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This study uses numerical methods (ANSYS-Fluent) to investigate the viscous fingering of the displaced phase as a shear-thinning fluid in the classic three-dimensional Hele-Shaw cell. Comparing the behavior of fingerings with different properties on the upper and lower surfaces of a three-dimensional model, it was found that when the upper and lower surfaces are walls, under the combined action of moving contact lines and Saffman-Taylor instability, fingering splitting occurs at the tip, resulting in the appearance of two fingers at the interface. In addition, we have found that interfacial tension has a suppressive effect on short waves. As the interfacial tension increases, the velocity at the advancing tip decreases. Therefore, when the interface tension is 0, viscous fingering displacement reaches the farthest distance. We have also conducted research on the viscous fingering at different temperatures. The results indicate that increasing the temperature leads to a decrease in the viscosity of the displaced phase, making the flow more stable. As the temperature rises, the pressure gradient inside the flow path increases, pushing the viscous fingering further., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wu 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.)

Insulin resistance is a common pathophysiology in patients with type 2 diabetes mellitus, cardiovascular disease, and non-alcoholic fatty liver disease. Thus, screening for the risk of insulin resistance is important to prevent disease progression. We evaluated the alanine aminotransferase/aspartate aminotransferase (ALT/AST) ratio to predict insulin resistance in the general population, regardless of comorbidities. Datasets from the 2015, 2019, and 2020 Korea National Health and Nutrition Examination Surveys were used, and the following four indices were implemented to indicate insulin resistance: fasting serum glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), and β-cell function. We analyzed the degree of association between the liver enzyme profile and insulin resistance indices using Pearson's correlation coefficient and determined the associations using linear or logistic regression analysis. Accordingly, ALT levels in both sexes were positively and consistently correlated with the four aforementioned insulin resistance indices in stratification analyses based on diabetes, dyslipidemia, alcohol consumption, and obesity status. In multivariate linear regression, when comparing with ALT levels, the ALT/AST ratio exhibited superior predictive performance for fasting serum glucose and HOMA-β in Korean men and improved outcomes for all insulin resistance indices in Korean women. In this analysis that included a large community-based population, the ALT/AST ratio was a more useful predictive marker than the HOMA-IR. Regarding the predicted presence or absence of insulin resistance, the ALT/AST ratio could better predict HOMA-IR than the ALT level alone in Koreans. A simple, precise marker that represents the ALT/AST ratio could be a practical method to screen for insulin resistance in the general population, regardless of diabetes mellitus, alcohol intake, and sex., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Han 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.)

Little is known about sexual and gender minority youth (SGMY) who have sex with men's unique patterns of substance use, even though they are at risk for substance use and adverse mental and other health outcomes. We used latent class analysis to examine typologies of substance use and multinomial logistic regression to investigate mental health outcomes (depression and anxiety) and HIV/STI testing correlates associated with different classes of substance use in a sample of SGMY who have sex with men in the USA and use substances (n = 414) who participated in an online survey. The average age was 22.50 years old (SD = 3.22). A four-class solution was identified representing: 'depressant and stimulant use' (3.4%), 'high polysubstance use' (4.6%), 'low substance use with moderate cannabis use' (79.2%), and 'high cannabis, stimulant and alcohol use' (12.8%). Membership to a specified substance use class varied by age, previous arrest, gender identity, anxiety, and lifetime HIV testing. Multivariate logistic regression results indicated that participants in the high polysubstance use (AOR = 5.48, 95% CI 1.51, 19.97) and high cannabis use class (AOR = 3.87, 95% CI 1.25, 11.94) were significantly more likely than those in the low substance use with moderate cannabis use class to report previous arrest. Those in the high polysubstance use class were also significantly less likely to have been tested for HIV than those in the low substance use with moderate cannabis use class (AOR = 0.21, 95% CI 0.05, 0.93). Findings will guide the development and implementation of tailored approaches to addressing the intersection of substance use and HIV risk among SGMY., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Carney 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.)

Objective: Tenosynovial giant cell tumors (TSGCTs) of the knee differ in their clinical outcome according to disease subtypes and severity. The aim of this study was to determine the predictive MRI features related to local recurrence in TSGCT of the knee regarding disease subtypes and severity., Methods: This retrospective study included 20 patients with pathology-proven TSGCT of the knee who underwent preoperative MRI and surgery from Jan. 2007 to Jan. 2022. The anatomical point of the lesion was determined with a knee mapping. And then MRI features related to disease subtype including nodularity (single vs. multinodular); margin (circumscribed vs. infiltrative); peripheral hypointenseity (present vs. absent); internal hypointensity reflecting hemosiderin deposition (speckled vs. granular) were assessed. Third, MRI features related to disease severity including involvement of bone, cartilage, and tendon were evaluated. MRI features for predicting local recurrence of TSGCT were tested using chi-square test and logistic regression analysis., Results: Ten patients with diffuse-type TSGCT (D-TSGCT) and 10 patients with localized-type TSGCT (L-TSGCT) were included. There were six cases of local recurrence and all of them were D-TSGCT and none for L-TSGCT with statistical difference (P = 0.015). D-TSGCT that was direct risk factor for local recurrence showed more multinodular (80.0% vs. 10.0%; P = 0.007), infiltrative margin (90.0% vs. 10.0%; P = 0.002), and absent peripheral hypointensity (100.0% vs. 20.0%; P = 0.001) than L-TSGCT. Multivariate analysis showed infiltrative margin (odds ratio [OR], 81.0; P = 0.003) was independent MRI factor for D-TSGCT. Disease severity for risk of local recurrence included cartilage (66.7% vs. 7.1%; P = 0.024) and tendon (100.0% vs. 28.6%; P = 0.015) involvement compared to no local recurrence. Multivariate analysis showed tendon involvement (OR, 12.5; P = 0.042) was predictive MRI parameter for local recurrence. By combining tumor margin and tendon involvement, local recurrence was predicted sensitively on preoperative MRI (sensitivity, 100%; specificity, 50%; accuracy, 65%)., Conclusion: D-TSGCTs was associated with local recurrence and showed multinodularity infiltrative margin, and absent peripheral hypointensity. Disease severity including cartilage and tendon involvement was associated with local recurrence. Preoperative MRI evaluation by combining disease subtypes and severity can predict local recurrence sensitively., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Kim 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.)

Mechanical products are becoming more diversified with the continuous development of precision processing and materials technologies. The friction force generated by the O-ring seal in a hydraulic cylinder was once considered redundant. However, its utilization has recently been proposed. The hardness of the O-ring and the inner diameter of its groove directly affect the normal pressure between the O-ring and the inner wall of the cylinder, thereby affecting the friction behavior. In order to explore this friction behavior, a strain-based friction force measurement system is developed in this study, and the steady-state and dynamic friction values under different working conditions are studied and discussed in depth. This research on the friction behavior in the cylinder provides a theoretical basis for more convenient design and utilization of the friction force generated between the O-ring and the inner wall of the cylinder., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Qin 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.)

Purpose: To investigate salivary gland ultrasonography (SGUS) findings in primary Sjögren's syndrome (pSS) patients positive for the anti-centromere antibody (ACA) and compare these with those in ACA-negative pSS patients., Methods: We analyzed demographic, clinical, laboratory, and SGUS data of pSS patients who fulfilled the 2002 American-European Consensus Group classification criteria for pSS. SGUS findings of four major salivary glands (bilateral parotid and submandibular glands) were scored in five categories and compared between ACA-positive and ACA-negative pSS patients. Linear regression analysis was performed to elucidate the factors associated with SGUS score., Results: In total, 121 pSS patients were enrolled (19, ACA-positive). The ACA-positive patients were older (67.0 vs 58.0 years, P = 0.028), whereas anti-Ro/SSA and anti-La/SSB positivity was more prevalent in the ACA-negative group (89.2% vs 21.1%, P < 0.001, and 47.1% vs 10.5%, P = 0.007, respectively). The total SGUS and hypoechoic area scores were lower in ACA-positive patients (16.0 vs 23.0, P = 0.027, and 4.0 vs 7.0, P = 0.004, respectively). In univariate regression analysis, being positive for unstimulated salivary flow rate (USFR < 1.5 ml/15 min), anti-Ro/SSA, and rheumatoid factor were positively associated whereas ACA positivity was negatively associated with the SGUS score. In multivariate regression analysis, being positive for USFR, anti-Ro/SSA, and rheumatoid factor showed significant association with the SGUS score., Conclusions: ACA-positive pSS patients showed a lower SGUS score than ACA-negative patients, which was especially prominent in the hypoechoic area component., Competing Interests: The authors declare that they have no competing interests relevant to this manuscript.

Background: Children with complex chronic multisystemic diseases frequently require care from multiple pediatric subspecialists. The aerodigestive program is a multidisciplinary program that diagnoses and treats pediatric patients with complex multi-systematic problems affecting airway, breathing, feeding, swallowing, or growth. The aim of this study is to present the protocol of the aerodigestive program of a children's hospital., Methods and Design: This study is a prospective study to evaluate and compare the overall improvement of patients' objective and subjective conditions before and after the AeroDigestive Team (ADT) program. Among children from 1 month to 18 years of age, patients with complex problems of the airway, breathing, feeding, swallowing, or growth meeting at least two parameters of the inclusion criteria were enrolled. The overall process included referral based on the inclusion criteria, enrollment of ADT program with informed consents, interview and questionnaire for assessing patients' medical condition, prescheduling appointment, multi-specialists' evaluation, monthly team meetings, wrap-up discussion with the patients and family, therapeutic intervention, and follow-up at 6 months with the assessment of outcome measures. The outcome was evaluated objectively and subjectively. The objective outcome measure was divided into surgical or medical intervention, assessment of changes in medical condition, and follow-up study. Both caregiver interviews and questionnaires using a scoring system were used as subjective outcome measures before and after the ADT program. Children were scheduled to be followed-up at 6 months after the interventions or ADT meeting., Discussion: The aerodigestive program is expected to provide comprehensive and multidisciplinary management of children with complex airway and digestive tract disorders., Competing Interests: The authors have declared that no competing interests exist.

This study aims to find out whether whole body vibration has an effect on the sprint ability to shorten the time of bobsled-skeleton athletes. Seventeen bobsled-skeleton athletes (male = 11, female = 6) were recruited from Korea Winter Olympics National Team. Participants were randomly assigned to either a sprint immediately after whole body vibration or a sprint without whole body vibration protocol during two separate visits by a period of 3 months. To evaluate the effects of the sprint ability, measurements were performed 60-m sprint recorded test. In males, at the 45m (p<0.05) significant faster sprint section record after WBV more than Non-WBV. In females, at the 15m (p<0.05), 30m (p<0.01), 45m (p<0.05), and 60m (p<0.05) significant faster sprint section record after WBV more than Non-WBV. In males, at the 30m (p<0.05), 45m (p<0.05), and 50m (p<0.05) significant faster sprint cumulative record after WBV more than Non-WBV. In females, at the 15m (p<0.05), 30m (p<0.05), 45m (p<0.01), 50m (p<0.01), and 60m (p<0.01) significant faster sprint cumulative record after WBV more than Non-WBV. This study indicated that significant faster after WBV more than Non-WBV in males and females bobsled-skeleton athletes., Competing Interests: The authors have declared that no competing interests exist.

Background: Autonomic nervous system dysfunction is implicated in the development of hypothalamic obesity. We investigated the relationship between hypothalamic involvement (HI), central obesity, and cardiac autonomic dysfunction by assessing heart rate variability (HRV) indices in patients with childhood-onset craniopharyngioma., Methods: A cross-sectional study of 48 patients (28 males, 10-30 years old) with hypothalamic damage after childhood-onset craniopharyngioma was performed. Postoperative HI was graded as mild (n = 19) or extensive (n = 29) on magnetic resonance imaging. Anthropometry, body composition and HRV indices including the standard deviation of all normal R-R intervals (SDNN) and total power (TP) as overall variability markers, root-mean square differences of successive R-R intervals (RMSSD) and high frequency (HF) as parasympathetic modulation markers, and low frequency (LF) as a sympathetic/sympathovagal modulation marker were measured., Results: Patients with extensive HI had increased means of body mass index, waist circumference, and fat mass than those with mild HI (P < 0.05, for all). Centrally obese patients had a lower mean HF, a parasympathetic modulation marker, than centrally non-obese patients (P < 0.05). The extensive HI group had lower means of overall variability (SDNN and TP), parasympathetic modulation (HF), and sympathetic/sympathovagal modulation (LF) than the mild HI group (P < 0.05, for all). The interaction effect of HI and central obesity on HRV indices was not significant. In models adjusted for age, sex, and family history of cardiometabolic disease, the means of the overall variability indices (P < 0.05 for both SDNN and TP) and a sympathetic/sympathovagal modulation index (P < 0.05 for LF) were lower with extensive HI, without differences according to central obesity., Conclusions: The reduced HRV indices with extensive HI suggests that hypothalamic damage may contribute to cardiac autonomic dysfunction, underscoring the importance of minimizing hypothalamic damage in patients with childhood-onset craniopharyngioma., Competing Interests: The authors have declared that no competing interests exist.

Objectives: We investigated the incidence and characteristics of pseudo-spontaneous nystagmus (PSN) in benign paroxysmal positional vertigo involving the lateral semicircular canal (LC-BPPV) and evaluated the correlation between PSN and the bow and lean test., Methods: We examined nystagmus in the sitting position using video-oculography goggles in 131 LC-BPPV patients. The positioning test and bow and lean test were also performed. Patients were divided into canalolithiasis and cupulolithiasis groups according to the character of nystagmus. In each group, the incidence and direction of PSN, correlation with the bow and lean test, and treatment outcome were analyzed., Results: PSN was observed in 25 cases (19.1%) in LC-BPPV patients, 7 of which were canalolithiasis and 18 of which were cupulolithiasis (p = 0.098). Of the 25 patients with PSN, 21 (84%) exhibited nystagmus consistent with the lean test whereas 4 (16%) exhibited nystagmus consistent with the bow test. In patients with PSN, nystagmus was observed in the bow and lean test in all cases (23/23), but in patients without PSN, no nystagmus was observed in 13 cases (13/87) in the bow and lean test (p = 0.048). The number of barbecue maneuvers performed until the end of treatment was 1.4 ± 0.7 in patients with PSN and 1.4 ± 0.9 in those without PSN (p = 0.976)., Conclusion: We identified PSN in patients with LC-BPPV irrelevant of subtype. Moreover, all patients with PSN showed nystagmus in the bow and lean test. The direction of PSN was mostly consistent with that of the lean test (21/25, 84%). The presence of PSN was not related to the treatment outcome in this study., Competing Interests: The authors have declared that no competing interests exist.

Objective: To compare the symptoms and magnetic resonance imaging (MRI) findings between digital peripheral nerve sheath tumor (PNST) and major-nerve PNST., Methods: A total 36 cases with benign PNSTs (16 digital, 20 major-nerve) were enrolled. Chief complaint and Tinel sign were reviewed. Five classic MRI features of PNST, the signal intensity (SI), the enhancement, and the shape of tumor were evaluated on MRI., Results: Half of each group showed tenderness. Tinel sign was less frequent in digital PNST (12.5%) than major-nerve PNST (95.0%, P < 0.001). Split fat sign, entering and exiting nerve, target sign, and thin hyperintense rim were only observed in major-nerve PNST (P = <0.001, <0.001, 0.492, and 0.002, respectively). Fascicular sign was found in digital PNSTs (31.3%), but more frequent in major-nerve PNST (P < 0.001). In digital PNSTs, mild hyperintense SIs (56.2%) on T1-weighted images (T1-WI) was noted, but none in major-nerve PNST (P < 0.001). Both groups showed hyperintense SIs on T2-WI (P = 0.371). Homogeneity on T2-WI was noted in 43.8% of digital PNSTs, but none in major-nerve PNSTs (P = 0.004). Both groups showed heterogeneous enhancement (P = 0.066), but four (25%) digital PNSTs showed homogeneous enhancement. Lobulated shape was noted in 50% of digital PNSTs but none of major-nerve PNSTs (P = 0.001). Digital nerve was involved at 81.3% of digital PNSTs. Three foot cases showed unusual manifestations: bone destruction, skin thickening, and subungual location., Conclusion: In digital PNSTs, Tinel sign is not commonly found and classic MRI findings is insufficient. In addition, some digital PNSTs show different SI and enhancement from major-nerve PNSTs. However, digital soft tissue tumor involving digital neurovascular bundle and especially representing a fascicular sign should be considered the possibility of a digital PNST., Competing Interests: The authors have declared that no competing interests exist.

Objective: To evaluate the added value of diffusion weighted image (DWI) including volumetric analysis to standard magnetic resonance imaging (MRI) for predicting poor responders to neoadjuvant chemotherapy in patients with osteosarcoma at 3-Tesla., Methods: 3-Tesla Standard MRI and DWI in 17 patients were reviewed by two independent readers. Standard MRI was reviewed using a five-level-confidence score. Two-dimensional (2D) apparent diffusion coefficient (ADC)mean and 2D ADCminimum were measured from a single-section region of interest. An ADC histogram derived from whole-tumor volume was generated including 3D ADCmean, 3D ADCskewness, and 3D ADCkurtosis. The Mann-Whitney-U test, receiver operating characteristic curve with area under the curve (AUC) analysis, and multivariate logistic regression analysis were performed., Results: There were 13 poor responders and 4 good responders. Statistical differences were found in posttreatment and percent change of both 2D ADCmean and 2D ADCminimum, posttreatment 3D ADCmean, and posttreatment 3D ADCskewness between two groups. The best predictors of poor responders were posttreatment 2D ADCmean and posttreatment 3D ADCskewness. Sensitivity and specificity of the 1st model (standard MRI alone), 2nd model (standard MRI+posttreatment 2D ADCmean), and 3rd model (standard MRI+posttreatment 2D ADCmean+posttreatment 3D ADCskewness) were 85% and 25%, 85% and 75%, and 85% and 100% for reader 1 and 77% and 25%, 77% and 50%, and 85% and 100% for reader 2, respectively. The AUC of the 1st, 2nd, and 3rd models were 0.548, 0.798, and 0.923 for reader 1 and 0.510, 0.635, and 0.923 for reader 2, respectively., Conclusion: The addition of DWI including volumetric analysis to standard MRI improves the diagnostic accuracy for predicting poor responders to neoadjuvant chemotherapy in patients with osteosarcoma at 3-Tesla., Competing Interests: The OncoTreat software used in this work was provided by Siemens Healthineers, Erlangen, Germany. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objective: To investigate the effects of lifestyle-related factors on ischemic heart disease (IHD) according to body mass index (BMI) and fasting blood glucose (FBG) levels among Korean adults., Methods: A total of 119,929 men and 89,669 women (from National Sample Cohort version 2.0, National Health Insurance Service) aged ≥20 years who were examined during 2003-2006 and had no preexisting type 2 diabetes or circulatory diseases were followed until December 2015 to confirm IHD incident cases. Data on lifestyle-related factors (BMI, FBG, diet, smoking, alcohol consumption, and physical activity) were collected at baseline. Lifestyle-related risk factors were defined as mainly vegetable/mainly meat diet, former/current smoking, alcohol consumption ≥3 times/week, and no physical activity. Associations between these factors and IHD were examined using Cox proportional hazards regression models., Results: High BMI (≥25 kg/m2), high FBG (≥100 mg/dL), mainly meat diet, and former/current smoking were associated with increased risk for IHD. Alcohol consumption ≤twice/week and physical activity ≤twice/week were associated with lower risk of IHD. With increased lifestyle-related risk factors, the risk of IHD also increased in women (hazard ratio [HR] = 3.21, 95% confidence interval [CI] 2.18-4.73) and men (HR = 1.66, 95% CI 1.48-1.85). This increase was larger in women, with a significant sex interaction (p = 0.0001). Significant interactions between BMI and alcohol consumption (p = 0.0002) and between BMI and physical activity (p = 0.0063) were observed. Interactions were seen between FBG level and meal type in both BMI<25 kg/m2 (p = 0.0106) and BMI≥25 kg/m2 (p = 0.0281) and between FBG level and alcohol consumption in BMI ≥25 kg/m2 (p = 0.0118)., Conclusions: The impact of lifestyle-related factors on IHD was more pronounced in women than in men and may be modified by BMI and FBG level among Korean adults. This might be taken into account when planning individual interventions to reduce IHD risk., Competing Interests: The authors have declared that no competing interests exist.

Background: Given the complexity of managing hepatocellular carcinoma (HCC), a multidisciplinary approach (MDT) is recommended to optimize management of HCC patients. However, evidence suggesting that MDT improves patient outcome is limited., Methods: We performed a retrospective cohort study of all patients newly-diagnosed with HCC between 2005 and 2013 (n = 6,619). The overall survival (OS) rates between the patients who were and were not managed via MDT were compared in the entire cohort (n = 6,619), and in the exactly matched cohort (n = 1,396)., Results: In the entire cohort, the 5-year survival rate was significantly higher in the patients who were managed via MDT compared to that of the patients who were not (71.2% vs. 49.4%, P < 0.001), with an adjusted hazard ratio (HR) of 0.47 (95% confidence interval [CI]; 0.41-0.53). In the exactly matched cohort, the 5-year survival rate was higher in patients who were managed via MDT (71.4% vs. 58.7%, P < 0.001; HR [95% CI] = 0.67 [0.56-0.80]). The survival benefit of MDT management was observed in most pre-defined subgroups, and was especially significant in patients with poor liver function (ALBI grade 2 or 3), intermediate or advanced tumor stage (BCLC stage B or C), or high alphafetoprotein levels (≥200 ng/ml)., Conclusion: MDT management was associated with improved overall survival in HCC patients, indicating that MDT management can be a valuable option to improve outcome of HCC patients. This warrants prospective evaluations., Competing Interests: The authors have declared that no competing interests exist.

Objective: The proportion of elderly patients with rheumatoid arthritis (RA) is continuously growing as a result of the increasing aging population. We compared disease activity between different age groups, and evaluated the clinical factors associated with high disease activity., Methods: This cross-sectional study analyzed the data of RA patients enrolled in the Korean College of Rheumatology Biologics registry (KOBIO-RA) between 2012 and 2014. Disease activity between elderly (age ≥ 65 years) and non-elderly patients (age < 65 years) was compared, and the association of clinical factors with high disease activity was assessed using a multivariate logistic regression model., Results: Of 1,227 patients in KOBIO-RA, 244 patients with RA were aged 65 years or over. In elderly patients, the proportion of men was higher (P = 0.012), and the duration of disease was longer (P < 0.001) compared with non-elderly patients. The elderly group showed a higher incidence of comorbidity (P < 0.001), and less use of methotrexate (P = 0.004). Assessment of disease activity using various composite measures showed a higher proportion of high disease activity in elderly patients than non-elderly patients. Longer disease duration, presence of comorbidity, and non-use of methotrexate were independently associated with high disease activity (P = 0.002, P < 0.001, and P = 0.029, respectively)., Conclusions: At enrollment of KOBIO-RA, elderly patients showed higher disease activity compared with non-elderly patients. Disease duration, use of methotrexate, and comorbidity are associated with disease activity control in Korean patients with RA., Competing Interests: The authors have declared that no competing interests exist.

Exposure to ultraviolet (UV) radiation is a major contributing factor to premature aging (photoaging) and skin cancer. In vitro models of cellular senescence have proven to be very useful for the study of slow and progressive accumulation of damage resulting in the growth arrest of aging skin cells. In this study, we compared UVA-induced cellular responses in non-senescent (NS) vs. senescent (S) human dermal fibroblasts (HDFs). HDFs were irradiated with a single dose of UVA (7.5 J/cm2) and QuantSeq 3' mRNA sequencing was performed to assess differential gene expression. Both NS and S HDFs expressed similar numbers of differentially expressed genes, although distinct sets of genes were differentially expressed between the two groups. Higher expression of matrix metalloproteinases (MMPs) and Toll-like receptor (TLR) pathway genes, such as TLR4, MyD88, and CXCL-8, was detected in S HDFs as compared with NS HDFs, and UVA exposure led to a downregulation of collagen genes, such as COL8A2 and COL5A3. Consistent with gene expression profiling, enhanced IL-6 and IL-8 secretion was observed in S HDFs compared with NS HDFs, in response to UVA. Furthermore, we show that TLR4-mediated ERK pathway is responsible for the UVA-mediated mitochondrial dysfunction as well as increased secretion of MMP-1 and IL-8 in S HDFs. Taken together, our results demonstrate the UVA-induced common and distinct molecular patterns of cellular responses between NS and S HDFs and suggest TLR4/ERK pathways as candidate targets to reduce senescent phenotypes., Competing Interests: The authors have declared that no competing interests exist.

Objectives: With the increasing use of multi-detector CT, the number of detected cases with coronary-to-pulmonary artery fistula (CPAF) has increased. Several previous studies reported severe cases of angina, but no appropriate tests to evaluate myocardial perfusion for patients with CPAF have been established. We evaluated the hemodynamic characteristics of CPAF using thallium-201 (Tl-201) single photon emission computed tomography (SPECT)., Materials and Methods: Tl-201 SPECT was performed in 17 patients with CPAF, but without evidence of coronary artery disease on coronary computed tomography angiography (CCTA) (age, 58.5±13.3 years; 8 men). Quantitative analysis of scintigraphic data was performed. Additionally, perfusion abnormalities were compared with CCTA findings. Medical records were obtained to define clinical data, diagnostic findings, symptoms, management, follow-up data, and major adverse cardiac events (MACE)., Results: Six patients (35.2%) showed perfusion abnormalities on SPECT studies and could be classified as follows: 3 patients, no reversible ischemia (3/17, 17.6%); 1 patient, mild ischemia (1/17, 5.8%); and 2 patients, moderate ischemia (2/17, 11.7%). During the follow-up, ten patients (58.8%) improved under medical management and 5 patients (29.4%) underwent surgical ligation for CPAF with symptomatic improvement in 4 patients. Seven patients performed follow-up myocardial perfusion SPECT, and symptomatic improvement correlated well with scintigraphic perfusion improvement in 6 patients No MACE was observed., Clinical Significance: Tl-201 myocardial perfusion SPECT might be useful for determining the hemodynamic status and for risk stratification in patients with CPAF.

On sedation motivated by the clinical needs for safety and reliability, recent studies have attempted to identify brain-specific signatures for tracking patient transition into and out of consciousness, but the differences in neurophysiological effects between 1) the sedative types and 2) the presence/absence of surgical stimulations still remain unclear. Here we used multimodal electroencephalography-functional near-infrared spectroscopy (EEG-fNIRS) measurements to observe electrical and hemodynamic responses during sedation simultaneously. Forty healthy volunteers were instructed to push the button to administer sedatives in response to auditory stimuli every 9-11 s. To generally illustrate brain activity at repetitive transition points at the loss of consciousness (LOC) and the recovery of consciousness (ROC), patient-controlled sedation was performed using two different sedatives (midazolam (MDZ) and propofol (PPF)) under two surgical conditions. Once consciousness was lost via sedatives, we observed gradually increasing EEG power at lower frequencies (<15 Hz) and decreasing power at higher frequencies (>15 Hz), as well as spatially increased EEG powers in the delta and lower alpha bands, and particularly also in the upper alpha rhythm, at the frontal and parieto-occipital areas over time. During ROC from unconsciousness, these spatio-temporal changes were reversed. Interestingly, the level of consciousness was switched on/off at significantly higher effect-site concentrations of sedatives in the brain according to the use of surgical stimuli, but the spatio-temporal EEG patterns were similar, regardless of the sedative used. We also observed sudden phase shifts in fronto-parietal connectivity at the LOC and the ROC as critical points. fNIRS measurement also revealed mild hemodynamic fluctuations. Compared with general anesthesia, our results provide insights into critical hallmarks of sedative-induced (un)consciousness, which have similar spatio-temporal EEG-fNIRS patterns regardless of the stage and the sedative used.

Brassinosteroids (BRs) are naturally occurring steroidal hormones that play diverse roles in various processes during plant growth and development. Thus, genetic manipulation of endogenous BR levels might offer a way of improving the agronomic traits of crops, including plant architecture and stress tolerance. In this study, we produced transgenic creeping bentgrass (Agrostis stolonifera L.) overexpressing a BR-inactivating enzyme, Arabidopsis thaliana BR-related acyltransferase 1 (AtBAT1), which is known to catalyze the conversion of BR intermediates to inactive acylated conjugates. After putative transgenic plants were selected using herbicide resistance assay, genomic integration of the AtBAT1 gene was confirmed by genomic PCR and Southern blot analysis, and transgene expression was validated by northern blot analysis. The transgenic creeping bentgrass plants exhibited BR-deficient phenotypes, including reduced plant height with shortened internodes (i.e., semi-dwarf), reduced leaf growth rates with short, wide, and thick architecture, high chlorophyll contents, decreased numbers of vascular bundles, and large lamina joint bending angles (i.e., erect leaves). Subsequent analyses showed that the transgenic plants had significantly reduced amounts of endogenous BR intermediates, including typhasterol, 6-deoxocastasterone, and castasterone. Moreover, the AtBAT1 transgenic plants displayed drought tolerance as well as delayed senescence. Therefore, the results of the present study demonstrate that overexpression of an Arabidopsis BR-inactivating enzyme can reduce the endogenous levels of BRs in creeping bentgrass resulting in BR-deficient phenotypes, indicating that the AtBAT1 gene from a dicot plant is also functional in the monocot crop.

Cryopreservation and transplantation of ovarian tissue (OT) represents a method for fertility preservation. However, as the transplantation is performed without vessel anastomosis, unavoidable ischemic damage occurs. To reduce this ischemic damage and improve outcomes after transplantation, we used two kind of angiogenic factors, angiopoietin-2 (ang-2) and vascular endothelial growth factor (VEGF). Fresh or vitrified-warmed bovine OTs were prepared for xenotransplantation (XT). Fresh OTs were immediately xenografted into nude mice (XT-Fresh). Vitrified-warmed OTs were xenografted into four subgroups of mice, which were injected intraperitoneally before XT with saline (XT-Vitri), Ang-2 (XT-Ang-2), VEGF (XT-VEGF), and a combination of Ang-2 and VEGF (XT-Combined). Seven or 28 days post-grafting, grafted OTs and blood samples were collected for evaluation. Follicle normality was higher in the angiogenic factor-treated groups than in the XT-Vitri group. The XT-VEGF and the XT-Combined showed higher (P<0.05) follicular density than the XT-Vitri group. The highest apoptotic follicle ratio was observed in the XT-Vitri group on day 7; this was decreased (P<0.05) in the XT-Combined group. Microvessel densities were higher in the angiogenic factor-treated groups than in the XT-Vitri group. The largest fibrotic area was showed in the XT-Vitri group on day 28, and it was decreased (P<0.05) in the XT-combined group. Based on these results, administration of Ang-2 and VEGF to recipients prior to XT appeared to alleviate ischemic damage by enhancing angiogenesis, which resulted in the maintenance of follicle integrity and density, and reduced follicle apoptosis and OT fibrosis.

Background: HIV disproportionately impacts young, black men who have sex with men (YBMSM) who experience disparities across the HIV care continuum. A more nuanced understanding of facilitators and barriers to engagement in care, missed visits, antiretroviral uptake, adherence and viral suppression could improve care and intervention design., Methods: A randomized controlled trial of an online intervention, healthMpowerment, enrolled 465 YBMSM (18-30 years); 193 identified as HIV-positive. Bivariable and multivariable analyses of baseline data explored predictors of: engagement in care, missed visits, antiretroviral uptake, self-reported adherence, and viral suppression., Results: Mean age was 24.9 years; most identified as gay (71.0%) and were receiving HIV care (89.1%). Among those in care, 52.1% reported no missed visits in the past 12 months, 41 (24.6%) reported one missed visit, and 39 (23.4%) reported two or more. Having insurance (prevalence odds ratio [POR] 4.5; 95% CI: 1.3, 15.8) and provider self-efficacy (POR 20.1; 95% CI: 6.1, 64.1) were associated with being in care. Those with a college degree (POR 9.1; 95% CI: 1.9, 45.2) and no recent marijuana (POR 2.6; 95% CI: 1.2, 5.6) or methamphetamine use (POR 5.4; 95% CI: 1.0, 28.5) were less likely to miss visits. Most (n = 153, 84.1%) had been prescribed antiretroviral therapy. A majority of participants (70.8%) reported ≥90% adherence; those with depressive symptoms had 4.7 times the odds of reporting adherence <90% (95% CI: 1.65, 13.37). Of participants who reported viral load testing in the past six months, 65% (n = 102) reported an undetectable viral load. Disclosure to sex partners was associated with viral suppression (POR 6.0; 95% CI: 1.6, 22.4)., Conclusions: Multi-level facilitators and barriers to engagement across the continuum of care were identified in this sample of YBMSM. Understanding the distinct needs of YBMSM at each stage of the continuum and addressing them through tailored approaches is critical for long term success in care.

The ginsenoside Rh2, a pharmaceutically active component of ginseng, is known to have anticancer and antitumor effects. However, white ginseng and red ginseng have extremely low concentrations of Rh2 or Rh2-Mix [20(S)-Rh2, 20(R)-Rh2, Rk2, and Rh3]. To enhance the production of food-grade ginsenoside Rh2, an edible enzymatic bioconversion technique was developed adopting GRAS host strains. A β-glucosidase (BglPm), which has ginsenoside conversion ability, was expressed in three GRAS host strains (Corynebacterium glutamicum, Saccharomyces cerevisiae and Lactococus lactis) by using a different vector system. Enzyme activity in these three GRAS hosts were 75.4%, 11.5%, and 9.3%, respectively, compared to that in the E. coli pGEX 4T-1 expression system. The highly expressed BglPm&#95;C in C. glutamicum can effectively transform the ginsenoside Rg3-Mix [20(S)-Rg3, 20(R)-Rg3, Rk1, Rg5] to Rh2-Mix [20(S)-Rh2, 20(R)-Rh2, Rk2, Rh3] using a scaled-up biotransformation reaction, which was performed in a 10-L jar fermenter at pH 6.5/7.0 and 37°C for 24 h. To our knowledge, this is the first report in which 50 g of PPD-Mix (Rb1, Rb2, Rb3, Rc, and Rd) as a starting substrate was converted to ginsenoside Rg3-Mix by acid heat treatment and then 24.5-g Rh2-Mix was obtained by enzymatic transformation of Rg3-Mix through by BglPm&#95;C. Utilization of this enzymatic method adopting a GRAS host could be usefully exploited in the preparation of ginsenoside Rh2-Mix in cosmetics, functional food, and pharmaceutical industries, thereby replacing the E. coli expression system.

The etiology and pathogenesis of moyamoya disease (MMD) are still obscure. Previous studies indicated that angiogenic chemokines may play an important role in the pathogenesis of the disease. Recently, it was discovered that peripheral blood-derived endothelial colony-forming cells (ECFCs) and smooth muscle progenitor cells (SPCs) have defective functions in MMD patients. Therefore, the interaction of ECFCs and SPCs, the precursors of two crucial cellular components of vascular walls, with some paracrine molecules is an intriguing subject. In this study, co-culture of ECFCs and SPCs from MMD patients and healthy normal subjects revealed that MMD ECFCs, not SPCs, are responsible for the defective functions of both ECFCs and SPCs. Enhanced migration of SPCs toward MMD ECFCs supported the role for some chemokines secreted by MMD ECFCs. Expression arrays of MMD and normal ECFCs suggested that several candidate cytokines differentially produced by MMD ECFCs. We selected chemokine (C-X-C motif) ligand 6 (CXCR6), interleukin-8 (IL8), chemokine (C-C motif) ligand 2 (CCL2), and CCL5 for study, based on the relatively higher expression of these ligands in MMD ECFCs and their cognate receptors in MMD SPCs. Migration assays showed that only CCL5 significantly augmented the migration activities of SPCs toward ECFCs. Treatment with siRNA for the CCL5 receptor (CCR5) abrogated the effect, confirming that CCL5 is responsible for the interaction of MMD ECFCs and SPCs. These data indicate that ECFCs, not SPCs, are the major players in MMD pathogenesis and that the chemokine CCL5 mediates the interactions. It can be hypothesized that in MMD patients, defective ECFCs direct aberrant SPC recruitment to critical vascular locations through the action of CCL5., Competing Interests: The authors have declared that no competing interests exist.

Periodontitis is a very common oral inflammatory disease that results in the destruction of supporting connective and osseous tissues of the teeth. Although the exact etiology is still unclear, Gram-negative bacteria, especially Porphyromonas gingivalis in subgingival pockets are thought to be one of the major etiologic agents of periodontitis. Endothelin (ET) is a family of three 21-amino acid peptides, ET-1, -2, and -3, that activate G protein-coupled receptors, ETA and ETB. Endothelin is involved in the occurrence and progression of various inflammatory diseases. Previous reports have shown that ET-1 and its receptors, ETA and ETB are expressed in the periodontal tissues and, that ET-1 levels in gingival crevicular fluid are increased in periodontitis patients. Moreover, P. gingivalis infection has been shown to induce the production of ET-1 along with other inflammatory cytokines. Despite these studies, however, the functional significance of endothelin in periodontitis is still largely unknown. In this study, we explored the cellular and molecular mechanisms of ET-1 action in periodontitis using human gingival epithelial cells (HGECs). ET-1 and ETA, but not ETB, were abundantly expressed in HGECs. Stimulation of HGECs with P. gingivalis or P. gingivalis lipopolysaccharide increased the expression of ET-1 and ETA suggesting the activation of the endothelin signaling pathway. Production of inflammatory cytokines, IL-1β, TNFα, and IL-6, was significantly enhanced by exogenous ET-1 treatment, and this effect depended on the mitogen-activated protein kinases via intracellular Ca2+ increase, which resulted from the activation of the phospholipase C/inositol 1,4,5-trisphosphate pathway. The inhibition of the endothelin receptor-mediated signaling pathway with the dual receptor inhibitor, bosentan, partially ameliorated alveolar bone loss and immune cell infiltration. These results suggest that endothelin plays an important role in P. gingivalis-mediated periodontitis. Thus, endothelin antagonism may be a potential therapeutic approach for periodontitis treatment., Competing Interests: The authors have declared that no competing interests exist.

The mechanisms underlying breast cancer progression of ductal carcinoma in situ (DCIS) associated with fatty acids are largely unknown. In the present study, we compared the action of oleic acid (OA) on two human DCIS cell lines, MCF10DCIS.COM (ER/PR/HER2-negative) and SUM225 (HER2 overexpressed). OA led to a significant increase in proliferation, migration, lipid accumulation and the expression of lipogenic proteins, such as SREBP-1, FAS and ACC-1, in MCF10DCIS.COM cells but not SUM225 cells. The ALDHhigh subpopulation analyzed by the ALDEFLUOR assay was approximately 39.2±5.3% of MCF10DCIS.COM cells but was small (3.11±0.9%) in SUM225 cells. We further investigated the different biological action of OA in the distinct ALDHlow and ALDHhigh subpopulations of MCF10DCIS.COM cells. OA led to an increase in the expression of ALDH1A1, ALDH1A2 and ALDH1A3 in MCF10DCIS.COM cells. SREBP-1 and ACC-1 were highly expressed in ALDHhigh cells relative to ALDHlow cells, whereas FAS was higher in ALDHlow cells. In the presence of OA, ALDHhigh cells were more likely to proliferate and migrate and displayed significantly high levels of SREBP-1 and FAS and strong phosphorylation of FAK and AKT relative to ALDHlow cells. This study suggests that OA could be a critical risk factor to promote the proliferation and migration of ALDHhigh cells in DCIS, leading to breast cancer progression., Competing Interests: The authors have declared that no competing interests exist.

Background: Vitamin D plays an important role in the immune system, and its deficiency has been implicated in various skin diseases, including atopic dermatitis and psoriasis. Acne is a common inflammatory skin disease; however, the association with vitamin D remains unclear., Objectives: We evaluated vitamin D levels in patients with acne to determine the effect of vitamin D supplementation., Methods: This study included 80 patients with acne and 80 healthy controls. Serum 25-hydroxyvitamin D (25(OH)D) levels were measured, and demographic data were collected. Vitamin D-deficient patients were treated with oral cholecalciferol at 1000 IU/day for 2 months., Results: Deficiency in 25(OH)D was detected in 48.8% of patients with acne, but in only 22.5% of the healthy controls. The level of 25(OH)D was inversely associated with the severity of acne, and there was a significant negative correlation with inflammatory lesions. In a subsequent trial, improvement in inflammatory lesions was noted after supplementation with vitamin D in 39 acne patients with 25(OH)D deficiency., Limitations: Limitations of the study include the small number of patients in the supplementation study and the natural fluctuation of acne., Conclusions: Vitamin D deficiency was more frequent in patients with acne, and serum 25(OH)D levels were inversely correlated with acne severity, especially in patients with inflammatory lesions., Competing Interests: The authors have declared that no competing interests exist.

Copepods, small aquatic crustaceans, are the most abundant metazoan zooplankton and outnumber every other group of multicellular animals on earth. In spite of ecological and biological importance in aquatic environment, their morphological plasticity, originated from their various lifestyles and their incomparable capacity to adapt to a variety of environments, has made the identification of species challenging, even for expert taxonomists. Molecular approaches to species identification have allowed rapid detection, discrimination, and identification of cryptic or sibling species based on DNA sequence data. We examined sequence variation of a partial mitochondrial cytochrome C oxidase I gene (COI) from 133 copepod individuals collected from the Korean Peninsula, in order to identify and discriminate 94 copepod species covering six copepod orders of Calanoida, Cyclopoida, Harpacticoida, Monstrilloida, Poecilostomatoida and Siphonostomatoida. The results showed that there exists a clear gap with ca. 20 fold difference between the averages of within-specific sequence divergence (2.42%) and that of between-specific sequence divergence (42.79%) in COI, suggesting the plausible utility of this gene in delimitating copepod species. The results showed, with the COI barcoding data among 94 copepod species, that a copepod species could be distinguished from the others very clearly, only with four exceptions as followings: Mesocyclops dissimilis-Mesocyclops pehpeiensis (0.26% K2P distance in percent) and Oithona davisae-Oithona similis (1.1%) in Cyclopoida, Ostrincola japonica-Pseudomyicola spinosus (1.5%) in Poecilostomatoida, and Hatschekia japonica-Caligus quadratus (5.2%) in Siphonostomatoida. Thus, it strongly indicated that COI may be a useful tool in identifying various copepod species and make an initial progress toward the construction of a comprehensive DNA barcode database for copepods inhabiting the Korean Peninsula.

In type 2 diabetic patients, the relationships between 25-hydroxyvitamin D and parathyroid hormone levels, and glycemic control, remain unclear. We evaluated associations between 25-hydroxyvitamin D, parathyroid hormone, and hemoglobin A1c levels after adjusting for other covariates, including log transformed 25-hydroxyvitamin D levels and log transformed parathyroid hormone levels, in Korean patients with type 2 diabetes. In total, 1,175 patients with type 2 diabetes were selected from 8,857 individuals who completed the baseline survey of the Dong-gu study, conducted in Korea from 2007 to 2010. After adjusting for other covariates, we found that the mean hemoglobin A1c level was inversely associated with the 25-hydroxyvitamin D level (Q1: 7.47% [7.30-7.63], Q2: 7.25% [7.09-7.40], Q3: 7.17% [7.02-7.32], Q4: 7.19% [7.02-7.35]; p for trend = 0.021, p for between groups = 0.050) and the parathyroid hormone level (Q1: 7.35% [7.19-7.51], Q2: 7.34% [7.19-7.50], Q3: 7.28% [7.13-7.43], Q4: 7.09% [6.94-7.24]; p for trend = 0.022, p for between groups = 0.048). However, the mean fasting glucose level was not associated with either the 25-hydroxyvitamin D or parathyroid hormone level. In conclusion, inverse associations were evident between hemoglobin A1c, 25-hydroxyvitamin D and parathyroid hormone levels in Korean patients with type 2 diabetes. The associations remained significant after adjusting for other covariates, including the log transformed 25-hydroxyvitamin D levels and log transformed parathyroid hormone levels.

Lysimachia foenum-graecum extract (LFE) and its active component foenumoside B (FSB) have been shown to inhibit adipocyte differentiation, but their mechanisms were poorly defined. Here, we investigated the molecular mechanisms responsible for their anti-adipogenic effects. Both LFE and FSB inhibited the differentiation of 3T3-L1 preadipocytes induced by peroxisome proliferator-activated receptor-γ (PPARγ) agonists, accompanied by reductions in the expressions of the lipogenic genes aP2, CD36, and FAS. Moreover, LFE and FSB inhibited PPARγ transactivation activity with IC50s of 22.5 μg/ml and 7.63 μg/ml, respectively, and showed selectivity against PPARα and PPARδ. Rosiglitazone-induced interaction between PPARγ ligand binding domain (LBD) and coactivator SRC-1 was blocked by LFE or FSB, whereas reduced NCoR-1 binding to PPARγ by rosiglitazone was reversed in the presence of LFE or FSB. In vivo administration of LFE into either ob/ob mice or KKAy mice reduced body weights, and levels of PPARγ and C/EBPα in fat tissues. Furthermore, insulin resistance was ameliorated by LFE treatment, with reduced adipose tissue inflammation and hepatic steatosis. Thus, LFE and FSB were found to act as PPARγ antagonists that improve insulin sensitivity and metabolic profiles. We propose that LFE and its active component FSB offer a new therapeutic strategy for metabolic disorders including obesity and insulin resistance.

Backgrounds: An outbreak of lung injury among South Korean adults was examined in a hospital-based case-control study, and the suspected cause was exposure to humidifier disinfectant (HD). However, a case-control study with community-dwelling controls was needed to validate the previous study's findings, and to confirm the exposure-response relationship between HD and lung injury., Methods: Each case of lung injury was matched with four community-dwelling controls, according to age (±3 years), sex, residence, and history of childbirth since 2006 (for women). Environmental risk factors, which included type and use of humidifier and HD, were investigated using a structured questionnaire during August 2011. The exposure to HD was calculated for both cases and controls, and the corresponding risks of lung injury were compared., Results: Among 28 eligible cases, 16 patients agreed to participate, and 60 matched controls were considered eligible for this study. The cases were more likely to have been exposed to HD (odds ratio: 116.1, 95% confidence interval: 6.5-2,063.7). All cases were exposed to HDs containing polyhexamethyleneguanidine phosphate, and the risk of lung injury increased with the cumulative exposure, duration of exposure, and exposure per day., Conclusions: This study revealed a statistically significant exposure-response relationship between HD and lung injury. Therefore, continuous monitoring and stricter evaluation of environmental chemicals' safety should be conducted.

Introduction: Oxidative stress plays a role in the pathogenesis of rheumatoid arthritis (RA). Anthocyanin is a plant antioxidant. We investigated the therapeutic effects of anthocyanin extracted from black soybean seed coats (AEBS) in a murine model of collagen-induced arthritis (CIA) and human peripheral blood mononuclear cells (PBMCs) and explored possible mechanisms by which AEBS might exert anti-arthritic effects., Material and Methods: CIA was induced in DBA/1J mice. Cytokine levels were measured via enzyme-linked immunosorbent assays. Joints were assessed in terms of arthritis incidence, clinical arthritis scores, and histological features. The extent of oxidative stress in affected joints was determined by measuring the levels of nitrotyrosine and inducible nitric oxide synthase. NF-κB activity was assayed by measuring the ratio of phosphorylated IκB to total IκB via Western blotting. Th17 cells were stained with antibodies against CD4, IL-17, and STAT3. Osteoclast formation was assessed via TRAP staining and measurement of osteoclast-specific mRNA levels., Results: In the CIA model, AEBS decreased the incidence of arthritis, histological inflammation, cartilage scores, and oxidative stress. AEBS reduced the levels of proinflammatory cytokines in affected joints of CIA mice and suppressed NF-κB signaling. AEBS decreased Th17 cell numbers in spleen of CIA mice. Additionally, AEBS repressed differentiation of Th17 cells and expression of Th17-associated genes in vitro, in both splenocytes of naïve DBA/1J mice and human PBMCs. In vitro, the numbers of both human and mouse tartrate-resistant acid phosphatase+ (TRAP) multinucleated cells fell, in a dose-dependent manner, upon addition of AEBS., Conclusions: The anti-arthritic effects of AEBS were associated with decreases in Th17 cell numbers, and the levels of proinflammatory cytokines synthesized by such cells, mediated via suppression of NF-κB signaling. Additionally, AEBS suppressed osteoclastogenesis and reduced oxidative stress levels.

Choline kinase-α (Chk-α) and autophagy have gained much attention, as they relate to the drug-resistance of breast cancer. Here, we explored the potential connection between Chk-α and autophagy in the mechanisms driving to tamoxifen (TAM) resistance, in estrogen receptor positive (ER+) breast cancer cells (BCCs). Human BCC lines (MCF-7 and TAM-resistant MCF-7 (MCF-7/TAM) cells) were used. Chk-α expression and activity was suppressed by the transduction of shRNA (shChk-α) with lentivirus and treatment with CK37, a Chk-α inhibitor. MCF-7/TAM cells had higher Chk-α expression and phosphocholine levels than MCF-7 cells. A specific downregulation of Chk-α by the transduction of shChk-α exhibited a significant decrease in phosphocholine levels in MCF-7 and MCF-7/TAM cells. The autophagy-related protein, cleaved microtubule-associated protein light chain 3 (LC3) and autophagosome-like structures were significantly increased in shChk-α-transduced or CK37-treated MCF-7 and MCF-7/TAM cells. The downregulation of Chk-α attenuated the phosphorylation of AKT, ERK1/2, and mTOR in both MCF-7 and MCF-7/TAM cells. In MCF-7 cells, the downregulation of Chk-α resulted in an induction of autophagy, a decreased proliferation ability and an activation of caspase-3. In MCF-7/TAM cells, despite a significant decrease in proliferation ability and an increase in the percentage of cells in the G0/G1 phase of the cell cycle, the downregulation of Chk-α did not induced caspase-dependent cell death and further enhanced autophagy and G0/G1 phase arrest. An autophagy inhibitor, methyladenine (3-MA) induced death and attenuated the level of elevated LC3 in MCF-7/TAM cells. Elucidating the interplay between choline metabolism and autophagy will provide unique opportunities to identify new therapeutic targets and develop novel treatment strategies that preferentially target TAM-resistance.

Objective: The relationship between mechanical stress and radiographic progression in rheumatoid arthritis (RA) is unclear. The assumption is that mechanical stress is greater in the dominant hand. Therefore, the aim of the present study was to compare the presence and progression of erosions and joint space narrowing (JSN) in the dominant and non-dominant hand., Methods: Data from 194 patients recently diagnosed with seropositive RA, and with hand radiographs taken at the time of diagnosis and at 2-year follow-up, were analyzed retrospectively. Radiographs were scored using the van der Heijde-modified Sharp Score (HSS) method. Each joint group within each hand was rated separately by two independent examiners in a double-blinded manner., Results: One hundred and ninety-four patients were enrolled (80% female, 88% positive rheumatoid factor, 92% positive anti-citrullinated protein antibody, and 95.4% right-handed). The baseline, follow-up erosion and JSN HSS were significantly higher in the dominant hand than in the non-dominant hand. The annual rate of radiographic progression was also higher in the dominant hand. The erosive progression in the wrist joints varied significantly according to handedness, but the erosion in the proximal interphalangeal joints and metacarpophalangeal joints was similar in both hands. The radiographic progression was associated with the dominant hand, an abnormal baseline C-reactive protein level, and joint damage at baseline. There was no significant difference in bone mineral density between the right and left hands., Conclusion: Radiological damage was worse and progressed faster in the dominant hand, suggesting that mechanical stress is associated with radiographic joint damage in early and active RA.

Rice blast fungus, Magnaporthe oryzae, is the most destructive pathogen in the rice-growing area. This fungus has a biotrophic phase early in infection and later switches to a necrotrophic lifestyle. During the biotrophic phase, the fungus competes with its host for nutrients and oxygen. Continuous uptake of oxygen is essential for successful establishment of blast disease of this pathogen. Here, we report transcriptional responses of the fungus to oxygen limitation. Transcriptome analysis using RNA-Seq identified that 1,047 genes were up-regulated in response to hypoxia. Those genes are involved in mycelial development, sterol biosynthesis, and metal ion transport based on hierarchical GO terms, and are well-conserved among three fungal species. In addition, null mutants of two hypoxia-responsive genes were generated and their roles in fungal development and pathogenicity tested. The mutant for the sterol regulatory element-binding protein gene, MoSRE1, exhibited increased sensitivity to a hypoxia-mimicking agent, increased conidiation, and delayed invasive growth within host cells, which is suggestive of important roles in fungal development. However, such defects did not cause any significant decrease in disease severity. The other null mutant, for the alcohol dehydrogenase gene MoADH1, showed no defect in the hypoxia-mimicking condition (using cobalt chloride) and fungal development. Taken together, this comprehensive transcriptional profiling in response to a hypoxic condition with experimental validations would provide new insights into fungal development and pathogenicity in plant pathogenic fungi.

Development of marker-free transgenic plants is a technical alternative for avoiding concerns about the safety of selectable marker genes used in genetically modified (GM) crops. Here, we describe the construction of a spontaneous self-excision binary vector using an oxidative stress-inducible modified FLP/FRT system and its successful application to produce marker-free transgenic rice plants with enhanced seed tocopherol content. To generate selectable marker-free transgenic rice plants, we constructed a binary vector using the hpt selectable marker gene and the rice codon-optimized FLP (mFLP) gene under the control of an oxidative stress-inducible promoter between two FRT sites, along with multiple cloning sites for convenient cloning of genes of interest. Using this pCMF binary vector with the NtTC gene, marker-free T1 transgenic rice plants expressing NtTC were produced by Agrobacterium-mediated stable transformation using hygromycin as a selective agent, followed by segregation of selectable marker genes. Furthermore, α-, γ-, and total tocopherol levels were significantly increased in seeds of the marker-free transgenic TC line compared with those of wild-type plants. Thus, this spontaneous auto-excision system, incorporating an oxidative stress-inducible mFLP/FRT system to eliminate the selectable marker gene, can be easily adopted and used to efficiently generate marker-free transgenic rice plants. Moreover, nutritional enhancement of rice seeds through elevation of tocopherol content coupled with this marker-free strategy may improve human health and public acceptance of GM rice.

In neuro-oncology, the biology of neural stem cells (NSCs) has been pursued in two ways: as tumor-initiating cells (TICs) and as a potential cell-based vehicle for gene therapy. NSCs as well as mesenchymal stem cells (MSCs) have been reported to possess tumor tropism capacities. However, there is little data on the migratory capacity of MSCs toward brain tumor-initiating cells (BTICs). This study focuses on the ability of human adipose tissue derived MSCs (hAT-MSCs) to target BTICs and their crosstalk in the microenvironment. BTICs were isolated from three different types of brain tumors. The migration capacities of hAT-MSCs toward BTICs were examined using an in vitro migration assay and in vivo bioluminescence imaging analysis. To investigate the crosstalk between hAT-MSCs and BTICs, we analyzed the mRNA expression patterns of cyto-chemokine receptors by RT-qPCR and the protein level of their ligands in co-cultured medium. The candidate cyto-chemokine receptors were selectively inhibited using siRNAs. Both in vitro and in vivo experiments showed that hAT-MSCs possess migratory abilities to target BTICs isolated from medulloblastoma, atypical teratoid/rhabdoid tumors (AT/RT) and glioblastoma. Different types of cyto-chemokines are involved in the crosstalk between hAT-MSCs and BTICs (medulloblastoma and AT/RT: CXCR4/SDF-1, CCR5/RANTES, IL6R/IL-6 and IL8R/IL8; glioblastoma: CXCR4/SDF-1, IL6R/IL-6, IL8R/IL-8 and IGF1R/IGF-1). Our findings demonstrated the migratory ability of hAT-MSCs for BTICs, implying the potential use of MSCs as a delivery vehicle for gene therapy. This study also confirmed the expression of hAT-MSCs cytokine receptors and the BTIC ligands that play roles in their crosstalk.

Background: Ovarian tissue (OT) cryopreservation is effective in preserving fertility in cancer patients who have concerns about fertility loss due to cancer treatment. However, the damage incurred at different steps during the cryopreservation procedure may cause follicular depletion; hence, preventing chilling injury would help maintain ovarian function., Objective: This study was designed to investigate the beneficial effects of different antifreeze proteins (AFPs) on mouse ovarian tissue cryopreservation and transplantation., Methodology: Ovaries were obtained from 5-week-old B6D2F1 mice, and each ovary was cryopreserved using two-step vitrification and four-step warming procedures. In Experiment I, ovaries were randomly allocated into fresh, vitrification control, and nine experimental groups according to the AFP type (FfIBP, LeIBP, type III) and concentration (0.1, 1, 10 mg/mL) used. After vitrification and warming, 5,790 ovarian follicles were evaluated using histology and TUNEL assays, and immunofluorescence for τH2AX and Rad51 was used to detect DNA double-strand breaks (DSBs) and repair (DDR), respectively. In Experiment II, 20 mice were randomly divided into two groups: one where the vitrification and warming media were supplemented with 10 mg/mL LeIBP, and the other where media alone were used (control). Ovaries were then autotransplanted under both kidney capsules 7 days after vitrification together with the addition of 10 mg/mL LeIBP in the vitrification-warming media. After transplantation, the ovarian follicles, the percentage of apoptotic follicles, the extent of the CD31-positive area, and the serum FSH levels of the transplanted groups were compared., Principal Findings: In Experiment I, the percentage of total grade 1 follicles was significantly higher in the 10 mg/mL LeIBP group than in the vitrification control, while all AFP-treated groups had significantly improved grade 1 primordial follicle numbers compared with those of the vitrification control. The number of apoptotic (TUNEL-positive) follicles was significantly decreased in the groups treated with 1 and 10 mg/mL LeIBP. The proportion of τH2AX-positive follicles was significantly reduced in all AFP-treated groups, while the proportion of Rad51-positive follicles was significantly decreased in only the FfIBP- and LeIBP-treated groups. In Experiment II, after autotransplantation of OT vitrified with 10 mg/mL of LeIBP, the percentage of total grade 1 and primordial grade 1 follicles, and the extent of the CD31-positive area, were increased significantly. Moreover, the levels of serum FSH and the percentage of TUNEL-positive follicles were significantly lower in the LeIBP-treated than in the control group., Conclusion: A supplementation with high concentrations of AFPs had protective effects on follicle preservation during OT vitrification-warming procedures. The group treated with LeIBP was protected most effectively. The beneficial effects of LeIBP were also observed after autotransplantation of vitrified-warmed OT. Further studies are necessary to determine the exact mechanism of these protective effects.

It was recently reported that factor H, a regulatory component of the alternative complement pathway, is stored with von Willebrand factor (VWF) in the Weibel-Palade bodies of endothelial cells. If this were to be the case, it would have therapeutic importance for patients with the atypical hemolytic-uremic syndrome that can be caused either by a heterozygous defect in the factor H gene or by the presence of an autoantibody against factor H. The in vivo Weibel-Palade body secretagogue, des-amino-D-arginine vasopressin (DDAVP), would be expected to increase transiently the circulating factor H levels, in addition to increasing the circulating levels of VWF. We describe experiments demonstrating that factor H is released from endothelial cell cytoplasm without a secondary storage site. These experiments showed that factor H is not stored with VWF in endothelial cell Weibel-Palade bodies, and is not secreted in response in vitro in response to the Weibel-Palade body secretagogue, histamine. Furthermore, the in vivo Weibel-Palade body secretagogue, DDAVP does not increase the circulating factor H levels concomitantly with DDAVP-induced increased VWF. Factor I, a regulatory component of the alternative complement pathway that is functionally related to factor H, is also located in endothelial cell cytoplasm, and is also not present in endothelial cell Weibel-Palade bodies. Our data demonstrate that the factor H and factor I regulatory proteins of the alternative complement pathway are not stored in Weibel-Palade bodies. DDAVP induces the secretion into human plasma of VWF--but not factor H.

According to the World Health Organization in 2013, 235 million people are afflicted with asthma. Asthma is a severe pulmonary disease that can be caused by the imbalance of T-helper (Th) type 1 (Th1) and type 2 (Th2) cells, and it is potentially fatal. In this study, we evaluated the anti-asthmatic effect of alginate oligosaccharide (AO), which was prepared from seaweed and converted by Bacillus subtilis KCTC 11782BP, in the mouse model of ovalbumin (OVA)-induced asthma. BALB/c mice were divided into the vehicle control (sensitized but not challenged), asthma induction, positive control (1 mg/kg dexamethasone), 50 mg/kg/day AO-treated, 200 mg/kg/day AO-treated, and 400 mg/kg/day AO-treated groups. The numbers or levels of inflammatory cells, eosinophils, and immunoglobulin (Ig) E were measured in bronchoalveolar lavage fluid (BALF), and asthma-related morphological and cytokine changes were analyzed in lung tissues. Our results show that AO dramatically reduced inflammatory cell numbers, eosinophil count, and IgE levels in BALF, and it dose-dependently inhibited asthmatic histopathological changes in the lung. In addition, AO dose-dependently suppressed the expression of CD3+ T-cell co-receptors, CD4+ Th cells, CD8+ cytotoxic T-cell-related factors, macrophages, and MHCII class. AO dose-dependently decreased the expression levels of Th1/2 cells-regulatory transcription factors such as GATA-3 which modulates Th2 cell proliferation and T-bet which does Th1 cell proliferation. The mRNA levels of all Th1/2-related cytokines, except IL-12α, were dose-dependently suppressed by AO treatment. In particular, the mRNA levels of IL-5, IL-6, and IL-13 were significantly inhibited by AO treatment. Our findings suggest that AO has the potential to be an anti-asthmatic drug candidate, due to its modulation of Th1/Th2 cytokines, which contribute to the pathogenesis of asthma.

Event-related potential (ERP)-based P300 spellers are commonly used in the field of brain-computer interfaces as an alternative channel of communication for people with severe neuro-muscular diseases. This study introduces a novel P300 based brain-computer interface (BCI) stimulus paradigm using a random set presentation pattern and exploiting the effects of face familiarity. The effect of face familiarity is widely studied in the cognitive neurosciences and has recently been addressed for the purpose of BCI. In this study we compare P300-based BCI performances of a conventional row-column (RC)-based paradigm with our approach that combines a random set presentation paradigm with (non-) self-face stimuli. Our experimental results indicate stronger deflections of the ERPs in response to face stimuli, which are further enhanced when using the self-face images, and thereby improving P300-based spelling performance. This lead to a significant reduction of stimulus sequences required for correct character classification. These findings demonstrate a promising new approach for improving the speed and thus fluency of BCI-enhanced communication with the widely used P300-based BCI setup.

Background: There has still been lack of evidence for definite imaging criteria of intra-arterial revascularization (IAR). Therefore, IAR selection is left largely to individual clinicians. In this study, we sought to investigate the overall agreement of IAR selection among different stroke clinicians and factors associated with good agreement of IAR selection., Methods: From the prospectively registered data base of a tertiary hospital, we identified consecutive patients with acute ischemic stroke. IAR selection based on the provided magnetic resonance imaging (MRI) results and clinical information were independently performed by 5 independent stroke physicians currently working at 4 different university hospitals. MRI results were also reviewed by 2 independent experienced neurologists blinded to clinical data and physicians' IAR selection. The Alberta Stroke Program Early Computed Tomography Score (ASPECTS) was calculated on initial DWI and MTT. We arbitrarily used ASPECTS differences between DWI and MTT (D-M ASPECTS) to quantitatively evaluate mismatch., Results: The overall interobserver agreement of IAR selection was fair (kappa = 0.398). In patients with DWI-ASPECTS >6, interobserver agreement was moderate to substantial (0.398-0.620). In patients with D-M ASPECTS >4, interobserver agreement was moderate to almost perfect (0.532-1.000). Patients with higher DWI or D-M ASPECTS had better agreement of IAR selection., Conclusion: Our study showed that DWI-ASPSECTS >6 and D-M ASPECTS >4 had moderate to substantial agreement of IAR selection among different stroke physicians. However, there is still poor agreement as to whether IAR should not be performed in patients with lower DWI and D-M ASPECTS.

In this study, we examined the effects of two phytoplankton species, Chlorella vulgaris and Stephanodiscus hantzschii, on growth of the zooplankton Daphnia magna. Our experimental approach utilized stable isotopes to determine the contribution of food algae to offspring characteristics and to the size of adult D. magna individuals. When equal amounts of food algae were provided (in terms of carbon content), the size of individuals, adult zooplankton, and their offspring increased significantly following the provision of S. hantzschii, but not after the provision of C. vulgaris or of a combination of the two species. Offspring size was unaffected when C. vulgaris or a mixture of the two algal species was delivered, whereas providing only S. hantzschii increased the production of larger-sized offspring. Stable isotope analysis revealed significant assimilation of diatom-derived materials that was important for the growth of D. magna populations. Our results confirm the applicability of stable isotope approaches for clarifying the contribution of different food algae and elucidate the importance of food quality for growth of D. magna individuals and populations. Furthermore, we expect that stable isotope analysis will help to further precisely examine the contribution of prey to predators or grazers in controlled experiments.

The dopamine D2 receptor (DRD2) is a key receptor that mediates dopamine-associated brain functions such as mood, reward, and emotion. Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase whose function has been implicated in the brain reward circuit. In this study, we revealed that the serine 321 residue (S321) in the third intracellular loop of DRD2 (D2i3) is a novel regulatory site of Cdk5. Cdk5-dependent phosphorylation of S321 in the D2i3 was observed in in vitro and cell culture systems. We further observed that the phosphorylation of S321 impaired the agonist-stimulated surface expression of DRD2 and decreased G protein coupling to DRD2. Moreover, the downstream cAMP pathway was affected in the heterologous system and in primary neuronal cultures from p35 knockout embryos likely due to the reduced inhibitory activity of DRD2. These results indicate that Cdk5-mediated phosphorylation of S321 inhibits DRD2 function, providing a novel regulatory mechanism for dopamine signaling.

Based on a recent model of paradigm shifts by Bornholdt et al., we studied mean-field opinion dynamics in an infinite population where an infinite number of ideas compete simultaneously with their values publicly known. We found that a highly innovative society is not characterized by heavy concentration in highly valued ideas: Rather, ideas are more broadly distributed in a more innovative society with faster progress, provided that the rate of adoption is constant, which suggests a positive correlation between innovation and technological disparity. Furthermore, the distribution is generally skewed in such a way that the fraction of innovators is substantially smaller than has been believed in conventional innovation-diffusion theory based on normality. Thus, the typical adoption pattern is predicted to be asymmetric with slow saturation in the ideal situation, which is compared with empirical data sets.

Background: The occurrence of numerous cases of interstitial lung disease in children (chILD) every spring in Korea starting in 2006 raised suspicion about a causal relationship with the use of humidifier disinfectants (HDs). The aim of this study was to evaluate the association between HD use and the risk of chILD., Methods: This retrospective, 1∶3 matched case-control study consisted of 16 cases of chILD that had developed between 2010 and 2011. The three groups of parallel controls (patients with acute lobar pneumonia, asthma, and healthy children) were matched by age, gender, and index date. Indoor/outdoor environmental risk factors, including HD use, were investigated by asking the guardians to complete a questionnaire., Results: The median age of the affected children (43.8% male) was 26 months (18.25-36.25). The chILD group did not differ significantly from the control groups with respect to socio-demographic and clinical variables. Indoor and outdoor environmental factors were not associated with a risk of chILD. However, the previous use of HDs (OR; 2.73. 95% CI; 1.41-5.90, P = 0.00) were independently associated with an increased risk., Conclusions: This study showed that HDs, which are widely used in South Korea in the winter season, independently increased the risk of chILD in spring. Therefore, continuous monitoring and, if needed, changes in policy are essential to prevent and control pediatric diseases caused by toxic chemicals.

Analysis of gene expression to define molecular mechanisms and pathways involved in human embryonic stem cells (hESCs) proliferation and differentiations has allowed for further deciphering of the self-renewal and pluripotency characteristics of hESC. Proteins associated with hESCs were discovered through isobaric tags for relative and absolute quantification (iTRAQ). Undifferentiated hESCs and hESCs in different stages of spontaneous differentiation by embryoid body (EB) formation were analyzed. Using the iTRAQ approach, we identified 156 differentially expressed proteins involved in cell proliferation, apoptosis, transcription, translation, mRNA processing, and protein synthesis. Proteins involved in nucleic acid binding, protein synthesis, and integrin signaling were downregulated during differentiation, whereas cytoskeleton proteins were upregulated. The present findings added insight to our understanding of the mechanisms involved in hESC proliferation and differentiation.

How to distribute welfare in a society is a key issue in the subject of distributional justice, which is deeply involved with notions of fairness. Following a thought experiment by Dworkin, this work considers a society of individuals with different preferences on the welfare distribution and an official to mediate the coordination among them. Based on a simple assumption that an individual's welfare is proportional to how her preference is fulfilled by the actual distribution, we show that an egalitarian preference is a strict Nash equilibrium and can be favorable even in certain inhomogeneous situations. These suggest how communication can encourage and secure a notion of fairness.

Chromatin remodeling through histone modifications has emerged as a key mechanism in the pathophysiology of psychiatric disorders. Valproate (VPA), a first-line medication for bipolar disorder, is known to have histone deacetylase (HDAC) inhibitor activity, but the relationship between its efficacy as a mood stabilizer and HDAC inhibitory activity is unclear. Here we provide evidence that prostate apoptosis response-4 (Par-4), an intracellular binding partner of dopamine D2 receptors (DRD2), plays a role in mediating the effectiveness of VPA. We found that chronic VPA treatment enhanced the expression of Par-4 in cultured neurons and adult mouse brains. This Par-4 induction phenomenon occurred at the transcriptional level and was correlated with an increase in histone H3 and H4 acetylation of the Par-4 promoter regions. Furthermore, chronic VPA treatment potentiated the suppression of the cAMP signaling cascade upon dopamine stimulation, which was blocked by sulpiride treatment. These results indicate that VPA potentiates DRD2 activity by enhancing Par-4 expression via a chromatin remodeling mechanism.