at 20% (not-sanctioned 234.6kg vs. sanctioned 281.5kg). These results are interpreted to mean that in male weightlifters 1) sanctioned athletes were detected in all ranges of performances regardless of age and body weight, 2) there were even higher rates of sanctioned athletes who performed within the top 10-25% of each age group and body weight category, 3) there were significant differences in performance between not-sanctioned and sanctioned group for all body weight categories, excluding +109, in the ages of 15-19 and 20-24, 4) therefore, performance data can be effectively used to better target suspected athletes for doping testing., Competing Interests: The authors have declared that no competing interests exist.

Purpose: The composite autonomic symptom scale-31 (COMPASS-31) is a self-rated questionnaire that evaluates diverse autonomic symptoms. In the present study, we developed the Korean version of the COMPASS-31 (K-COMPASS-31) with appropriate translation, and verified its reliability and internal and external validity in patients with Parkinson's disease (PD)., Methods: The original COMPASS-31 was translated independently into Korean by two bilingual neurologists. Test-retest reliability was evaluated at a 2-week interval. We investigated the correlations between the K-COMPASS-31, the scale for outcomes in PD-autonomic (SCOPA-AUT), and the results of an autonomic function test (AFT), respectively., Results: A total of 90 patients with PD (47 females; mean age, 63.4 ± 10.8 years) were enrolled. The K-COMPASS-31 showed excellent test-retest reliability (intra-class correlation coefficient = 0.874, p < 0.001) and internal validity (Cronbach's α-coefficient = 0.878). The COMPASS-31 was positively correlated with SCOPA-AUT (r = 0.609, p < 0.001) and the results of the AFT., Conclusions: In conclusion, the K-COMPASS-31 showed excellent reliability and validity for the assessment of autonomic symptoms in PD patients. The K-COMPASS-31 is an easy-to-repeat and widely used tool for investigating autonomic dysfunction in various neurologic disorders and enables comparison of autonomic dysfunction among neurologic disorders. We recommend the K-COMPASS-31 as a valid instrument for use in clinical practice for patients with PD., Competing Interests: The authors have read the journal’s policy and have the following competing interests: JY received speakers’ honoraria from SK Chemicals and Boston Scientific, and research support from Medtronic and Boston Scientific. However, this support is unrelated to this study. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.

Traffic congestion has become common in urban areas worldwide. To solve this problem, the method of searching a solution using artificial intelligence has recently attracted widespread attention because it can solve complex problems such as traffic signal control. This study developed two traffic signal control models using reinforcement learning and a microscopic simulation-based evaluation for an isolated intersection and two coordinated intersections. To develop these models, a deep Q-network (DQN) was used, which is a promising reinforcement learning algorithm. The performance was evaluated by comparing the developed traffic signal control models in this research with the fixed-time signal optimized by Synchro model, which is a traffic signal optimization model. The evaluation showed that the developed traffic signal control model of the isolated intersection was validated, and the coordination of intersections was superior to that of the fixed-time signal control method., Competing Interests: The authors have declared that no competing interests exist.

Objective: The molecular mechanisms of the degeneration of the aortic wall in abdominal aortic aneurysm (AAA) are poorly understood. The monomeric form of C-reactive protein (mCRP) is deposited in damaged cardiovascular organs and aggravates the prognosis; however, it is unknown whether mCRP is deposited in the degenerated aorta of abdominal aortic aneurysm (AAA). We investigated whether mCRP is deposited in AAA and examined the associated pathogenic signaling pathways., Methods: Twenty-four cases of AAA were analyzed and their histological features were compared according to the level of serum CRP and the degree of mCRP deposition. Proteomic analysis was performed in AAA cases with strong and diffuse CRP immunopositivity (n = 7) and those with weak, focal, and junctional CRP immunopositivity (n = 3)., Results: mCRP was deposited in the aortic specimens of AAA in a characteristic pattern that coincided with the lesion of the diminished elastic layer of the aortic wall. High serum CRP level was associated with stronger mCRP immunopositivity and a larger maximal diameter of aortic aneurysm. Proteomic analysis in AAA showed that multiple proteins were differentially expressed according to mCRP immunopositivity. Also, ingenuity pathway analysis showed that pathways associated with atherosclerosis, acute phase response, complement system, immune system, and coagulation were enriched in AAA cases with high mCRP immunopositivity., Conclusions: AAA showed a characteristic deposition of mCRP, and multiple potentially pathologic signaling pathways were upregulated in AAA cases with strong CRP immunopositivity. mCRP and the aforementioned pathological pathways may serve as targets for managing the progression of AAA., Competing Interests: Eun Na Kim, Jiyoung Yu, Hwangkyo Jeong, Chong Jai Kim, So Ra Kim, Kyunggon Kim, and Se Jin Oh are named as inventors on a pending patent application filed by the University of Ulsan and Seoul National University on the use of proteomic biomarkers for AAA. Other authors report no conflicts of interest. Our information about the patent is shown below. “I have read the journal’s policy and the authors of this manuscript have the following competing interests: The following authors are named as inventors on a patent application (Title: BIOMARKER OF AORTIC ANEURYSM AND USES THEREOF, Application number: 10-2020-0138521, Applicant: ASAN Foundation, Ulsan University, Seoul National University Hospital, Authority: Korea, Republic of) on the use of proteomic biomarkers for abdominal aortic aneurysm: Eun Na Kim, Jiyoung Yu, Hwangkyo Jeong, Chong Jai Kim, Kyunggon Kim, and Se Jin Oh. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Dynamics of complex social systems has often been described in the framework of temporal networks, where links are considered to exist only at the moment of interaction between nodes. Such interaction patterns are not only driven by internal interaction mechanisms, but also affected by environmental changes. To investigate the impact of the environmental changes on the dynamics of temporal networks, we analyze several face-to-face interaction datasets using the multiscale entropy (MSE) method to find that the observed temporal correlations can be categorized according to the environmental similarity of datasets such as classes and break times in schools. By devising and studying a temporal network model considering a periodically changing environment as well as a preferential activation mechanism, we numerically show that our model could successfully reproduce various empirical results by the MSE method in terms of multiscale temporal correlations. Our results demonstrate that the environmental changes can play an important role in shaping the dynamics of temporal networks when the interactions between nodes are influenced by the environment of the systems., Competing Interests: Hang-Hyun Jo is currently serving on the editorial board of PLOS ONE. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Context: Obesity is a growing global health concern. The increased body mass and altered mass distribution associated with obesity may be related to increases in plantar shear that putatively leads to physical functional deficits. Therefore, measurement of plantar shear may provide unique insights on the effects of body mass and body distribution on physical function or performance., Purpose: 1) To investigate the effects of body mass and distribution on plantar shear. 2) To examine how altered plantar shear influences postural control and gait kinetics., Hypothesis: 1) a weighted vest forward distributed (FV) would shift the center of pressure (CoP) location forward during standing compared with a weighted vest evenly distributed (EV), 2) FV would increase plantar shear spreading forces more than EV during standing, 3) FV would increase postural sway during standing while EV would not, and 4) FV would elicit greater compensatory changes during walking than EV., Methods: Twenty healthy young males participated in four different tests: 1) static test (for measuring plantar shear and CoP location without acceleration, 2) bilateral-foot standing postural control test, 3) single-foot standing postural test, and 4) walking test. All tests were executed in three different weight conditions: 1) unweighted (NV), 2) EV with 20% added body mass, and 3) FV, also with 20% added body mass. Plantar shear stresses were measured using a pressure/shear device, and several shear and postural control metrics were extracted. Repeated measures ANOVAs with Holms post hoc test were used to compare each metric among the three conditions (α = 0.05)., Results: FV and EV increased both AP and ML plantar shear forces compared to NV. FV shifted CoP forward in single-foot trials. FV and EV showed decreased CoP range and velocity and increased Time-to-Boundary (TTB) during postural control compared to NV. EV and FV showed increased breaking impulse and propulsive impulse compared to NV. In addition, EV showed even greater impulses than FV. While EV increased ML plantar shear spreading force, FV increased AP plantar shear spreading force during walking., Conclusion: Added body mass increases plantar shear spreading forces. Body mass distribution had greater effects during dynamic tasks. In addition, healthy young individuals seem to quickly adapt to external stimuli to control postural stability. However, as this is a first step study, follow-up studies are necessary to further support the clinical role of plantar shear in other populations such as elderly and individuals with obesity or diabetes., Competing Interests: The authors have declared that no competing interests exist.

Numerical body models of children are used for designing medical devices, including but not limited to optical imaging, ultrasound, CT, EEG/MEG, and MRI. These models are used in many clinical and neuroscience research applications, such as radiation safety dosimetric studies and source localization. Although several such adult models have been reported, there are few reports of full-body pediatric models, and those described have several limitations. Some, for example, are either morphed from older children or do not have detailed segmentations. Here, we introduce a 29-month-old male whole-body native numerical model, "MARTIN", that includes 28 head and 86 body tissue compartments, segmented directly from the high spatial resolution MRI and CT images. An advanced auto-segmentation tool was used for the deep-brain structures, whereas 3D Slicer was used to segment the non-brain structures and to refine the segmentation for all of the tissue compartments. Our MARTIN model was developed and validated using three separate approaches, through an iterative process, as follows. First, the calculated volumes, weights, and dimensions of selected structures were adjusted and confirmed to be within 6% of the literature values for the 2-3-year-old age-range. Second, all structural segmentations were adjusted and confirmed by two experienced, sub-specialty certified neuro-radiologists, also through an interactive process. Third, an additional validation was performed with a Bloch simulator to create synthetic MR image from our MARTIN model and compare the image contrast of the resulting synthetic image with that of the original MRI data; this resulted in a "structural resemblance" index of 0.97. Finally, we used our model to perform pilot MRI safety simulations of an Active Implantable Medical Device (AIMD) using a commercially available software platform (Sim4Life), incorporating the latest International Standards Organization guidelines. This model will be made available on the Athinoula A. Martinos Center for Biomedical Imaging website., Competing Interests: N/A

Bacteria often possess relatively flexible genome structures and adaptive genetic variants that allow survival in unfavorable growth conditions. Bacterial survival tactics in disadvantageous microenvironments include mutations that are beneficial against threats in their niche. Here, we report that the aerobic rice bacterial pathogen Burkholderia glumae BGR1 changes a specific gene for improved survival in static culture conditions. Static culture triggered formation of colony variants with deletions or point mutations in the gene bspP (BGLU&#95;RS28885), which putatively encodes a protein that contains PDC2, PAS-9, SpoIIE, and HATPase domains. The null mutant of bspP survived longer in static culture conditions and produced a higher level of bis-(3'-5')-cyclic dimeric guanosine monophosphate than the wild type. Expression of the bacterial cellulose synthase regulator (bcsB) gene was upregulated in the mutant, consistent with the observation that the mutant formed pellicles faster than the wild type. Mature pellicle formation was observed in the bspP mutant before pellicle formation in wild-type BGR1. However, the population density of the bspP null mutant decreased substantially when grown in Luria-Bertani medium with vigorous agitation due to failure of oxalate-mediated detoxification of the alkaline environment. The bspP null mutant was less virulent and exhibited less effective colonization of rice plants than the wild type. All phenotypes caused by mutations in bspP were recovered to those of the wild type by genetic complementation. Thus, although wild-type B. glumae BGR1 prolonged viability by spontaneous mutation under static culture conditions, such genetic changes negatively affected colonization in rice plants. These results suggest that adaptive gene sacrifice of B. glumae to survive unfavorable growth conditions is not always desirable as it can adversely affect adaptability in the host., Competing Interests: The authors have declared that no competing interests exist.

In this study, we aimed to investigate the molecular biomarkers that are pivotal for the development and progression of gastric cancer (GC). We analyzed clinical specimens using RNA sequencing to identify the target genes. We found that the expression of HOXC6 mRNA was upregulated with the progression of cancer, which was validated by quantitative real time PCR and RNA in-situ hybridization. To compare the protein expression of HOXC6, we evaluated GC and normal gastric tissue samples using western blot analysis and immunohistochemistry. We detected significantly higher levels of HOXC6 in the GC tissues than in the normal controls at both mRNA and protein levels. The expression levels of HOXC6 mRNA in patients with advanced gastric cancer (AGC) were significantly higher than those in patients with early gastric cancer (EGC). Kaplan-Meier curves showed that high expression of HOXC6 mRNA is significantly associated with poor clinical prognosis. Our findings suggest that HOXC6 mRNA may be a novel biomarker and can be potentially valuable in predicting the prognosis of GC patients. Especially, HOXC6 mRNA in-situ hybridization may be a diagnostic tool for predicting prognosis of individual GC patients., Competing Interests: The authors have declared that no competing interests exist.

Acinetobacter baumannii is a highly potent nosocomial pathogen that is associated with increased in-hospital mortality. Here, we investigated the changes in molecular characteristics of carbapenem-resistant A. baumannii (CRAB) isolated from the blood samples of patients admitted to a tertiary hospital in South Korea from January 2009 to July 2015. Whole genome sequencing using the Illumina MiSeq platform and multi-locus sequence typing (MLST) were performed for 98 CRAB clinical isolates. In silico analyses for the prediction of antimicrobial resistance and virulence factor genes were performed. Plasmid sequences, including complete forms, were reconstructed from the sequence reads. Epidemiologic data were collected from the hospital database. MLST using the Oxford scheme revealed 10 sequence types of CRAB, of which ST191 was the dominant type (n = 59). Although blaOXA-23 was shared by most analysed strains, the compositions of antimicrobial resistance determinants differed among sequence types. ST447 and ST451/ST1809 with a few resistance genes were isolated during the later years of the study period. The number of virulence genes increased, while that of ST191 did not change significantly over the investigation period. Intriguingly MLST types, compositions of antimicrobial resistance genes, and virulence genes had no association with clinical outcomes of CRAB bacteraemia. In conclusion, active changes in or accumulations of antimicrobial resistance determinants and virulence genes in CRAB were not observed during the research period. Molecular characteristics of CRAB had no association with clinical outcomes of CRAB bacteraemia., Competing Interests: The authors have declared that no competing interests exist.

Comparative network analysis provides effective computational means for gaining novel insights into the structural and functional compositions of biological networks. In recent years, various methods have been developed for biological network alignment, whose main goal is to identify important similarities and critical differences between networks in terms of their topology and composition. A major impediment to advancing network alignment techniques has been the lack of gold-standard benchmarks that can be used for accurate and comprehensive performance assessment of such algorithms. The original NAPAbench (network alignment performance assessment benchmark) was developed to address this problem, and it has been widely utilized by many researchers for the development, evaluation, and comparison of novel network alignment techniques. In this work, we introduce NAPAbench 2-a major update of the original NAPAbench that was introduced in 2012. NAPAbench 2 includes a completely redesigned network synthesis algorithm that can generate protein-protein interaction (PPI) network families whose characteristics closely match those of the latest real PPI networks. Furthermore, the network synthesis algorithm comes with an intuitive GUI that allows users to easily generate PPI network families with an arbitrary number of networks of any size, according to a flexible user-defined phylogeny. In addition, NAPAbench 2 provides updated benchmark datasets-created using the redesigned network synthesis algorithm-which can be used for comprehensive performance assessment of network alignment algorithms and their scalability., Competing Interests: The authors have declared that no competing interests exist.

Background: Mitral annular calcification (MAC) is associated with risk of stroke. This study aimed to define the morphological and functional characteristics of MAC that are related to stroke., Methods: A total of 460 subjects with MAC from transthoracic echocardiography in a single center from 2012 to 2016 was retrospectively reviewed. Subjects were classified into two groups according to history of stroke [Group 1 (n = 366): without stroke; Group 2 (n = 94): with stroke]. Morphological and functional features of MAC on echocardiogram were scored from 0 to 3 according to MAC mobility, presence of echodense mass with central echolucencies in the periannular region suggesting caseous necrosis, and functional stenosis., Results: Significantly more patients in group 2 were men and had history of diabetes mellitus, dyslipidemia, atrial fibrillation, or infective endocarditis. Although MAC thickness and extent did not differ between the two groups, group 2 showed a considerably higher MAC score than group 1 (0.50 ± 0.77 vs. 0.23 ±0.52 p<0.001) as a result of the higher prevalence of each component in group 2 [mobility (22 vs. 11%, p = 0.003), echodense mass with central areas of echolucencies suggesting caseous necrosis (23 vs. 7%, p<0.001), and functional mitral stenosis (12 vs. 7%, p = 0.042)]. On logistic regression analysis, MAC score was independently associated with stroke and showed significant incremental value to demographic factors and comorbidities in association with stroke in a consecutive manner., Conclusions: In conclusion, morphological and functional characteristics of MAC had incremental value in association with stroke over traditional risk factors. MAC score consisting of MAC mobility, typical echodense mass with central echolucencies suggesting caseous necrosis, and functional mitral stenosis was independently associated with stroke. MAC with high-risk features may act as a source of stroke or more potent composite surrogate markers for stroke-related risk factors., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To assess the utility of voided volume on initial uroflowmetry in predicting symptom severity in men with storage symptoms. In addition, we assessed the probability that men would show a voided volume of ≥ 150 mL on uroflowmetry if the examination is repeated., Methods: Between 2016 and 2017, 352 men with storage symptoms were enrolled in the study. The patients completed the frequency-volume chart and were divided into four groups based on the voided volume. A multivariate analysis was performed to determine the variables affecting voided volume., Results: The VV was < 68.8 mL in 88 patients (25.0%), 68.9-150 in 89 (25.3%), 150-250 in 87 (24.7%), and ≥ 250 in 88 (25.0%) patients. Although the International Prostate Symptom Score did not differ among the groups, the storage subscore was significantly higher in patients with decreased voided volume (p = 0.010). The total number of voids was greater in patients with decreased voided volume (p < 0.001), as was the number of nocturnal voids (p = 0.007). The maximum voided volume (p < 0.001) and 24-h urine output (p = 0.003) decreased as voided volume decreased. The proportions of patients with a mean daytime urine output ≥ 150 mL were 30.1%, 43.0%, 64.7%, and 66.7% in each group, respectively (p < 0.001). Older age and decreased maximum voided volume significantly affected the voided volume on initial uroflowmetry., Conclusions: A decreased voided volume on initial uroflowmetry may be a sign of severe storage symptoms in men. This finding is related to older age and decreased functional capacity. In these patients, it is better to perform a careful clinical assessment to diagnose and treat overactive bladder., Competing Interests: The authors have declared that no competing interests exist.

Painting is an art form that has long functioned as a major channel for the creative expression and communication of humans, its evolution taking place under an interplay with the science, technology, and social environments of the times. Therefore, understanding the process based on comprehensive data could shed light on how humans acted and manifested creatively under changing conditions. Yet, there exist few systematic frameworks that characterize the process for painting, which would require robust statistical methods for defining painting characteristics and identifying human's creative developments, and data of high quality and sufficient quantity. Here we propose that the color contrast of a painting image signifying the heterogeneity in inter-pixel chromatic distance can be a useful representation of its style, integrating both the color and geometry. From the color contrasts of paintings from a large-scale, comprehensive archive of 179 853 high-quality images spanning several centuries we characterize the temporal evolutionary patterns of paintings, and present a deep study of an extraordinary expansion in creative diversity and individuality that came to define the modern era., Competing Interests: The affiliation with Samsung SDS does not alter our adherence to PLOS ONE policies on sharing data and materials. This commercial affiliation does not alter our adherence to all PLOS ONE policies on sharing data and materials.

Purpose: We aimed to determine the usefulness of the frequency-volume chart over the International Prostate Symptom Score in patients with benign prostatic hyperplasia. Furthermore, we investigated the clinical characteristics suggesting that patients could benefit from frequency-volume chart assessment in addition to International Prostate Symptom Score assessment., Methods: A total of 193 patients with benign prostatic hyperplasia were analyzed. The relationship between the information obtained from the frequency-volume chart and the International Prostate Symptom Score was assessed. Because the urine output per kilogram per hour was not associated with any question in the International Prostate Symptom Score questionnaire, patients were divided into 2 groups according to the presence of global polyuria, defined as urine output >40 mL·kg-1·h-1. Multivariable analysis was performed to determine the predictors of global polyuria, and the results were externally validated using 397 patients with benign prostatic hyperplasia., Results: Although the other information obtained from the frequency-volume chart correlated with the International Prostate Symptom Score, the urine output was not associated with the International Prostate Symptom Score. Based on these results, patients were dichotomized into the global polyuria group (n = 19, 9.8%) and the non-global polyuria group. Although the patient characteristics did not differ between the 2 groups, the number of voids was higher in patients with global polyuria. Multivariable analysis showed that diabetes mellitus (odds ratio: 3.497, p = 0.039) and increased number of voids (odds ratio: 1.320, p < 0.001) were significant predictors of global polyuria. On external validation, the area under curve for the model was 0.723., Conclusions: Global polyuria cannot be suspected using the International Prostate Symptom Score, although it worsens the lower urinary tract symptoms of patients with benign prostatic hyperplasia. Assessment with the frequency-volume chart needs to be considered in diabetic patients with increased number of voids., Competing Interests: The authors have declared that no competing interests exist.

[This corrects the article DOI: 10.1371/journal.pone.0192856.].

Objectives: As personalized medicine (PM) is expected to greatly improve health outcomes, efforts have recently been made for its clinical implementation in Korea. We aimed to evaluate public awareness and attitude regarding PM., Methods: We performed a self-administered questionnaire survey to 703 adults, who participated in the survey on a voluntary basis. The primary outcome measures included public knowledge, attitude, and acceptance of PM. We conducted multinomial multivariate logistic analysis for outcome variables with three response categories and performed multivariate logistic regression analyses for dichotomous outcome variables., Results: Only 28% of participants had knowledge that genetic factors can contribute to inter-individual variations in drug response and the definition of PM (199 out of 702). Higher family income was correlated with greater knowledge concerning PM (OR = 3.76, p = 0.034). A majority of respondents preferred integrated pharmacogenomic testing over drug-specific testing and agreed to inclusion of pharmacogenomic testing in the national health examination (64% and 77%, respectively), but only 51% were willing to pay for it., Discussion: Our results identify the urgent need for public education as well as the potential health disparities in access to PM. This study helps to frame policies for implementing PM in clinical practice.

Objectives: This study aimed to evaluate the association of knee osteoarthritis (OA) with comorbidities and health-related quality of life (HRQOL)., Methods: A total of 8,907 (weighted n = 13,687,058) participants aged ≥50 years who had undergone knee radiography were selected from the 2010-2012 Korea National Health and Nutrition Examination Survey. OA was classified into four subgroups based on the presence or absence of pain and radiographic OA (ROA): non-OA (Pain-/ROA-), pain only (Pain+/ROA-), ROA only (Pain-/ROA+), and painful ROA (Pain+/ROA+). ROA was defined as Kellgren-Lawrence grade ≥ 2. HRQOL measurements including EuroQOL visual analogue scale (EQ-VAS) scores and the five dimensions and summary index of the EuroQOL-5 dimension (EQ-5D index) were also analyzed. Multivariable logistic regression and linear regression analyses were performed., Results: After adjustment for socioeconomic and lifestyle characteristics, cardiovascular disease, malignancy, and other comorbidities were not significantly associated with OA. Pain only and painful ROA were each significantly associated with limitations in physical activity (odds ratio (OR) 2.66, 95% CI 2.07-3.44, p < 0.001 and OR 2.83, 95% CI 2.25-3.58, p < 0.001, respectively), lower EQ-VAS (β-coefficient = -10.95, p < 0.001 and β-coefficient = -9.75, p < 0.001, respectively), and EQ-5D index (β-coefficient = -0.10, p < 0.001 and β-coefficient = -0.13, p < 0.001) compared with the non-OA group, whereas ROA only was not associated with limitations in physical activity or lower HRQOL score., Conclusions: Comorbidities were not significantly associated with knee OA after adjustment. Knee OA was associated with physical activity and HRQOL. Painful knee OA, with or without ROA, was more strongly associated with decreased physical activity and lower quality of life than ROA without pain.

Purpose: To investigate 5-year long-term postoperative efficacy in benign prostate hyperplasia (BPH) following 120-W GreenLight high-performance system photoselective vaporization of the prostate (HPS-PVP)., Methods: This was a retrospective study of surgical outcomes in 159 men who underwent HPS-PVP and were followed over 60 months postoperatively. Definitions of treatment success were established based on the following three variables: international prostate symptom scores (IPSS), maximum flow rates (Qmax), and quality of life scores QoL). Logistic regression analyses were performed to determine predictors of the postoperative success., Results: Postoperative IPSS/QoL, Qmax and post-voided residual urine volume were significantly improved after HPS-PVP. Postoperative Prostate specific antigen and prostate volume were also well reduced and sustained for 5 years. The postoperative success rate was assessed as 82.1%, 80.8% and 76.1% for each 1-, 3-, and 5-year. Thirty-eight (23.9%) patients had immediate postoperative complications, which were managed successfully with nonsurgical methods. None required transfusions, two (1.2%) patients required endoscopic reoperation for postoperative voiding difficulty due to bladder neck contracture or urethral stricture, and five (3.1%) required HPS-PVP reoperation. Presence of diabetes, voiding symptom subscore, QoL, maximal cystometric capacity, and bladder outlet obstructive index were valuable preoperative parameters for predicting postoperative success., Conclusions: HPS-PVP is an effective, long-term treatment option for BPH, with sustained efficacy of 76.1% at 5-year follow up. Several preoperative parameters could help to predict the durable surgical improvements.

Acetaminophen (APAP) is a commonly used analgesic and antipyretic that can cause hepatotoxicity due to production of toxic metabolites via cytochrome P450 (Cyp) 1a2 and Cyp2e1. Previous studies have shown conflicting effects of fructose (the major component in Western diet) on the susceptibility to APAP-induced hepatotoxicity. To evaluate the role of fructose-supplemented diet in modulating the extent of APAP-induced liver injury, male C57BL/6J mice were given 30% (w/v) fructose in water (or regular water) for 8 weeks, followed by oral administration of APAP. APAP-induced liver injury (determined by serum levels of liver enzymes) was decreased by two-fold in mice pretreated with fructose. Fructose-treated mice exhibited (~1.5 fold) higher basal glutathione levels and (~2 fold) lower basal (mRNA and activity) levels of Cyp1a2 and Cyp2e1, suggesting decreased bioactivation of APAP and increased detoxification of toxic metabolite in fructose-fed mice. Hepatic mRNA expression of heat shock protein 70 was also found increased in fructose-fed mice. Analysis of bacterial 16S rRNA gene amplicons from the cecal samples of vehicle groups showed that the fructose diet altered gut bacterial community, leading to increased α-diversity. The abundance of several bacterial taxa including the genus Anaerostipes was found to be significantly correlated with the levels of hepatic Cyp2e1, Cyp1a2 mRNA, and glutathione. Together, these results suggest that the fructose-supplemented diet decreases APAP-induced liver injury in mice, in part by reducing metabolic activation of APAP and inducing detoxification of toxic metabolites, potentially through altered composition of gut microbiota.

Diacylglycerol acyltransferases (DGATs) have a crucial role in the biosynthesis of triacylglycerol (TG), the major storage form of metabolic energy in eukaryotic organisms. Even though DGAT2, one of two distinct DGATs, has a vital role in TG biosynthesis, little is known about the regulation of DGAT2 activity. In this study, we examined the role of cysteine and its oxidation in the enzymatic activity of human DGAT2 in vitro. Human DGAT2 activity was considerably inhibited not only by thiol-modifying reagents (NEM and IA) but also by ROS-related chemicals (H2O2 and β-lapachone), while human DGAT1 and GPAT1 were little affected. Particularly, ROS-related chemicals concomitantly induced intermolecular disulfide crosslinking of human DGAT2. Both the oxidative inactivation and disulfide crosslinking were almost completely reversed by the treatment with DTT, a disulfide-reducing agent. These results clearly demonstrated the significant role of ROS-induced intermolecular crosslinking in the inactivation of human DGAT2 and also suggested DGAT2 as a redox-sensitive regulator in TG biosynthesis.

Background: The use of circulating tumor cells (CTCs) as an early diagnostic biomarker and prognostic indicator after surgery or chemotherapy has been suggested for various cancers. This study aimed to evaluate CTCs in patients who underwent gastrectomy for gastric cancer and to explore their clinical usefulness in the early diagnosis of gastric cancer., Methods: A total of 116 patients with gastric cancer who underwent gastrectomy and 31 healthy volunteers were prospectively included between 2014 and 2015. Peripheral blood samples were collected before gastrectomy, and CTCs were examined using a centrifugal microfluidic system with a new fluid-assisted separation technique., Results: After creating a receiver operating characteristic curve to identify the discriminative CTC value needed differentiate patients with gastric cancer from healthy volunteers, sensitivity and specificity were nearly optimized at a CTC threshold of 2 per 7.5 mL of blood. Of the 102 persons with a CTC level ≥2 per 7.5 mL of blood, 99 (97.1%) had gastric cancer, and of the 45 persons with a CTC level <2 per 7.5 mL of blood, 28 (62.2%) were healthy controls. Accordingly, the sensitivity and specificity for the differentiation of patients with gastric cancer from healthy controls were 85.3% and 90.3%, respectively. However, the presence of CTCs was not associated with any clinicopathologic features such as staging, histologic type, or mucin phenotype., Conclusion: Although we could not prove the clinical feasibility of CTCs for gastric cancer staging, our results suggest a potential role of CTCs as an early diagnostic biomarker of gastric cancer.

This study aimed to evaluate the prevalence of comorbidities in patients with rheumatoid arthritis (RA) compared with the non-RA population. The 2010-2012 Korea National Health and Nutrition Examination Survey (KNHANES), which assesses the general health status of populations in South Korea using interviews and basic health assessment, was analyzed retrospectively. Weighted prevalence and odds ratio (OR) of comorbidities were analyzed in patients with RA compared with the non-RA population. The overall weighted (n = 37,453,158) prevalence of RA was 1.5%. Patients with RA were older and more female predominant than subjects without RA. The prevalence of living in an urban area, college graduation, alcohol consumption and smoking was lower in patients with RA than non-RA. Patients with RA had more comorbidities including hypertension, dyslipidemia, myocardial infarction (MI) or angina, stoke, osteoarthritis, lung cancer, colon cancer, pulmonary tuberculosis, asthma, diabetes, depression, thyroid disease and chronic kidney disease. After adjusting socioeconomic and lifestyle characteristics, RA was associated with an increased prevalence of MI or angina (OR 1.86, 95% CI 1.17-2.96, p = 0.009), pulmonary TB (OR 1.95, 95% CI 1.24-3.09, p = 0.004), asthma (OR 1.97, 95% CI 1.05-3.71, p = 0.036), thyroid disease (OR 1.71, 95% CI 1.05-2.77), depression (OR 2.38, 95% CI 1.47-3.85, p < 0.001) and hepatitis B (OR 2.34, 95% CI 1.15-4.80, p = 0.020) compared with the non-RA population. Prevalence of solid cancer was not significantly associated with RA after adjustment.

Congenital cataracts can occur as a non-syndromic isolated ocular disease or as a part of genetic syndromes accompanied by a multi-systemic disease. Approximately 50% of all congenital cataract cases have a heterogeneous genetic basis. Here, we describe three generations of a family with an autosomal dominant inheritance pattern and common complex phenotypes, including bilateral congenital cataracts, short stature, macrocephaly, and minor skeletal anomalies. We did not find any chromosomal aberrations or gene copy number abnormalities using conventional genetic tests; accordingly, we conducted whole-exome sequencing (WES) to identify disease-causing genetic alterations in this family. Based on family WES data, we identified a novel BRD4 missense mutation as a candidate causal variant and performed cell-based experiments by ablation of endogenous BRD4 expression in human lens epithelial cells. The protein expression levels of connexin 43, p62, LC3BII, and p53 differed significantly between control cells and cells in which endogenous BRD4 expression was inhibited. We inferred that a BRD4 missense mutation was the likely disease-causing mutation in this family. Our findings may improve the molecular diagnosis of congenital cataracts and support the use of WES to clarify the genetic basis of complex diseases., Competing Interests: WK is employed by C&K Genomics. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

This study aimed to evaluate the association between rheumatoid arthritis (RA) and hearing impairment in the Korean adult population. Audiometric and laboratory test data from the 2010-2012 Korean National Health and Nutrition Examination Survey (KNHANES) were used for analysis. The relationship between RA and hearing impairment was analyzed, adjusting for various known risk factors associated with hearing impairment. RA was defined in the questionnaire as "RA diagnosed by a physician (yes/no) through a standardized interview." We defined hearing impairment according to 2 categories of frequency (low/mid and high) as follows (average values in kHz): low/mid frequency, 0.5, 1.0, and 2.0, and high frequency, 3.0, 4.0, and 6.0. Of the subjects, 15,158 (weighted n = 32,035,996) completed the audiometric tests. The overall weighted prevalence of RA was 1.5%. The prevalence of hearing impairment was higher in the subjects with RA than in those without RA, in both, the low/mid- and high-frequency categories (21.1% vs 7.5%, p < 0.001 and 43.3% vs. 26.2%, p < 0.001, respectively). In the multivariable logistic analysis, RA (odds ratios [OR] 1.47, 95% confidence interval [CI] 1.05-2.06, p = 0.025) was an independent risk factor of low/mid-frequency hearing impairment along with age (OR 1.12, 95% CI 1.12-1.13, p < 0.001), current smoking (OR 1.27, 95% CI 1.03-1.56, p = 0.026), and college graduation (OR 0.53, 95% CI 0.39-0.72, p < 0.001). In the multivariable analysis of high-frequency hearing impairment, RA did not show any association with hearing impairment. This study suggests that RA is associated with low/mid-frequency hearing impairment after adjustment for various known risk factors. Further study is needed to verify the hearing impairment in RA., Competing Interests: The authors have declared that no competing interests exist.

Purpose: To externally validate models to predict LN metastsis; Karakiewicz nomogram, clinical nodal staging score (cNSS), and pathologic nodal staging score (pNSS) using a different cohort., Materials and Methods: Clinicopathologic data from 500 patients who underwent radical cystectomy and pelvic lymphadenectomy were analyzed. The overall predictive values of models were compared with the criteria of overall performance, discrimination, calibration, and clinical usefulness., Results: Presence of pN+ stages was recorded in 117 patients (23.4%). Agreement between clinical and pathologic stage was noted in 174 (34.8%). Based on Nagelkerke's peudo-R2 and brier score, pNSS demonstrated best overall performance. Area under the receiver operating characteristics curve, showed that pNSS had the best discriminatory ability. In all models, calibration was on average correct (calibration-in-the-large coefficient = zero). On decision curve analysis, pNSS performed better than other models across a wide range of threshold probabilities., Conclusions: When compared to pNSS, current precystectomy models such as the Karakiewicz nomogram and cNSS cannot predict the probability of LN metastases accurately. The findings suggest that the application of pNSS to Asian patients is feasible.

The chemotherapeutic use of cisplatin is limited by its severe side effects. In this study, by conducting different omics data analyses, we demonstrated that cisplatin induces cell death in a proximal tubular cell line by suppressing glycolysis- and tricarboxylic acid (TCA)/mitochondria-related genes. Furthermore, analysis of the urine from cisplatin-treated rats revealed the lower expression levels of enzymes involved in glycolysis, TCA cycle, and genes related to mitochondrial stability and confirmed the cisplatin-related metabolic abnormalities. Additionally, an increase in the level of p53, which directly inhibits glycolysis, has been observed. Inhibition of p53 restored glycolysis and significantly reduced the rate of cell death at 24 h and 48 h due to p53 inhibition. The foremost reason of cisplatin-related cytotoxicity has been correlated to the generation of mitochondrial reactive oxygen species (ROS) that influence multiple pathways. Abnormalities in these pathways resulted in the collapse of mitochondrial energy production, which in turn sensitized the cells to death. The quenching of ROS led to the amelioration of the affected pathways. Considering these observations, it can be concluded that there is a significant correlation between cisplatin and metabolic dysfunctions involving mROS as the major player.

Objectives: To investigate the role of EphA2 in malignant cellular behavior in renal cell carcinoma (RCC) cells and whether FAK/RhoA signaling can act as downstream effectors of EphA2 on RCC cells., Methods: Expression of EphA2 protein in non-metastatic RCC (Caki-2 and A498), metastatic RCC cells (Caki-1 and ACHN), HEK-293 cells and prostate cancer cells (PC-3 and DU-145; positive controls of EphA2 expression) was evaluated by Western blot. Changes in mRNA or protein expression of EphA2, FAK or membrane-bound RhoA following EphA2, FAK or RhoA small interfering RNA (siRNA) transfection were determined by reverse transcription polymerase chain reaction or Western blot. The effect of siRNA treatment on cellular viability, apoptosis and invasion was analyzed by cell counting kit-8, Annexin-V and modified Matrigel-Boyden assays, respectively., Results: In all RCC cell lines, the expression of EphA2 protein was detectable at variable levels; however, in HEK-293 cells, EphA2 expression was very low. Treatment with EphA2 siRNA significantly reduced the expression of EphA2 mRNA and protein in all RCC cell lines. For non-metastatic RCC cells (Caki-2 and A498) but not metastatic RCC cells (Caki-1 and ACHN), cellular viability, invasiveness, resistance to apoptosis, expression of membrane-bound RhoA protein and FAK phosphorylation were significantly decreased in EphA2 siRNA-treated cells compared to the control. In non-metastatic RCC cells, FAK siRNA significantly attenuated the invasiveness, resistance to apoptosis, as well as expression of membrane-bound RhoA protein without changing protein expression of EphA2. RhoA siRNA significantly decreased the malignant cellular behavior and expression of membrane-bound RhoA protein without changing EphA2 protein expression or FAK phosphorylation., Conclusions: Our data provide the first functional evidence that the EphA2/FAK/RhoA signaling pathway plays a critical role in the malignant cellular behavior of RCC and appears to be functional particularly in the early stage of malignant progression of non-metastatic RCC.

When sounds occur with temporally structured patterns, we can feel a rhythm. To memorize a rhythm, perception of its temporal patterns and organization of them into a hierarchically structured sequence are necessary. On the other hand, rhythm perception can often cause unintentional body movements. Thus, we hypothesized that rhythm information can be manifested in two different ways; temporal and motor representations. The motor representation depends on effectors, such as the finger or foot, whereas the temporal representation is effector-independent. We tested our hypothesis with a working memory paradigm to elucidate neuronal correlates of temporal or motor representation of rhythm and to reveal the neural networks associated with these representations. We measured brain activity by fMRI while participants memorized rhythms and reproduced them by tapping with the right finger, left finger, or foot, or by articulation. The right inferior frontal gyrus and the inferior parietal lobule exhibited significant effector-independent activations during encoding and retrieval of rhythm information, whereas the left inferior parietal lobule and supplementary motor area (SMA) showed effector-dependent activations during retrieval. These results suggest that temporal sequences of rhythm are probably represented in the right fronto-parietal network, whereas motor sequences of rhythm can be represented in the SMA-parietal network.

Unlabelled: The purpose of this study was to investigate if multi-domain cognitive training, especially robot-assisted training, alters cortical thickness in the brains of elderly participants. A controlled trial was conducted with 85 volunteers without cognitive impairment who were 60 years old or older. Participants were first randomized into two groups. One group consisted of 48 participants who would receive cognitive training and 37 who would not receive training. The cognitive training group was randomly divided into two groups, 24 who received traditional cognitive training and 24 who received robot-assisted cognitive training. The training for both groups consisted of daily 90-min-session, five days a week for a total of 12 weeks. The primary outcome was the changes in cortical thickness. When compared to the control group, both groups who underwent cognitive training demonstrated attenuation of age related cortical thinning in the frontotemporal association cortices. When the robot and the traditional interventions were directly compared, the robot group showed less cortical thinning in the anterior cingulate cortices. Our results suggest that cognitive training can mitigate age-associated structural brain changes in the elderly., Trial Registration: ClnicalTrials.gov NCT01596205.

The quest for historically impactful science and technology provides invaluable insight into the innovation dynamics of human society, yet many studies are limited to qualitative and small-scale approaches. Here, we investigate scientific evolution through systematic analysis of a massive corpus of digitized English texts between 1800 and 2008. Our analysis reveals great predictability for long-prevailing scientific concepts based on the levels of their prior usage. Interestingly, once a threshold of early adoption rates is passed even slightly, scientific concepts can exhibit sudden leaps in their eventual lifetimes. We developed a mechanistic model to account for such results, indicating that slowly-but-commonly adopted science and technology surprisingly tend to have higher innate strength than fast-and-commonly adopted ones. The model prediction for disciplines other than science was also well verified. Our approach sheds light on unbiased and quantitative analysis of scientific evolution in society, and may provide a useful basis for policy-making.

Pink-pigmented facultative methylotrophs in the Rhizobiales are widespread in the environment, and many Methylobacterium species associated with plants produce plant growth-promoting substances. To gain insights into the life style at the phyllosphere and the genetic bases of plant growth promotion, we determined and analyzed the complete genome sequence of Methylobacterium oryzae CBMB20T, a strain isolated from rice stem. The genome consists of a 6.29-Mb chromosome and four plasmids, designated as pMOC1 to pMOC4. Among the 6,274 coding sequences in the chromosome, the bacterium has, besides most of the genes for the central metabolism, all of the essential genes for the assimilation and dissimilation of methanol that are either located in methylotrophy islands or dispersed. M. oryzae is equipped with several kinds of genes for adaptation to plant surfaces such as defense against UV radiation, oxidative stress, desiccation, or nutrient deficiency, as well as high proportion of genes related to motility and signaling. Moreover, it has an array of genes involved in metabolic pathways that may contribute to promotion of plant growth; they include auxin biosynthesis, cytokine biosynthesis, vitamin B12 biosynthesis, urea metabolism, biosorption of heavy metals or decrease of metal toxicity, pyrroloquinoline quinone biosynthesis, 1-aminocyclopropane-1-carboxylate deamination, phosphate solubilization, and thiosulfate oxidation. Through the genome analysis of M. oryzae, we provide information on the full gene complement of M. oryzae that resides in the aerial parts of plants and enhances plant growth. The plant-associated lifestyle of M. oryzae pertaining to methylotrophy and plant growth promotion, and its potential as a candidate for a bioinoculant targeted to the phyllosphere and focused on phytostimulation are illuminated.

Objectives: To evaluate the impact of glycemic control of diabetes mellitus (DM) on prostate cancer detection in a biopsy population., Patients and Methods: We retrospectively reviewed the records of 1,368 men who underwent prostate biopsy at our institution. We divided our biopsy population into three groups according to their history of DM, and their Hemoglobin A1c (HbA1c) level: a no-DM (DM-) group; a good glycemic control (DM+GC) group (HbA1c <6.5%); and a poor glycemic control (DM+PC) group (HbA1c ≥6.5%). For sub-analyses, the DM+PC group was divided into a moderately poor glycemic control (DM+mPC) group (6.5≤ HbA1c <7.5%) and a severely poor glycemic control (DM+sPC) group (HbA1c ≥7.5%)., Results: Among 1,368 men, 338 (24.7%) had a history of DM, and 393 (28.7%) had a positive biopsy. There was a significant difference in prostatic specific antigen density (PSAD) (P = 0.037) and the frequency of abnormal DRE findings (P = 0.031) among three groups. The occurrence rate of overall prostate cancer (P<0.001) and high-grade prostate cancer (P = 0.016) also presented with a significantly difference. In the multivariate analysis, the DM+PC group was significantly associated with a higher rate of overall prostate cancer detection in biopsy subjects compared to the DM- group (OR = 2.313, P = 0.001) but the DM+PC group was not associated with a higher rate of high-grade (Gleason score ≥7) diseases detected during the biopsy (OR = 1.297, P = 0.376). However, in subgroup analysis, DM+sPC group was significantly related to a higher risk of high-grade diseases compared to the DM- group (OR = 2.446, P = 0.048)., Conclusions: Poor glycemic control of DM was associated with a higher risk of prostate cancer detection, including high-grade disease, in the biopsy population.