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Nucleocytoplasmic large DNA viruses (NCLDVs) are known to infect phytoplankton and play a significant role in regulating their population dynamics. In this study, we aimed to investigate the co-occurrence patterns between phytoplankton and NCLDVs in the southern coastal ecosystem of South Korea. We collected seawater every month from March 2018 to December 2020 and analyzed the samples using Cytochrome c Oxidase subunit I metabarcoding and metagenomic analyses. Chlorophyta (36.08%) was the most abundant eukaryotic taxon, with Bathycoccaceae (58.25%) and Mamiellaceae (41.51%) being the most dominant families within Chlorophyta. Bathycoccaceae was dominant in winter, whereas Mamiellaceae was dominant in summer. In the NCLDV community, Phycodnaviridae (75.12%) was found to be the major family. The co-occurrence pattern of Phycodnaviridae showed a high correlation with Bathycoccaceae and Mamiellaceae, which is explained by the "boom-and-bust" concept. In particular, we predicted co-occurrence patterns between Bathycoccus prasinos and Prasnovirus, with known infectious relationships, and confirmed co-occurrence patterns between B. prasinos and Coccolithovirus and Micromonas pusilla and Prymnesiovirus, with unknown infectious relationships. These co-occurrence patterns between Chlorophyta and Phycodnaviridae provide valuable insights into the control of pico-sized primary production and the microbial loop of the coastal ecosystem., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

This study employed 16S rRNA metabarcoding to establish the diversity of prokaryotic communities and specific characteristics of potentially pathogenic prokaryotic primary colonizers of four plastic materials (EPS, expanded polystyrene; PE, polyethylene; PP, polypropylene; and PET, polyethylene terephthalate). Bacteria inhabiting plastic and seawater differ; thus, distinct changes in the attached prokaryotic community were observed over an exposure time of 21 days, specifically on Days 3, 6, 9, and 12-21. Frist colonizers were Gammaproteobacteria and Alphaproteobacteria; Bacilli and Clostridia represented secondary colonizers. On Day 3, Pseudoalteromonas had a relative abundance >80 %; whereas, the prevalence of Vibrio spp. (potentially pathogenic prokaryotes) increased rapidly on Days 6 and 9. However, after Day 12, the prevalence of other potential pathogens, namely, Clostridium spp., steadily increased. Despite the diversity of the plastic surfaces, attached prokaryotes changed over time instead of showing similar adherent diversity in all plastic materials., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Type 2 diabetes is associated with a risk factor for Alzheimer's disease (AD). Activation of glial cells, such as microglia and astrocytes, is crucial for the development of neuroinflammation in both diabetes and AD. The role of amyloid-beta oligomer (AβO) in the hippocampus of diabetic mice has been investigated; however, the effect of galectin-3 and lipocalin-2 (LCN2) on amyloid toxicity-related glial activation in diabetic mice is not known. To fill this knowledge gap, we fed mice a high-fat diet (HFD) for 20 weeks to induce a diabetic state and then injected the hippocampus with AβO. Sholl analysis of iba-1-positive microglia showed retraction of microglial ramifications in the hippocampus of HFD-fed diabetic mice. AβO treatment caused more retraction of microglial process in HFD-fed mice. In particular, microglial galectin-3 levels and astrocytic LCN2 levels were increased in the hippocampus of HFD-fed mice with AβO treatment. These findings suggest that galectin-3 and LCN2 are involved in amyloid toxicity mechanisms, especially glial activation under diabetic conditions., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Lipocalin-2 (LCN2) is an acute phase protein used as a biomarker for acute lung injury (ALI). Although the innate immune functions of LCN2 have been studied, how LCN2 contributes to ALI induced by lipopolysaccharide (LPS) remains unknown. In this study, we investigated the effect of LCN2 deletion on LPS-induced ALI using RNA-sequencing. LPS-treated LCN2 knockout (KO) mice had a decreased histopathological score and reduced neutrophil and macrophage infiltration in lung tissue compared with LPS-treated WT mice. RNA-sequencing analysis identified 38 differentially expressed genes (DEGs), including Cxcl5, Cxcl13, Xcl1, Saa1, and Cd14. In particular, Gene Ontology analysis of DEGs revealed a significant reduction in the inflammatory response, neutrophil chemotaxis, and chemokine-mediated signaling in LPS-treated LCN2KO mice compared with LPS-treated WT mice. Thus, these results suggest that LCN2 deletion alleviates LPS-induced ALI and that LCN2 may be involved in chemotaxis-related gene expression., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)

To understand the co-variance between common free-living bacteria and Cochlodinium polykrikoides harmful algal blooms (HABs) and their metabolic functions, we investigated 110 sampling sites in the Southern Sea of South Korea. These sampling sites were divided into three groups based on environmental factors and phytoplankton data with a similarity of 85% using non-metric multidimensional scaling. One group represented high-severity C. polykrikoides blooms, while the other two represented low-severity or no blooms. In high-severity HABs, inorganic phosphorous and dissolved organic carbon concentrations were strongly correlated with C. polykrikoides density (p < 0.01). This may reflect the changes in biochemical cycling due to inorganic and organic substrates released by HAB cells (or by cell destruction). Furthermore, 88 common bacterial operational taxonomic units (OTUs, with mean relative abundance > 1%) were identified. These included Gammaproteobacteria (36 OTUs), Flavobacteriia (24), Alphaproteobacteria (18), and other taxa (11). When C. polykrikoides blooms intensified, the relative abundances of Gammaproteobacteria also increased. OTU #030 (Flavicella sp., Flavobacteria, 96%) was positively correlated with C. polykrikoides abundance (r = 0.77, p < 0.001). Functional analysis based on the dominant bacterial OTUs revealed that chemoheterotrophy-related functions were more common in high-severity sites of HABs than in other groups. Therefore, the occurrence of HABs highlighted their interactions with bacteria and affected the bacterial community structure and metabolic functions., Competing Interests: Declaration of Competing Interest There are no conflicts of interests to declare., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Doxorubicin (DOX) is an effective anticancer drug with the side effect of irreparable cardiomyopathy. Lipocalin-2 (LCN2) has been identified as an important regulator of oxidative stress and inflammation in cardiovascular disease pathophysiology. Here, we demonstrate that LCN2 deletion increases autophagic flux in the DOX-treated hearts. Mice were injected intraperitoneally six times with 30 mg/kg DOX. Echocardiography showed that DOX-treated wild-type (WT) mice had markedly weaker cardiac function compared to saline-treated WT mice. In DOX-treated LCN2 knockout (KO) mice, cardiac function was partially restored. Histological analysis showed a reduction in cardiomyocyte diameter in DOX-treated WT mice that was ameliorated in DOX-treated LCN2KO mice. Cardiac levels of phosphorylated signal transducer and activator of transcription 3, LCN2, heme oxygenase-1, and NAD (P) H dehydrogenase were markedly greater in DOX-treated WT mice than in DOX-treated LCN2KO mice. Light chain 3B (LC3B)II expression was higher in DOX-treated WT mice, but lower in DOX-treated LCN2KO mice when compared to saline-treated WT mice. Less co-localization of LC3B and lysosomal-associated membrane protein 1 was observed in DOX-treated WT mice than in DOX-treated LCN2KO mice. LCN2 co-localized with LC3B-stained cells in the DOX-treated WT mouse heart, but not in the DOX-treated LCN2KO mouse heart. These findings indicate that the cardiotoxic effect of DOX is due to autophagosome accumulation mediated by LCN2 upregulation and that LCN2 may inhibit autophagic flux, leading to DOX-induced cardiomyopathy., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: To investigate the long-term progression of pericentral hydroxychloroquine retinopathy., Design: Multicenter, retrospective cohort study., Participants: Eighty eyes (60 with pericentral pattern) of 41 Korean patients with hydroxychloroquine retinopathy followed up for 2 years or more after drug cessation., Methods: Patients were screened for hydroxychloroquine retinopathy using spectral-domain or swept-source OCT, fundus autofluorescence (FAF), and Humphrey visual field (VF) tests. Follow-up was divided into short-term (≤2 years) and subsequent periods, and progression was evaluated in each period and severity group. Retinopathy progression on OCT was defined as increased length of the ellipsoid zone defect, decreased distance from the fovea to the photoreceptor defects, or newly developed or enlarged retinal pigment epithelium defects. On FAF, progression was defined as an increase in the area of hyperautofluorescence or hypoautofluorescence. Functional progression was defined as a regression coefficient of less than 0 dB/year for mean deviation and more than 0 dB/year for pattern standard deviation, based on linear regression analysis of 3 or more VF tests. Structural and functional progression rates were calculated using the slopes of retinal thicknesses on the Early Treatment Diabetic Retinopathy Study grid and perimetric parameters over time, respectively., Main Outcome Measures: Structural and functional progression of retinopathy., Results: Approximately one third of eyes with early pericentral retinopathy showed limited progression during the short-term period after drug cessation, but they subsequently showed stable or improved photoreceptors. Most eyes with moderate pericentral retinopathy showed continuous progression, particularly when converted to the severe stage. Severe eyes showed progressive damage throughout the follow-up period. In all severity groups, the rates of retinal thinning decreased over time. In eyes with pericentral retinopathy showing progression, circumferential enlargement of retinal damage was prominent in earlier stages, whereas centripetal enlargement of the ring-shaped lesion was noted in advanced stages. Functional progression, noted in 58.7% of the pericentral eyes, corresponded with structural progression., Conclusions: Pericentral hydroxychloroquine retinopathy showed severity-dependent progression. Moderate pericentral retinopathy usually progressed, but centripetal progression threatening the fovea was remarkable mostly in severe retinopathy. Our results suggest that early detection of retinopathy may minimize the risk of progression to foveal involvement in pericentral retinopathy., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the use of a retinal thickness deviation map generated from swept-source (SS) OCT images for hydroxychloroquine retinopathy screening., Design: Retrospective cohort study., Participants: This study included 1192 Korean patients with a history of hydroxychloroquine treatment: 881 patients (1723 eyes) in the discovery set and 311 patients (591 eyes) in the validation set. Patients were screened for retinal toxicity using SS OCT, fundus autofluorescence, and standard automated perimetry., Methods: According to the 2016 American Academy of Ophthalmology guidelines, hydroxychloroquine retinopathy was diagnosed by the presence of abnormalities on ≥1 objective structural tests alongside corresponding visual field defects. The 12 × 9-mm 2 macular volume SS OCT scan was performed, and the retinal thickness deviation map was generated automatically using the built-in software. On this map, yellow (retinal thickness, <5% of the normative level) or red (<1% of the normative level) pixels were defined as abnormal. Abnormal findings were evaluated, and diagnostic criteria were developed based on the discovery set data; criteria were validated using the validation set data., Main Outcome Measures: The rate and patterns of abnormalities on the retinal thickness deviation map and sensitivity and specificity of the diagnostic criteria., Results: The retinal thickness deviation map showed the following abnormal patterns in eyes with hydroxychloroquine retinopathy: pericentral (36.0%) or parafoveal (6.1%) ring, mixed-ring (34.2%), central island (13.2%), and whole macular thinning (10.5%). The criterion of ≥5 contiguous red pixels showing 1 of the 5 characteristic patterns in both eyes yielded the greatest diagnostic performance (sensitivity and specificity of 98.2% and 89.1% and of 100% and 87.5% in the discovery and validation set data, respectively). Moreover, the area of abnormal pixels on the map was correlated significantly with the mean deviation (P < 0.001) and pattern standard deviation (P < 0.001) on the Humphrey 30-2 test in eyes with hydroxychloroquine retinopathy., Conclusions: The retinal thickness deviation map may facilitate the objective evaluation of hydroxychloroquine retinopathy because it does not require subjective, morphologic evaluation of the outer retinal layers. The map has the potential to enhance hydroxychloroquine retinopathy screening when used in conjunction with conventional screening methods., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: Aromatase inhibitors (AIs) are the preferred endocrine treatment for postmenopausal hormonal receptor-positive breast cancer. However, there is controversy on the long-term cardiovascular and cerebrovascular safety of AIs over that of tamoxifen., Methods: We analyzed the National Health Information Database (NHID) of 281,255 women over a 20-year-old diagnosed with breast cancer between 2009 and 2016. Cardiovascular events (CVEs) were defined as the development of the following, acute coronary syndrome (ACS), ischemic and hemorrhagic stroke, defined by using insurance claim records. The model was constructed by Cox proportional hazard regression and this model was used to analyze the effects of AI and tamoxifen on CVE., Results: We included 47,569 women for the final analysis. Patients were classified into 'No hormonal treatment (n = 18,807), 'Switch (n = 2097)', 'Tamoxifen (n = 7081)' and 'AI (n = 19,584)'. There were 2147 CVEs in 2032 patients (4.1%). Univariate analysis showed that women with tamoxifen had significantly lower risk for CVEs compared to no-treatment (hazard ratio (HR) 0.84, 95% confidence interval (CI) 0.74-0.97) while AI showed no such effect (HR 0.93, 95% CI 0.84-1.02). After adjusting for other risk factors (hypertension, dyslipidemia, family history), the use of tamoxifen was associated with significant protective effect against ACS (HR 0.63, 95% CI 0.47-0.84)., Conclusions: Our results, based on the NHID, supports the protective effect of tamoxifen against CVE in Korean breast cancer patients aged 55 and older that is not seen with AIs. Our results can guide the selection of adjuvant hormonal treatment agents for Korean breast cancer patients based on their risk of developing CVE., Competing Interests: Declaration of competing interest The authors indicated no potential conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Chemotherapy is commonly used as a major therapeutic option for breast cancer treatment, but its efficacy is often diminished by disruption of patient's anti-tumor immunity. Chemotherapy-generated tumor cell debris could hijack accumulated tumor-associated macrophages (TAMs), provoking tumor recurrence. Therefore, reprogramming TAMs to acquire an immunocompetent phenotype is a promising strategy to potentiate therapeutic efficacy. In this study, we analyzed the proportion of immune cells in the breast cancer patients who received chemotherapy. To validate our findings in vivo, we used a syngeneic murine breast cancer (4T1) model. Chemotherapy generates an immunosuppressive tumor microenvironment in breast cancer. Here, we show that phagocytic engulfment of tumor cell debris by TAMs reduces chemotherapeutic efficacy in a 4T1 breast cancer model. Specifically, the engulfment of tumor cell debris by macrophages reduced M1-like polarization through heme oxygenase-1 (HO-1) upregulation. Conversely, genetic or pharmacologic inhibition of HO-1 in TAMs restored the M1-like polarization. Our results demonstrate that tumor cell debris-induced HO-1 expression in macrophages regulates their polarization. Inhibition of HO-1 overexpression in TAMs may provoke a robust anti-tumor immune response, thereby potentiating the efficacy of chemotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/objective: In anterior cruciate ligament ​reconstruction, a tendon graft, anchored by interference screws (IFSs), is frequently used as a replacement for the damaged ligament. Generally, IFSs are classified as being either metallic or polymeric. Metallic screws have sharp threads that lacerate the graft, preventing solid fixation. These constructs are difficult to image ​and can limit bone--screw integration because of the higher stiffness of the screw. Polymeric materials are often a better match to bone's material properties, but lack the strength needed to hold grafts in place. Magnesium (Mg) is a material of great promise for orthopaedic applications. Mg has mechanical properties similar to bone, ability to be seen on magnetic resonance imagings, and promotes bone healing. However, questions still remain regarding the strength of Mg-based screws. Previous ex vivo  ​animal experiments found stripping of the screw drive when the full torque was applied to Mg screws during surgery, preventing full insertion and poor graft fixation. The similar design of the Mg screw led to questions regarding the relationship between material properties and design, and the ultimate impact on mechanical behaviour. Thus, the objective of this study was to analyze the stresses in the screw head, a key factor in the stripping mechanism of IFS, then use that information to improve screw design, for this material., Methods: Using finite element analysis, a comparison study of six drive designs (hexagonal, quadrangle, torx, trigonal, trilobe, and turbine) was performed. This was followed by a parametric analysis to determine appropriate drive depth and drive width., Results: It was observed that with a typical torque (2 ​Nm) used for screw insertion during anterior cruciate ligament reconstruction, the maximum von Mises and shear stress values were concentrated in the corners or turns of the drive, which could lead to stripping if the values were greater than the yield stress of Mg (193 ​MPa). With a four-time ​increase in drive depth to be fully driven and a 30% greater drive width, these maximum stress values were significantly decreased by more than 75%., Conclusion: It was concluded that improving the design of a Mg-based screw may increase surgical success rates, by decreasing device failure at insertion., The Translational Potential of This Article: The results of this work have the potential to improve designs of degradable IFSs, allowing for greater torque to be applied and thus greater screw fixation between host bone and the graft. Such a fixation will allow greater integration, better patient healing, and ultimately improved patient outcomes., (© 2019 The Authors.)

A new model, SWNano (Sewer-Water Nano), has been developed in the present study that quantitatively simulates the spatio-temporal changes in the concentrations of TiO 2 ENPs of dispersed and aggregated forms in the sewage water and sediment of a sewer network. As a brief example of SWNano applications, a small section of the entire sewer network of Seoul, Korea, was chosen to study where the sewage water was experimentally characterized. The predictions of SWNano present important findings that i) heteroaggregation is the most significant process following the advective transport among the fate and transport processes in the sewer pipes, ii) the heteroaggregation of TiO 2 ENPs with SPMs in the sewage water can substantially (a few % to more than 50%) reduce the freely dispersed TiO 2 ENPs depending on the magnitude of attachment efficiency, and iii) accurate determination of attachment efficiency is of critical importance in predicting the quantity of individual forms of ENPs exiting the sewer system. The predictions strongly suggest that the fate and transport of TiO 2 ENPs in the sewer networks be taken into account to improve the assessment of exposure to TiO 2 ENPs in the aquatic ecosystems, which warrants further development and use of models like SWNano., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Erythroid differentiation regulator 1 (Erdr1) has been identified as a stromal survival factor released under stressful conditions. Previously, Erdr1 was reported to be expressed highly in thymus, but roles of Erdr1 in thymus were not known. Here, the effects of Erdr1 on T cell development were investigated. The expression of Erdr1 was higher in thymus than bone marrow and Erdr1 was detected in both the cortex and medulla of thymus. Erdr1 treatment significantly induced the expression of activation marker, CD69, from thymocytes in the presence of TCR stimuli in vitro and the induction was dependent on increased Ca 2+ influx. In addition, in vivo administration of Erdr1 resulted in significant increase of total and positive selected thymocyte numbers, particularly in the number of CD3TCR hi CD69 + DP thymocytes. Taken together, our results show that Erdr1 enhances the strength of TCR signaling and cellularity of thymocytes by amplifying Ca 2+ influx in thymocytes receiving TCR signals., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Hypothalamic inflammation has been known as a contributor to high-fat diet (HFD)-induced insulin resistance and obesity. Myeloid-specific sirtuin 1 (SIRT1) deletion aggravates insulin resistance and hypothalamic inflammation in HFD-fed mice. Neurogranin, a calmodulin-binding protein, is expressed in the hypothalamus. However, the effects of myeloid SIRT1 deletion on hypothalamic neurogranin has not been fully clarified. To investigate the effect of myeloid SIRT1 deletion on food intake and hypothalamic neurogranin expression, mice were fed a HFD for 20 weeks. Myeloid SIRT1 knockout (KO) mice exhibited higher food intake, weight gain, and lower expression of anorexigenic proopiomelanocortin in the arcuate nucleus than WT mice. In particular, KO mice had lower ventromedial hypothalamus (VMH)-specific neurogranin expression. However, SIRT1 deletion reduced HFD-induced hypothalamic neurogranin. Furthermore, hypothalamic phosphorylated AMPK and parvalbumin protein levels were also lower in HFD-fed KO mice than in HFD-fed WT mice. Thus, these findings suggest that myeloid SIRT1 deletion affects food intake through VMH-specific neurogranin-mediated AMPK signaling and hypothalamic inflammation in mice fed a HFD., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: We assessed the association of insulin resistance as indicated by the homeostatic model assessment of insulin resistance (HOMA-IR) with inflammatory molecules, lipopolysaccharide-binding protein (LBP), high sensitivity C-reactive protein (hs-CRP), Tumor necrosis factor-α (TNF-α), and Interleukin-6 (IL-6) in urban young adolescents., Methods: Seventy-six adolescents (36 subjects with HOMA-IR ≥ 2.6 and 40 subjects with HOMA-IR < 2.6) were included in the study. We assessed anthropometric and laboratory measures, such as BMI, blood pressure, insulin sensitivity, liver enzymes, and lipid profiles along with the aforementioned inflammatory biomarkers. The diagnostic accuracy of LBP, hs-CRP, TNF-α, and IL-6 for insulin resistance was evaluated by using the receiver operating characteristic (ROC) curve analysis., Results: The mean age of the study subjects was 12.0 [12.0-13.0] y. Circulating LBP plasma concentration and hs-CRP were significantly increased in subjects with HOMA-IR ≥ 2.6 when compared with those with HOMA-IR < 2.6 (P < .0001). There was no difference in TNF-α or IL-6 concentrations between groups. Comparisons based on the area under the ROC curve for LBP, hs-CRP, TNF-α, and IL-6 with regard to insulin resistance (HOMA-IR ≥ 2.6) were 0.8384 (95% CI: 0.7380 to 0.9388), 0.7907 (95% CI: 0.6701 to 0.9113), 0.6207 (95% CI: 0.4770 to 0.7643), and 0.5763 (95% CI: 0.4285 to 0.7241), respectively., Conclusions: Among LBP, hs-CRP, TNF-α, and IL-6, plasma LBP has the greatest diagnostic accuracy for insulin resistance in young adolescents. Prospective studies are warranted to delineate the value of LBP in the prediction of insulin resistance., (Copyright © 2018. Published by Elsevier B.V.)

Purpose: To develop a new scoring system that uses topographic diagnostic signs of spectral-domain (SD) OCT to enhance glaucoma diagnostic performance for myopic eyes and to validate the system's diagnostic ability., Design: Cross-sectional study., Participants: A total of 517 patients (517 eyes; spherical equivalent [SE] <-1.0 diopters [D] or axial length >24.0 mm), including 175 highly myopic eyes (SE <-6.0 D or axial length >26.0 mm), were recruited and divided into 2, training (241 eyes) and validation (276 eyes) test sets., Methods: Retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GCIPL) topographic signs were selected based on the morphologic patterns of RNFL (size, shape, location, and agreement between deviation and thickness maps) and GCIPL (size, shape, location, color tone, agreement between maps, and step sign) abnormalities indicative of higher likelihood of myopic glaucoma on deviation and thickness maps. The diagnostic score was compiled according to the sensitivity, specificity, and positive likelihood ratio (PLR) of each diagnostic sign using the training set. The area under the receiver operating characteristic curve (AUC) was plotted and compared between the OCT-provided parameters and the scoring system in the validation set., Main Outcome Measures: The diagnostic performance of a new scoring system as validated by AUC., Results: Among all of the RNFL and GCIPL parameters, the presence of temporal hemifield asymmetry on the GCIPL thickness map (PLR, 5.98) showed the highest diagnostic ability, followed by location of the RNFL defect (PLR, 5.79) and color tone of the GCIPL defect (PLR, 5.04). The AUC of the topographic scoring system in myopic eyes was 0.979, which was significantly higher than those of the inferior (0.895; P < 0.001) and average (0.894; P < 0.001) RNFL thickness parameters. For highly myopic eyes, the scoring system (AUC, 0.983) also showed a higher diagnostic performance than that of the RNFL and GCIPL thickness parameters (all P < 0.001)., Conclusions: Our scoring system including OCT topographic parameters demonstrated to be beneficial for clinicians to differentiate real glaucomatous damage from myopic healthy eyes. Our results support the value of using multitopographic OCT parameters for detecting glaucoma in myopic eyes., (Copyright © 2018 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

The shape of the earlobes has a variety of genetic significance. This study analyzed the frequencies of the earlobe shapes in the Korean population. Data were collected on randomly selected 500 males and 500 females in Daegu Metropolitan City, with all participant ages being in their twenties. Obtuse angled earlobes accounted for 41.2% of the earlobes observed, while acute angled earlobes prevalence was calculated at 38.8% and right angled earlobe was 20.0% of the total (sexes combined). In men, the acute angled earlobe was the most frequent type (43.0%), while the obtuse angled earlobe was the most frequent type in females (45.2%). These differences were statistically significant (p = 0.015). Overall, attached type earlobe (61.2%) was more frequent than free type earlobe. The attached type earlobe was more common in both sex groups (57.0% in male and 65.4% in female), and the proportion was significantly higher for females (p = 0.006). In conclusion, the findings in this study suggest that the attached earlobe type is the most common among Koreans, and the proportion of earlobe types among males and females is significantly different. Further studies are needed to understand the genetic background of earlobe types among Koreans., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Background: Zonulin is acknowledged as the only physiological mediator established to reversibly regulate intestinal permeability through modulation of intercellular tight junctions. We aimed to determine whether there are differences in zonulin levels between 74 subjects with overweight or obesity and 76 with normal-weight and to assess correlations of circulating zonulin levels with anthropometric measures and obesity-related biomarkers., Methods: We assessed anthropometric and laboratory measures, including body mass index (BMI) z-score, blood pressure, liver enzymes, lipid profiles, and insulin resistance. Serum zonulin levels were measured using an enzyme-linked immunosorbent assay., Results: The mean age of the participants was 12.8 ± 1.5 years. Circulating serum zonulin levels were significantly increased in subjects with overweight/obesity compared with those of normal-weight (P = 0.03). Zonulin levels were significantly and positively associated with BMI z-score, alanine aminotransferase levels, triglyceride, fasting insulin, and insulin resistance as indicated by the homeostatic model assessment of insulin resistance (HOMA-IR) (all P < 0.05). In multivariate linear regression analysis, alanine aminotransferase was significantly and positively associated with circulating zonulin levels in adolescents with overweight or obesity (P < 0.01) after controlling for the effect of potential confounding factors. BMI z-score tended to be positively associated with serum zonulin levels in this subgroup analysis (P = 0.06)., Conclusions: Serum zonulin is a biomarker associated with hepatic metabolic disturbances in young adolescents with overweight or obesity. The positive relationship suggests a potentially relevant pathophysiological mechanism linking zonulin to hepatic metabolism in this age group of young adolescents with overweight or obesity., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Chronic low-grade inflammation-induced insulin resistance is associated with neuroinflammation. Myeloid sirtuin1 (SIRT1) deficiency aggravates high-fat diet (HFD)-induced insulin resistance. However, the function of myeloid-specific SIRT1 in the hippocampus of obese mice is largely unknown. To address this question, we fed myeloid SIRT1 knockout (KO) mice a HFD for 40 weeks. We found that HFD-fed SIRT1 KO mice had increased insulin resistance and macrophage infiltration in adipose tissue than wild type (WT) mice. Levels of HFD-induced lipocalin-2 (LCN2) were lower in SIRT1 KO mice than in WT. HFD-induced hippocampal LCN2 expression was lower in HFD-fed SIRT1 KO mice than in WT. Hippocampal acetylation of nuclear factor-κB (NF-κB) and amyloid precursor protein levels were higher in HFD-fed SIRT1 KO mice than in HFD-fed WT mice. Taken together, our results suggest that targeted induction of the anti-inflammatory effects of SIRT1 and LCN2 may help prevent obesity-associated insulin resistance and neuroinflammation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Alternative splicing is an essential process in eukaryotes, as it increases the complexity of gene expression by generating multiple proteins from a single pre-mRNA. However, information on the regulatory mechanisms for alternative splicing is lacking, because splicing occurs over a short period via the transient interactions of proteins within functional complexes of the spliceosome. Here, we investigated in detail the molecular mechanisms connecting alternative splicing with epigenetic mechanisms. We identified interactions between histone proteins and splicing factors such as Rbfox2, Rbfox3, and splicing factor proline and glutamine rich protein (SFPQ) by in vivo crosslinking and immunoprecipitation. Furthermore, we confirmed that splicing factors were bound to specific modified residues of histone proteins. Additionally, changes in histone methylation due to histone methyltransferase inhibitor treatment notably affected alternative splicing in selected genes. Therefore, we suggested that there may be crosstalk mechanisms connecting histone modifications and RNA-binding proteins that increase the local concentration of RNA-binding proteins in alternative exon loci of nucleosomes by binding specific modified histone proteins, leading to alternative splicing. This crosstalk mechanism may play a major role in epigenetic processes such as histone modification and the regulation of alternative splicing., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Diabetes may adversely affect cognitive function and, conversely, caloric restriction (CR) increases longevity and improves memory. To shed light on the unknown underlying mechanisms involved in these observations, we examined the effects of CR on serum metabolic parameters and hippocampal protein expression in the ob/ob mice model of obesity-induced diabetes. We found that CR reduced hepatic steatosis and insulin resistance in ob/ob mice. In addition, CR increased the levels of hippocampal O-linked-N-acetylglucosamine (O-GlcNAc) and GlcNAc transferase and decreased the expression of calcium/calmodulin-dependent protein kinase II, lipocalin-2, and phosphorylated tau. Furthermore, CR lessened the learning deficits that are typically seen in ob/ob mice. These findings indicate that CR may reverse obesity-related brain glucose impairment and intracellular Ca(2+) dysfunction and relieve learning impairment associated with diabetes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Environmental air pollution encompasses various particulate matters (PMs). The increased ambient PM from industrialization and urbanization is highly associated with morbidity and mortality worldwide, presenting one of the most severe environmental pollution problems. This article focuses on the correlation between PM and skin diseases, along with related immunological mechanisms. Recent epidemiological studies on the cutaneous impacts of PM showed that PM affects the development and exacerbation of skin diseases. PM induces oxidative stress via production of reactive oxygen species and secretion of pro-inflammatory cytokines such as TNF-α, IL-1α, and IL-8. In addition, the increased production of ROS such as superoxide and hydroxyl radical by PM exposure increases MMPs including MMP-1, MMP-2, and MMP-9, resulting in the degradation of collagen. These processes lead to the increased inflammatory skin diseases and skin aging. In addition, environmental cigarette smoke, which is well known as an oxidizing agent, is closely related with androgenetic alopecia (AGA). Also, ultrafine particles (UFPs) including black carbon and polycyclic aromatic hydrocarbons (PAHs) enhance the incidence of skin cancer. Overall, increased PM levels are highly associated with the development of various skin diseases via the regulation of oxidative stress and inflammatory cytokines. Therefore, anti-oxidant and anti-inflammatory drugs may be useful for treating PM-induced skin diseases., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Rbfox3, an RNA-binding fox protein, binds to the antibody to pan-neuronal marker, neuronal nuclei (NeuN). Rbfox3 is expressed in neural tissues across a wide range of species including mammals, birds, and amphibians. However, the molecular identity of Rbfox3 in the zebrafish is largely unknown. In this study, we cloned two zebrafish Rbfox3 genes, Rbfox3a and Rbfox3b. We also cloned the Rbfox3-d31 isoform, which excludes a 93-nucleotide alternative exon within the RNA-recognition motif in both, Rbfox3a and Rbfox3b. Multiple protein sequence alignment revealed that the amino acid sequence for residues 1-20 of the zebrafish Rbfox3, which is the epitope region of NeuN antibody, was different from that of other species. Therefore, NeuN antibody lost its function as a neuronal marker antibody in zebrafish. Reverse transcriptase-polymerase chain reaction showed that both Rbfox3-d31 transcripts were abundant in the early blastula stage, after which they dramatically reduced, suggesting that these isoforms exist mainly as maternal transcripts. In contrast, full-length Rbfox3 transcripts were detected from the 24 h post-fertilization embryo, expression was also maintained at a constant level. Furthermore, full-length Rbfox3-expressing cells were located within the central nervous system during later stages of the zebrafish embryo. Our study provides insight into the molecular structure of zebrafish Rbfox3 as a step towards genetic association studies investigating the developmental role of Rbfox3., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To investigate the prevalence, awareness, and risk factors for primary open-angle glaucoma (POAG) in the Korean population., Design: The Korea National Health and Nutrition Examination Survey (KNHANES), a population-based cross-sectional study using a complex, stratified, multistage, probability-cluster survey., Participants: A total of 13,831 participants 40 years of age or older were included from the KNHANES database for the years 2008 through 2011., Methods: Glaucoma diagnosis was based on the International Society of Geographical and Epidemiological Ophthalmology criteria. The prevalence of POAG and the proportion of POAG patients previously informed of the disease were calculated using KNHANES sample weights. Ocular and systemic factors were compared between the POAG and control groups. Univariate and multivariate logistic regression analyses were used to evaluate the risk factors for POAG., Main Outcome Measures: Weighted prevalence, awareness, and risk factors for POAG., Results: The prevalence of POAG in the Korean population was 4.7% (95% confidence interval, 4.2-5.1): 5.5% in men and 3.9% in women, respectively, which increased with age (P < 0.001). The mean intraocular pressure (IOP) in POAG eyes was 15.0±0.4 mmHg, which was higher than that of the control group (14.0±0.1 mmHg; P < 0.001). Multivariate logistic regression analysis revealed that older age (P < 0.001), male gender (P < 0.001), higher IOP (P < 0.001), myopia (P < 0.001), hypertension (P = 0.031), and nonoverweight status (P = 0.017) were associated significantly with POAG in the Korean population. Among the 710 study participants diagnosed with POAG, only 8.0% were aware of the disease., Conclusions: This was the first study to examine the prevalence, awareness, and risk factors of POAG in the Korean population using 4-year KNHANES data. Koreans with higher IOP, myopia, older age, male gender, hypertension, and nonoverweight status require more attention and support from the glaucoma screening and surveillance systems., (Copyright © 2016 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Function of cellular prion protein (PrP(c)) in cancer progression has not been elucidated yet. Ectopic expression of PrP(c) increases the invasion and migration of breast cancer cell line, MCF-7 cells. Overexpressed PrP(c) increases matrix metalloprotease-9 (MMP-9) expression by enhancing association of NF-κB in promoter of MMP-9 gene and ERK signaling in MCF-7 cells. Whereas, silencing of PrP(c) by siRNA suppresses ERK activation and MMP-9 expression resulting the down-regulation of MD-MB231 cell migration and invasion. Overall, these results suggest that PrP(c) contribute the breast cancer invasion and migration via MMP-9., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Studying the regulatory mechanism of the glycoprotein hormone α subunit (αGSU) gene in thyrotropes is essential for understanding the synthesis of functional thyroid-stimulating hormone (TSH). Here, we investigated the influence of a homeodomain transcription factor Msx1 (Msh homeobox 1) on αGSU expression in thyrotropes. The transient expression of Msx1 inhibited the activity of an αGSU reporter gene, as well as its endogenous mRNA level in thyrotrope-derived αTSH cells. Luciferase reporter assays with serial deletion constructs and a close examination of the sequences revealed that the putative Msx1 binding site (PMS) in the αGSU promoter is not responsible for Msx1-mediated transcriptional repression. We also identified the TATA-box binding protein (TBP) as an interacting protein in thyrotropes. Interaction of TBP with Msx1 attenuates the inhibitory effect of Msx1 on αGSU gene expression in a DNA binding-independent manner. Furthermore, transient transfection studies with mutant Msx1 revealed that the interaction of TBP and Msx1 is critical for Msx1-mediated transcriptional repression of the αGSU. These results suggest that Msx1 functions as a transcriptional repressor of αGSU and that its interaction with TBP is an integral part of the mechanism by which Msx1 regulates the inhibition of αGSU gene expression., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background/objective: We have previously shown that an extracellular matrix (ECM) bioscaffold derived from porcine small intestine submucosa (SIS) enhanced the healing of a gap injury of the medial collateral ligament as well as the central third defect of the patellar tendon. With the addition of a hydrogel form of SIS, we found that a transected goat anterior cruciate ligament (ACL) could also be healed. The result begs the research question of whether SIS hydrogel has positive effects on ACL fibroblasts (ACLFs) and thus facilitates ACL healing., Methods: In the study, ECM-SIS hydrogel was fabricated from the digestion of decellularised and sterilised sheets of SIS derived from αGal-deficient (GalSafe) pigs. As a comparison, a pure collagen hydrogel was also fabricated from commercial collagen type I solution. The morphometrics of hydrogels was assessed with scanning electron microscopy. The ECM-SIS and collagen hydrogels had similar fibre diameters (0.105 ± 0.010 μm vs. 0.114 ± 0.004 μm), fibre orientation (0.51 ± 0.02 vs. 0.52 ± 0.02), and pore size (0.092 ± 0.012 μm vs. 0.087 ± 0.008 μm). The preservation of bioactive properties of SIS hydrogel was assessed by detecting bioactive molecules sensitive to processing and enzyme digestion, such as growth factors fibroblast growth factor-2 (FGF-2) and transforming growth factor-beta 1 (TGF-β1), with enzyme-linked immunosorbent assay. ACLFs were isolated and expanded in culture from explants of rat ACLs ( n  = 3). The cells were then seeded on the hydrogels and cultured with 0%, 1%, and 10% foetal bovine serum (FBS) for 3 days and 7 days. Cell attachment was observed using a light microscope and scanning electron microscopy, whereas cell proliferation and matrix production (collagen types I and III) were examined with bromodeoxyuridine assays and reverse transcription-polymerase chain reaction, respectively., Results: The results showed that FGF-2 and TGF-β1 in the SIS hydrogel were preserved by 50% (65.9 ± 26.1 ng/g dry SIS) and 90% (4.4 ± 0.6 ng/g dry SIS) relative to their contents in ECM-SIS sheets, respectively. At Day 3 of culture, ACLFs on the SIS hydrogel were found to proliferate 39%, 31%, and 22% more than those on the pure collagen hydrogel at 0%, 1%, and 10% FBS, respectively ( p  < 0.05). Collagen type I mRNA expression was increased by 150%, 207%, and 100%, respectively, compared to collagen hydrogel ( p  < 0.05), whereas collagen type III mRNA expression was increased by 123% and 132% at 0% and 1% FBS, respectively (all p  < 0.05) but not at 10% FBS. By Day 7, collagen type I mRNA expression was still elevated by 137% and 100% compared to collagen hydrogel at 1% and 10% FBS, respectively ( p  < 0.05). Yet, collagen type III mRNA levels were not significantly different between the two groups at any FBS concentrations., Conclusion: Our data showed that the ECM-SIS hydrogel not only supported the growth of ACLFs, but also promoted their proliferation and matrix production relative to a pure collagen hydrogel. As such, ECM-SIS hydrogel has potential therapeutic value to facilitate ACL healing at the early stage after injury.

Purpose: To investigate the rate and associated factors of false-positive diagnostic classification of ganglion cell analysis (GCA) and retinal nerve fiber layer (RNFL) maps, and characteristic false-positive patterns on optical coherence tomography (OCT) deviation maps., Design: Prospective, cross-sectional study., Participants: A total of 104 healthy eyes of 104 normal participants., Methods: All participants underwent peripapillary and macular spectral-domain (Cirrus-HD, Carl Zeiss Meditec Inc, Dublin, CA) OCT scans. False-positive diagnostic classification was defined as yellow or red color-coded areas for GCA and RNFL maps. Univariate and multivariate logistic regression analyses were used to determine associated factors. Eyes with abnormal OCT deviation maps were categorized on the basis of the shape and location of abnormal color-coded area. Differences in clinical characteristics among the subgroups were compared., Main Outcome Measures: (1) The rate and associated factors of false-positive OCT maps; (2) patterns of false-positive, color-coded areas on the GCA deviation map and associated clinical characteristics., Results: Of the 104 healthy eyes, 42 (40.4%) and 32 (30.8%) showed abnormal diagnostic classifications on any of the GCA and RNFL maps, respectively. Multivariate analysis revealed that false-positive GCA diagnostic classification was associated with longer axial length and larger fovea-disc angle, whereas longer axial length and smaller disc area were associated with abnormal RNFL maps. Eyes with abnormal GCA deviation map were categorized as group A (donut-shaped round area around the inner annulus), group B (island-like isolated area), and group C (diffuse, circular area with an irregular inner margin in either). The axial length showed a significant increasing trend from group A to C (P=0.001), and likewise, the refractive error was more myopic in group C than in groups A (P=0.015) and B (P=0.014). Group C had thinner average ganglion cell-inner plexiform layer thickness compared with other groups (group A=B>C, P=0.004)., Conclusions: Abnormal OCT diagnostic classification should be interpreted with caution, especially in eyes with long axial lengths, large fovea-disc angles, and small optic discs. Our findings suggest that the characteristic patterns of OCT deviation map can provide useful clues to distinguish glaucomatous changes from false-positive findings., (Copyright © 2015 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

A brachial plexus lesion is not common in hereditary neuropathy with liability to pressure palsy (HNPP). We report the clinical and electrodiagnostic features of young soldiers with HNPP presenting with brachial plexopathy. By reviewing 2year medical records from Korean military hospitals, we identified soldiers with brachial plexus lesions. Among them, patients diagnosed with HNPP were determined and clinical and electrophysiological findings were compared between HNPP and non-HNPP patients with a brachial plexus lesion. Thirteen patients (6.8%) were diagnosed with HNPP among 189 patients with a brachial plexus lesion. Push-ups, as either a punishment or an exercise, was the most frequent preceding event in HNPP patients (76.9%), whereas it was rare in non-HNPP patients. The distal motor latency of the median nerve showed the highest sensitivity (90.9%) and specificity (100%) for HNPP in patients with a brachial plexus lesion. In conclusion, HNPP should be suspected in patients with brachial plexopathy if brachial plexopathy develops after push-ups or if the distal motor latency of median nerves is prolonged., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Purpose: The purpose of this study is to test a model linking infant health problem, mother's depression and marital relationship to infant abuse., Methods: This study employed a cross-sectional survey design. Data were collected from 2009 Data of Index Studies for Korean Children and Adolescents Development. Survey data from 1,060 infants and their mothers (including infant health status and infant physical illness scale, depression scale, marital relationship scale, and child abuse scale) were used to test the model. The model was tested using path analysis techniques within structural equation modeling., Results: The model fit indices suggested that the original hypothesized model adequately fit the data (χ(2) = .33, df = 5, p = .84, Tucker-Lewis Index = 1.04, Comparative Fit Index = 1.00, Root Mean Square Error of Approximation = .00). Infant health problem and mother's depression had a negative direct effect on marital relationship, which in turn had a direct negative effect on infant abuse. Infant health problems directly affected infant abuse and also influenced infant abuse indirectly through the marital relationship. Mother's depression had significant direct effects on infant abuse and also influenced infant abuse indirectly through the marital relationship., Conclusion: The findings from this study demonstrate the fundamental importance of infant health as linked to the mother's mental health, and marital relationship and increasing the quality of marital relationship may be the key to infant abuse prevention., (Copyright © 2014. Published by Elsevier B.V.)

C(2)H(2)-type zinc finger proteins (ZFPs) play diverse roles in plant response to abiotic stresses. ZAT6, an Arabidopsis C(2)H(2)-type ZFP, has been reported to regulate root development and nutrient stress responses. However, its roles in regulation of abiotic stress response are incompletely known. Here, we demonstrate that salt or osmotic stress triggers a strong increase in ZAT6 expression in leaves. Transgenic plants overexpressing ZAT6 showed improved seed germination under salt and osmotic stress. Intriguingly, ZAT6 interacts with a stress-responsive mitogen-activated protein kinase MPK6 in vitro and in planta. ZAT6 is phosphorylated by both recombinant and plant endogenous MPK6. Serine 8 and serine 223 in ZAT6 were identified as the sites phosphorylated by MPK6. In contrast to wild-type form of ZAT6, overexpression of phosphorylation mutant form did not display significantly enhanced salt and osmotic stress tolerance. Altogether, our results suggest that phosphorylation by MPK6 is required for the functional role of ZAT6 in seed germination under salt and osmotic stress., (Copyright © 2012. Published by Elsevier Inc.)

This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy., (Copyright © 2012. Published by Elsevier Inc. All rights reserved.)

Lhx2, a member of LIM homeobox transcription factors, plays a key role in central nervous system (CNS) and embryonic tissue development. However, molecular mechanism of Lhx2 gene regulation remains largely unknown. Here, we identified and characterized a regulatory region of Lhx2 gene which mediates responses to two different signals such as inhibition of HDAC3 and stimulation by E2F1. In particular, the promoter region of -229 to -126 was responsible not only for basal expression but also for a inhibitor of histone deacetylase, trichostatin A (TSA)-mediated activation of Lhx2 gene. Intriguingly, transcription factor E2F1 also activates Lhx2 gene via direct binding to the same -229 to -126 region. Based on these observations, we could have demonstrated that E2F1 is necessary for TSA-mediated activation of Lhx2 gene and acetylation of histone 3 is involved in this event. This study provides evidence that the histone modification and E2F1 binding are integral parts of the mechanism for Lhx2 gene expression., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Exposure to 100% oxygen causes hyperoxic acute lung injury characterized by cell death and injury of alveolar epithelial cells. Recently, the role of chitinase 3-like 1 (CHI3L1), a member of the glycosyl hydrolase 18 family that lacks chitinase activity, in oxidative stress was demonstrated in murine models. High levels of serum CHI3L1 have been associated with various diseases of the lung, such as asthma, chronic obstructive pulmonary disease, and cancer. However, the role of CHI3L1 in human airway epithelial cells undergoing oxidative stress remains unknown. In addition, the signaling pathways associated with CHI3L1 in this process are poorly understood., Purpose: In this study, we demonstrate the role of CHI3L1, along with the MAPK and PI3K signaling pathways, in hyperoxia-exposed airway epithelial cells., Method: The human airway epithelial cell line, BEAS-2B, was exposed to >95% oxygen (hyperoxia) for up to 72h. Hyperoxia-induced cell death was determined by assessing cell viability, Annexin-V FITC staining, caspase-3 and -7 expression, and electron microscopy. CHI3L1 knockdown and overexpression studies were conducted in BEAS-2B cells to examine the role of CHI3L1 in hyperoxia-induced apoptosis. Activation of the MAPK and PI3K pathways was also investigated to determine the role of these signaling cascades in this process., Results: Hyperoxia exposure increased CHI3L1 expression and apoptosis in a time-dependent manner. CHI3L1 knockdown protected cells from hyperoxia-induced apoptosis. In contrast, CHI3L1 overexpression promoted cell death after hyperoxia exposure. Finally, phosphorylation of ERK1/2, p38, and Akt were affected by CHI3L1 knockdown., Conclusion: This study indicates that CHI3L1 is involved in hyperoxia-induced cell death, suggesting that CHI3L1 may be one of several cell death regulators influencing the MAPK and PI3K pathways during oxidative stress in human airway epithelial cells., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Although the blood vessel-specific fluorescent transgenic mouse has been an excellent tool to study vasculogenesis and angiogenesis, a lymphatic-specific fluorescent mouse model has not been established to date. Here we report a transgenic animal model that expresses the green fluorescent protein under the promoter of Prox1, a master control gene in lymphatic development. Generated using an approximately 200-kb-long bacterial artificial chromosome harboring the entire Prox1 gene, this Prox1-green fluorescent protein mouse was found to faithfully recapitulate the expression pattern of the Prox1 gene in lymphatic endothelial cells and other Prox1-expressing organs, and enabled us to conveniently visualize detailed structure and morphology of lymphatic vessels and networks throughout development. Our data demonstrate that this novel transgenic mouse can be extremely useful for detection, imaging, and isolation of lymphatic vessels and monitoring wound-associated lymphangiogenesis. Together, this Prox1-green fluorescent protein transgenic mouse will be a great tool for the lymphatic research.

Cadmium (Cd) is a non-essential toxic heavy metal that influences normal growth and development of plants. However, the molecular mechanisms by which plants recognize and respond to Cd remain poorly understood. We show that, in Arabidopsis, Cd activates the mitogen-activated protein kinases, MPK3 and MPK6, in a dose-dependent manner. Following treatment with Cd, these two MAPKs exhibited much higher activity in the roots than in the leaves, and pre-treatment with the reactive oxygen species (ROS) scavenger, glutathione, effectively inhibited their activation. These results suggest that the Cd sensing signaling pathway uses a build-up of ROS to trigger activation of Arabidopsis MPK3 and MPK6., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Introduction: The purpose of this study was to investigate the success rate of midpalatal miniscrews used for orthodontic anchorage and the factors affecting clinical success., Methods: One hundred twenty-eight consecutive patients (101 female, 27 male; mean age, 23.4 years), who received a total of 210 miniscrews in the midpalatal suture area, were examined. Success rates were determined according to 10 clinical variables., Results: The overall success rates were 88.20% for the total number of patients and 90.80% for the total number of miniscrews. There were no significant associations among success rate and sex, total period of treatment with miniscrews, diameter of miniscrews, types of tooth movements, and variables that represent sagittal and vertical skeletal relationships (ANB, FMA, and Sn-GoGn). The operator's learning curve, patient's age, area (midpalatal or parapalatal), and splinting significantly influenced the success rates. After adjusting for other variables, only 1- splinting-showed a significant effect on the success rate., Conclusions: The joining of 2 miniscrews by splinting, placement of the miniscrew in the midpalatal suture, patient's age (especially >15 years), and operator's skill were factors influencing the clinical success of orthodontic miniscrews in the palate., (Copyright 2010 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.)

Lymphatic vessels in the diaphragm are essential for draining peritoneal fluid, but little is known about their pathological changes during inflammation. Here we characterized diaphragmatic lymphatic vessels in a peritonitis model generated by daily i.p. administration of lipopolysaccharide (LPS) in mice. Intraperitoneal LPS increased lymphatic density, branching, sprouts, connections, and network formation in the diaphragm in time- and dose-dependent manners. These changes were reversible on discontinuation of LPS administration. The LPS-induced lymphatic density and remodeling occur mainly through proliferation of lymphatic endothelial cells. CD11b+ macrophages were massively accumulated and closely associated with the lymphatic vessels changed by i.p. LPS. Both RT-PCR assays and experiments with vascular endothelial growth factor-C/D blockade and macrophage-depletion indicated that the CD11b+ macrophage-derived lymphangiogenic factors vascular endothelial growth factor-C/D could be major mediators of LPS-induced lymphangiogenesis and lymphatic remodeling through paracrine activity. Functional assays with India ink and fluorescein isothiocyanate-microspheres indicated that impaired peritoneal fluid drainage in diaphragm of LPS-induced peritonitis mice was due to inflammatory fibrosis and massive attachment of CD11b+ macrophages on the peritoneal side of the diaphragmatic lymphatic vessels. These findings reveal that CD11b+ macrophages play an important role in i.p. LPS-induced aberrant lymphangiogenesis and lymphatic dysfunction in the diaphragm.

Background: Amphiregulin, a member of the epidermal growth factor family, has been shown to promote the growth of fibroblasts, to be associated with the T-helper type 2 cell adaptive immune response, and to up-regulate mucin gene expression. We aimed to determine whether sputum amphiregulin is expressed at elevated levels in patients with asthma or eosinophilic bronchitis (EB), and whether it is associated with eosinophilic inflammation, pulmonary function, and bronchial hyperresponsiveness in children., Methods: A total of 117 children with asthma, 77 with EB, and 84 control subjects were enrolled in this study. Amphiregulin and eosinophil cationic protein (ECP) levels were measured in sputum supernatants. We performed pulmonary function and methacholine challenge tests while measuring total eosinophil count, and serum levels of total IgE and ECP in all children., Results: The children with asthma had significantly higher levels of sputum amphiregulin (mean, 10.80 pg/mL; range, 4.07 to 38.75 pg/mL) than both the children with EB (mean, 5.76 pg/mL; range, 0.61 to 21.65 pg/mL; p = 0.013) and the control subjects (mean, 6.56 pg/mL; range, 0.51 to 17.98 pg/mL; p = 0.003). Sputum amphiregulin levels positively correlated with levels of sputum eosinophils (gamma = 0.221; p = 0.007) and sputum ECP (gamma = 0.601; p < 0.0001). Negative significant correlations were found between sputum amphiregulin and FEV(1) (gamma = -0.181; p = 0.006) or post-bronchodilator therapy FEV(1) (gamma = -0.233; p = 0.002). In children with asthma who were not receiving any controller medications, sputum amphiregulin level was negatively correlated with the provocative concentration of methacholine causing a 20% fall in FEV(1) (r = -0.398; p = 0.008)., Conclusions: Our findings suggest that childhood asthma is associated with sputum amphiregulin, whereas EB is not, and that sputum amphiregulin would be a supportive marker of airway inflammation in asthma.

Plant cells often use cell surface receptors to sense environmental changes and then transduce external signals via activated signaling pathways to trigger adaptive responses. In Arabidopsis, the receptor-like protein kinase (RLK) gene family contains more than 600 members, and some of these are induced by pathogen infection, suggesting a possible role in plant defense responses. We previously characterized an S-locus RLK (CBRLK1) at the biochemical level. In this study, we examined the physiological function of CBRLK1 in defense responses. CBRLK1 mutant and CBRLK1-overexpressing transgenic plants showed enhanced and reduced resistance against a virulent bacterial pathogen, respectively. The altered pathogen resistances of the mutant and overexpressing transgenic plants were associated with increased and reduced induction of the pathogenesis-related gene PR1, respectively. These results suggest that CBRLK1 plays a negative role in the disease resistance signaling pathway in Arabidopsis.

The lymphatic vessel is a major conduit for immune cell transport; however, little is known about how lymphatic vessels regulate immune cell trafficking and how lymphatic vessels themselves respond to inflammation. Toll-like receptor 4 (TLR4) plays a central role in lipopolysaccharide (LPS)-induced inflammation, but the role of TLR4 in lymphatic endothelial cells (LECs) is poorly understood. Here, we found that LECs express high amounts of TLR4 in the intracellular region, and that the TLR4 of LECs is the main mediator of nuclear factor-kappaB (NF-kappaB) activation by LPS. LPS-TLR4 signaling in LECs resulted in the production of various chemokines for chemotaxis of macrophage. In addition, TLR4 in LECs actively contributed to the recruitment of macrophages to the draining lymphatic vessel. Furthermore, the macrophages that infiltrated into the lymphatic vessel induced lymphangiogenesis by secreting lymphangiogenic growth factors. These phenomena were largely attenuated not only in the mice defective in TLR4 signaling but also in the chimeric mice defective in TLR4 signaling that were recipients for bone marrow transplantation from normal TLR4-signaling mice. In conclusion, TLR4 in LECs plays an essential role in LPS-induced inflammatory lymphangiogenesis by chemotactic recruitment of macrophages.

Protease-activated receptor-2 (PAR-2) is known to be involved in epidermal permeability barrier function homeostasis. PAR-2 activation occurs after barrier disruption and further activation of PAR-2 by activating peptide significantly delays barrier recovery rate. Cockroach and house dust mite allergens, both known to be associated with the development of asthma, allergic rhinitis, and atopic dermatitis, have protease activity, which can activate PAR-2. In this study, we investigated the effects of both allergens on the epidermal barrier function as well as on the epidermal calcium gradient. Both allergens, when topically applied on the barrier-disrupted site, increased protease activities in the epidermis and delayed barrier recovery and lamellar body secretion in murine skin. The topical application of PAR-2-specific antagonist or protease inhibitors normalized the barrier recovery. Cockroach allergens induced intracellular calcium oscillations in cultured human keratinocytes through PAR-2-involved pathway, which was confirmed by desensitization protocol. Abnormal calcium ion distribution after barrier disruption was also observed in allergens-applied skin. These results suggest that allergens with protease activity can influence the epidermal permeability barrier homeostasis through PAR-2 activation and consequent modulation of the calcium ions in skin.