TonEBP recognizes R-loops and initiates m6A RNA methylation for R-loop resolution.

R-loops are three-stranded, RNA-DNA hybrid, nucleic acid structures produced due to inappropriate processing of newly transcribed RNA or transcription-replication collision (TRC). Although R-loops are important for many cellular processes, their accumulation causes genomic instability and malignant diseases, so these structures are tightly regulated. It was recently reported that R-loop accumulation is resolved by methyltransferase-like 3 (METTL3)-mediated m6A RNA methylation under physiological conditions. However, it remains unclear how R-loops in the genome are recognized and induce resolution signals. Here, we demonstrate that tonicity-responsive enhancer binding protein (TonEBP) recognizes R-loops generated by DNA damaging agents such as ultraviolet (UV) or camptothecin (CPT). Single-molecule imaging and biochemical assays reveal that TonEBP preferentially binds a R-loop via both 3D collision and 1D diffusion along DNA in vitro. In addition, we find that TonEBP recruits METTL3 to R-loops through the Rel homology domain (RHD) for m6A RNA methylation. We also show that TonEBP recruits RNaseH1 to R-loops through a METTL3 interaction. Consistent with this, TonEBP or METTL3 depletion increases R-loops and reduces cell survival in the presence of UV or CPT. Collectively, our results reveal an R-loop resolution pathway by TonEBP and m6A RNA methylation by METTL3 and provide new insights into R-loop resolution processes.

Tonicity-responsive enhancer-binding protein promotes hepatocellular carcinogenesis, recurrence and metastasis.

OBJECTIVES: Hepatocellular carcinoma (HCC) is a common cancer with high rate of recurrence and mortality. Diverse aetiological agents and wide heterogeneity in individual tumours impede effective and personalised treatment. Tonicity-responsive enhancer-binding protein (TonEBP) is a transcriptional cofactor for the expression of proinflammatory genes. Although inflammation is intimately associated with the pathogenesis of HCC, the role of TonEBP is unknown. We aimed to identify function of TonEBP in HCC. DESIGN: Tumours with surrounding hepatic tissues were obtained from 296 patients with HCC who received completion resection. TonEBP expression was analysed by quantitative reverse transcription-quantitative real-time PCR (RT-PCR) and immunohfistochemical analyses of tissue microarrays. Mice with TonEBP haplodeficiency, and hepatocyte-specific and myeloid-specific TonEBP deletion were used along with HCC and hepatocyte cell lines. RESULTS: TonEBP expression is higher in tumours than in adjacent non-tumour tissues in 92.6% of patients with HCC regardless of aetiology associated. The TonEBP expression in tumours and adjacent non-tumour tissues predicts recurrence, metastasis and death in multivariate analyses. TonEBP drives the expression of cyclo-oxygenase-2 (COX-2) by stimulating the promoter. In mouse models of HCC, three common sites of TonEBP action in response to diverse aetiological agents leading to tumourigenesis and tumour growth were found: cell injury and inflammation, induction by oxidative stress and stimulation of the COX-2 promoter. CONCLUSIONS: TonEBP is a key component of the common pathway in tumourigenesis and tumour progression of HCC in response to diverse aetiological insults. TonEBP is involved in multiple steps along the pathway, rendering it an attractive therapeutic target as well as a prognostic biomarker.

Grouping schemes of welding fume exposure in shipyard welders.

Welding fume exposure can increase the risk of chronic obstructive pulmonary disease (COPD). The aim of this study was to evaluate the optimal grouping schemes of welding fume exposure in shipyard welders for future accurate examination of the association between welding fume exposure and COPD. Industrial hygiene records, including welding fume measurements between 2002 and 2009 were collected from a shipyard. A total of 2,360 personal welding fume measurements was compiled with a geometric mean of 1.66 mg/m3 and a geometric standard deviation of 4.02. Welding jobs were categorized into 8 groups. There were 9 working areas. To obtain the optimal grouping scheme, various grouping schemes were created using job, area, and job*area combination. To compare various grouping schemes, contrast and precision were calculated for each grouping scheme. For all measurement data, group mean ranking method created by ranking geometric means of the job*area combination into 3 groups (group mean ranking method) showed the best contrast and precision values among various grouping schemes, followed by grouping based on the job. For a subset of the data excluding job*area combinations with less than 10 measurements, grouping based on the job showed greater contrast than group mean ranking method, while for other subsets, including only repeated measurement data or further excluding job*area combinations with less than 10 measurements from the repeated measurement subset, group mean ranking method showed greater contrast than grouping based on the job. Our results showed that group mean ranking or grouping based on the job could be a candidate for the optimal grouping schemes in this shipyard. Our efforts for optimal grouping scheme may aid future cohort study to elucidate the association between welding fume exposure and COPD.

Predictive factors for rapid neutrophil and platelet engraftment after allogenic peripheral blood stem cell transplantation in patients with acute leukemia.

The aim of this study was to investigate predictive factors for rapid engraftment after allogeneic peripheral blood stem cell transplantation (alloPBSCT) in patients with acute leukemia. Two hundred sixty-two patients receiving alloPBSCT were analyzed. Subset analyses of donor stem cells were conducted using a flow cytometric method. The correlation between rapid engraftment of neutrophils, platelets, and donor stem cells doses, as well as other recipient and donor clinical factors, was analyzed. In univariate analysis, factors correlated with neutrophil engraftment (≥0.5 × 10(9)/L) by day 12 were achievement of complete remission (CR) after induction chemotherapy (CR1) before hematopoietic cell transplantation (HCT) and high numbers of CD34+ cells, CD3+ T cells, and CD3+/CD4+ T cells. Factors correlated with platelet engraftment (≥20 × 10(9)/L) by day 12 were achievement of CR1 before HCT, donor and recipient sex mismatch, and high numbers of mononuclear cells, CD34+ cells, CD3+ T cells, CD3+/CD4+ T cells, CD3+/CD8+ T cells, and CD56+ NK cells. In multivariate analysis, independent predictive factors for rapid neutrophil and platelet engraftment were CR1 before HCT (p < 0.001 and p = 0.002, respectively), high number of donor CD34+ cells (p = 0.005 and p < 0.001, respectively), and high number of CD3+ T cells (p = 0.005 and p = 0.001, respectively). In conclusion, achieving CR1 before HCT, as well as larger quantities of donor CD34+ and CD3+ T cells, may predict rapid neutrophil and platelet engraftment after PBSCT.

Association between Shift Work and Metabolic Syndrome: A 4-Year Retrospective Cohort Study.

(1) Background: Previous studies on the association between shift work and metabolic syndrome have had inconsistent results. This may be due to the cross-sectional study design and non-objective data used in those studies. Hence, this study aimed to identify risk factors for Metabolic syndrome using objective information provided by the relevant companies and longitudinal data provided in health examinations. (2) Methods: In total, 1211 male workers of three manufacturing companies, including shift workers, were surveyed annually for 4 years. Data on age, smoking, drinking, physical activity, length of shift work, type of shift, past history, waist circumference, blood pressure, blood sugar, triglyceride, and high-density cholesterol (HDL) were collected and analyzed using generalized estimating equations (GEE) to identify the risk factors for Metabolic syndrome. (3) Results: In the multivariate analysis of Metabolic syndrome risk factors, age (OR = 1.078, 95% CI: 1.045-1.112), current smoking (OR = 1.428, 95% CI: 1.815-5.325), and BMI (OR = 1.498, 95% CI: 1.338-1.676) were statistically significant for day workers (n= 510). Additionally, for shift workers (N = 701), age (OR = 1.064, 95% CI: 1.008-1.174), current smoking (OR = 2.092, 95% CI: 1.854-8.439), BMI (OR = 1.471, 95% CI: 1.253-1.727) and length of shift work (OR = 1.115, 95% CI: 1.010-1.320) were statistically significant. Shift work was associated with a higher risk of Metabolic syndrome (OR = 1.093, 95% CI: 1.137-2.233) compared to day workers. For shift workers, shift work for more than 20 years was associated with Metabolic syndrome (OR = 2.080, 95% CI: 1.911-9.103), but the dose-response relationship was not statistically significant. (4) Conclusions: This study revealed that age, current smoking, BMI, and shift work are potential risk factors for Metabolic syndrome. In particular, the length of shift work (>20 years) is a potential risk factor for Metabolic syndrome in shift workers. To prevent metabolic syndrome in shift workers, health managers need to actively accommodate shift workers (especially those who have worked for more than 20 years), current smokers, and obese people. A long-term cohort study based on objective data is needed to identify the chronic health impact and the risk factors of shift work.

Risk perceptions of a population living near a municipal waste incinerator and associated factors with the prevalence of environmental disease.

Background: This study investigated the risk perceptions, prevalence of environmental diseases (EDs) and associated factors with the prevalence of environmental disease among the population living near an incinerator. Methods: Study area were divided into 3 local areas near the incinerator by distance (A, B, C) and control area (D) by distance and geographic isolation. A Questionnaire was conducted with 1,380 in local residents (A, B, C) and 390 in control area (D), gathered information of demographic characteristics, lifestyle, perception of damage by incinerators, experience of EDs (atopic dermatitis, allergic rhinitis, asthma) diagnosed by physician. Analysis of variance, χ2 test, and Kruskal Wallis test was applied to determine the difference by area. Logistic regression analysis was performed to identify factors associated with the prevalence of allergic rhinitis. Results: Residents residing closer to the incinerator had negative perception in most items in questionnaire compared with control. The prevalence of allergic rhinitis was higher as they lived nearby the incinerator (p = 0.008). The associated factors with the prevalence of allergic rhinitis were carpet (odds ratio [OR]: 1.79, p = 0.001), residential area (marginally significant), duration of residence (OR: 1.09, p < 0.001). The perception of environmental pollution around the residential area was inversely associated with the prevalence of allergic rhinitis: perceived as very dissatisfied (OR: 4.21, p = 0.02) compared with very satisfied. Conclusions: As closer to the incinerator, the risk perception tend to negative and prevalence of EDs were increased. Carpet, residential area, duration of residence and perception of environmental air pollution around the residential area were associated with prevalence of allergic rhinitis. These results may be useful for the communication with residents to discuss the environmental problems caused by the incinerator.

TonEBP in Myeloid Cells Promotes Obesity-Induced Insulin Resistance and Inflammation Through Adipose Tissue Remodeling.

The phenotypic and functional plasticity of adipose tissue macrophages (ATMs) during obesity plays a crucial role in orchestration of adipose and systemic inflammation. Tonicity-responsive enhancer binding protein (TonEBP) (also called NFAT5) is a stress protein that mediates cellular responses to a range of metabolic insults. Here, we show that myeloid cell-specific TonEBP depletion reduced inflammation and insulin resistance in mice with high-fat diet-induced obesity but did not affect adiposity. This phenotype was associated with a reduced accumulation and a reduced proinflammatory phenotype of metabolically activated macrophages, decreased expression of inflammatory factors related to insulin resistance, and enhanced insulin sensitivity. TonEBP expression was elevated in the ATMs of obese mice, and Sp1 was identified as a central regulator of TonEBP induction. TonEBP depletion in macrophages decreased induction of insulin resistance-related genes and promoted induction of insulin sensitivity-related genes under obesity-mimicking conditions and thereby improved insulin signaling and glucose uptake in adipocytes. mRNA expression of TonEBP in peripheral blood mononuclear cells was positively correlated with blood glucose levels in mice and humans. These findings suggest that TonEBP in macrophages promotes obesity-associated systemic insulin resistance and inflammation, and downregulation of TonEBP may induce a healthy metabolic state during obesity.

Herpesviridae viral infections following rituximab combined chemotherapy in patients with diffuse large B-cell lymphoma.

BACKGROUND: Herpesviridae viral infections (HVIs) are particularly common in patients with hematologic malignancies after undergoing hematopoietic stem cell transplantation or receiving chemotherapy. However, there have been few reports on the incidence and risk factors of HVIs in diffuse large B-cell lymphoma (DLBL) patients treated with rituximab combined chemotherapy. METHODS: We analyzed 270 patients who were newly diagnosed with DLBL. All of the patients had received rituximab combined chemotherapy between June 2004 and April 2010. RESULTS: Twenty-nine patients (10.7%) developed HVI a median of 5.57 months (range 0.37-30.03) after initial chemotherapy. The estimated cumulative incidence rates of HVIs were 8.3 and 12.8% at 1 and 3 years, respectively, in all patients. Independent risk factors for HVIs were a high international prognostic index risk [p = 0.017, hazard ratio (HR) 2.633, 95% confidence interval (CI) 1.185-5.850], neutropenic fever (p = 0.023, HR 2.476, 95% CI 1.134-5.406) and a high cumulative dose of steroids (p = 0.023, HR 2.921, 95% CI 1.162-7.346). CONCLUSION: A high international prognostic index risk, neutropenic fever and a high cumulative dose of steroids appear to be risk factors for HVI in DLBL patients who are undergoing rituximab combined chemotherapy.

PARP1-mediated PARylation of TonEBP prevents R-loop-associated DNA damage.

Lack of coordination between the DNA replication and transcription machineries can increase the frequency of transcription-replication conflicts, leading ultimately to DNA damage and genomic instability. A major source of these conflicts is the formation of R-loops, which consist of a transcriptionally generated RNA-DNA hybrid and the displaced single-stranded DNA. R-loops play important physiological roles and have been implicated in human diseases. Although these structures have been extensively studied, many aspects of R-loop biology and R-loop-mediated genome instability remain unclear. We found that in cancer cells, tonicity-responsive enhancer-binding protein (TonEBP, also called NFAT5) interacted with PARP1 and localized to R-loops in response to DNA-damaging agent camptothecin (CPT), which is associated with R-loop formation. PARP1-mediated PARylation was required for recruitment of TonEBP to the sites of R-loop-associated DNA damage. Loss of TonEBP increased levels of R-loop accumulation and DNA damage, and promoted cell death in response to CPT. These findings suggest that TonEBP mediates resistance to CPT-induced cell death by preventing R-loop accumulation in cancer cells.

Development of a Chatbot Program for Follow-Up Management of Workers' General Health Examinations in Korea: A Pilot Study.

(1) Background: Follow-up management of workers' general health examination (WGHE) is important, but it is not currently well done. Chatbot, a type of digital healthcare tool, is used in various medical fields but has never been developed for follow-up management of WGHE in Korea. (2) Methods: The database containing results and explanations related to WGHE was constructed. Then, the channel, which connects users with the database was created. A user survey regarding effectiveness was administered to 23 healthcare providers. Additionally, interviews on applicability for occupational health services were conducted with six nurses in the agency of occupational health management. (3) Results: Chatbot was implemented on a small scale on the Amazon cloud service (AWS) EC2 using KaKaoTalk and Web Chat as user channels. Regarding the effectiveness, 21 (91.30%) rated the need for chatbots as very high; however, 11 (47.83%) rated the usability as not high. Of the 23 participants, 14 (60.87%) expressed overall satisfaction. Nurses appreciated the chatbot program as a method for resolving accessibility and as an aid for explaining examination results and follow-up management. (4) Conclusions: The effectiveness of WGHE and the applicability in the occupational health service of the chatbot program for follow-up management can be confirmed.

Experience and Awareness of Health Managers, Administrators, and Workers on a Hearing Conservation Program in Korea: A Qualitative Study.

This study aims to evaluate the experience and awareness of a hearing conservation program to explore its activation plan. Three focus group discussions were conducted with five health managers, five labor supervisors, and five workers. A single in-depth interview was conducted with a health manager. Since hearing loss has a significant influence on the quality of life of workers, all participants recognized the importance of management. Although the need for hearing conservation programs was acknowledged, the participants had negative views about their effectiveness. Most health managers have not been able to demonstrate tangible results from their efforts to solve hearing problems, and they have been unable to demand that their employers actively invest resources and personnel in solving or preventing hearing problems. The participants in this study did not entirely understand the hearing conservation program, negative comments suggested that it is impossible to eliminate noise sources from the workplace, and measures for noise reduction would reduce work efficiency. This study can be supplied not only as a basis for reidentifying the real problems of the hearing conservation program but also for the tailored implementation method of future hearing conservation programs at each worksite.

TonEBP in dendritic cells mediates pro-inflammatory maturation and Th1/Th17 responses.

Dendritic cells (DCs) are potent antigen-presenting cells that link the innate and adaptive immune responses; as such they play pivotal roles in initiation and progression of rheumatoid arthritis (RA). Here, we report that the tonicity-responsive enhancer-binding protein (TonEBP or NFAT5), a Rel family protein involved in the pathogenesis of autoimmune disease and inflammation, is required for maturation and function of DCs. Myeloid cell-specific TonEBP deletion reduces disease severity in a murine model of collagen-induced arthritis; it also inhibits maturation of DCs and differentiation of pathogenic Th1 and Th17 cells in vivo. Upon stimulation by TLR4, TonEBP promotes surface expression of major histocompatibility complex class II and co-stimulatory molecules via p38 mitogen-activated protein kinase. This is followed by DC-mediated differentiation of pro-inflammatory Th1 and Th17 cells. Taken together, these findings provide mechanistic basis for the pathogenic role of TonEBP in RA and possibly other autoimmune diseases.

Tonicity-responsive enhancer-binding protein promotes stemness of liver cancer and cisplatin resistance.

BACKGROUND: High recurrence and chemoresistance drive the high mortality in hepatocellular carcinoma (HCC). Although cancer stem cells are considered to be the source of recurrent and chemoresistant tumors, they remain poorly defined in HCC. Tonicity-responsive enhancer binding protein (TonEBP) is elevated in almost all HCC tumors and associated with recurrence and death. We aimed to identify function of TonEBP in stemness and chemoresistance of liver cancer. METHODS: Tumors obtained from 280 HCC patients were analyzed by immunohistochemical analyses. Stemness and chemoresistance of liver CSCs (LCSCs) were investigated using cell culture. Tumor-initiating activity was measured by implanting LCSCs into BALB/c nude mice. FINDINGS: Expression of TonEBP is higher in LCSCs in HCC cell lines and correlated with markers of LCSCs whose expression is significantly associated with poor prognosis of HCC patients. TonEBP mediates ATM-mediated activation of NF-κB, which stimulates the promoter of a key stem cell transcription factor SOX2. As expected, TonEBP is required for the tumorigenesis and self-renewal of LSCSs. Cisplatin induces the recruitment of the ERCC1/XPF dimer to the chromatin in a TonEBP-dependent manner leading to DNA repair and cisplatin resistance. The cisplatin-induced inflammation in LSCSs is also dependent on the TonEBP-ERCC1/XPF complex, and leads to enhanced stemness via the ATM-NF-κB-SOX2 pathway. In HCC patients, tumor expression of ERCC1/XPF predicts recurrence and death in a TonEBP-dependent manner. INTERPRETATION: TonEBP promotes stemness and cisplatin resistance of HCC via ATM-NF-κB. TonEBP is a key regulator of LCSCs and a promising therapeutic target for HCC and its recurrence.

TonEBP/NFAT5 promotes obesity and insulin resistance by epigenetic suppression of white adipose tissue beiging.

Tonicity-responsive enhancer binding protein (TonEBP or NFAT5) is a regulator of cellular adaptation to hypertonicity, macrophage activation and T-cell development. Here we report that TonEBP is an epigenetic regulator of thermogenesis and obesity. In mouse subcutaneous adipocytes, TonEBP expression increases > 50-fold in response to high-fat diet (HFD) feeding. Mice with TonEBP haplo-deficiency or adipocyte-specific TonEBP deficiency are resistant to HFD-induced obesity and metabolic defects (hyperglycemia, hyperlipidemia, and hyperinsulinemia). They also display increased oxygen consumption, resistance to hypothermia, and beiging of subcutaneous fat tissues. TonEBP suppresses the promoter of ß3-adrenoreceptor gene, a critical regulator of lipolysis and thermogenesis, in ex vivo and cultured adipocytes. This involves recruitment of DNMT1 DNA methylase and methylation of the promoter. In human subcutaneous adipocytes TonEBP expression displays a correlation with body mass index but an inverse correlation with ß3-adrenoreceptor expression. Thus, TonEBP is an attractive therapeutic target for obesity, insulin resistance, and hyperlipidemia.

TonEBP Suppresses the HO-1 Gene by Blocking Recruitment of Nrf2 to Its Promoter.

TonEBP is a key transcriptional activator in macrophages with an M1 phenotype. High expression of TonEBP is associated with many inflammatory diseases. Heme oxygenase-1 (HO-1), a stress-inducible protein, is induced by various oxidative and inflammatory signals, and its expression is regarded as an adaptive cellular response to inflammation and oxidative injury. Here, we show that TonEBP suppresses expression of HO-1 by blocking Nrf2 binding to the HO-1 promoter, thereby inducing polarization of macrophages to the M1 phenotype. Inhibition of HO-1 expression or activity significantly reduced the inhibitory responses on M1 phenotype and stimulatory effects on M2 phenotype by TonEBP knockdown. Additional experiments showed that HO-1 plays a role in the paracrine anti-inflammatory effects of TonEBP knockdown in macrophages. Identification of HO-1 as a downstream effector of TonEBP provides new possibilities for improved therapeutic approaches to inflammatory diseases.

Association between supervisors' behavior and wage workers' job stress in Korea: analysis of the fourth Korean working conditions survey.

BACKGROUND: In modern society, many workers are stressed. Supervisors' support or behavior can affect the emotional or psychological part of the worker. The purpose of this study is to investigate the effect of supervisor's behavior on worker's stress. METHODS: The study included 19,272 subjects following the assignment of weighted values to workers other than soldiers using data from the Fourth Korean Working Condition Survey. Supervisors' behavior was measured using 5 items: "supervisor feedback regarding work," "respectful attitude," "good conflict-resolution ability," "good work-related planning and organizational ability," and the encouragement of participation in important decision making. Job stress was measured using 1 item: "I experience stress at work." Multiple logistic regression analysis was performed to examine the effects of supervisors' behavioral, general, occupational, and psychosocial characteristics on job stress in workers. Organizational characteristics associated with supervisors' behavior were also analyzed. RESULTS: The results showed that supervisors' provision of feedback regarding work increased workers' job stress (OR = 1.329, 95% CI = 1.203 ~ 1.468). When a supervisor respect workers (OR = 0.812, 95% CI = 0.722 ~ 0.913) or good at planning and organizing works (OR = 0.816, 95% CI: 0.732 ~ 0.910), workers' job stress decreased. In particular, the two types of supervisor behaviors, other than feedback regarding work, were high in private-sector organizations employing less than 300 employees. CONCLUSION: Supervisors' behavior influenced job stress levels in workers. Therefore, it is necessary to increase education regarding the effects of supervisors' behavior on job stress, which should initially be provided in private-sector organizations with up to 300 employees.

Investigation of Health Effects According to the Exposure of Low Concentration Arsenic Contaminated Ground Water.

Recent epidemiological studies have reported adverse health effects, including skin cancer, due to low concentrations of arsenic via drinking water. We conducted a study to assess whether low arsenic contaminated ground water affected health of the residents who consumed it. For precise biomonitoring results, the inorganic (trivalent arsenite (As III) and pentavalent arsenate (As V)) and organic forms (monomethylarsonate (MMA) and dimethylarsinate (DMA)) of arsenic were separately quantified by combining high-performance liquid chromatography and inductively coupled plasma mass spectroscopy from urine samples. In conclusion, urinary As III, As V, MMA, and hair arsenic concentrations were significantly higher in residents who consumed arsenic contaminated ground water than control participants who consumed tap water. But, most health screening results did not show a statistically significant difference between exposed and control subjects. We presume that the elevated arsenic concentrations may not be sufficient to cause detectable health effects. Consumption of arsenic contaminated ground water could result in elevated urinary organic and inorganic arsenic concentrations. We recommend immediate discontinuation of ground water supply in this area for the safety of the residents.

Prevalence and Factors Associated with the Use of Eye Care Services in South Korea: Korea National Health and Nutrition Examination Survey 2010-2012.

PURPOSE: To estimate the factors and prevalence of eye care service utilization in the South Korean population. METHODS: This cross-sectional, population-based study included data from 22,550 Koreans aged ≥5 years who participated in the Korea National Health and Nutrition Examination Survey from 2010 to 2012. For people aged 5 to 11 years (young children), information was based on self-reports of contact with eye care service in the past year; for people aged ≥12 years (older population), the information was based on the self-reported lifetime contact with eye care service. Univariate and multivariate logistic regression analyses of the complex sample survey data were performed. RESULTS: The prevalence of eye care service use in young children during the past year was 61.1% (95% confidence interval, 58.1%-64.1%), while that in the older population during their lifetime was 73.5%. Subjects aged 7 to 11 years were more likely to have had an eye examination in the past year than subjects aged 5 to 6 years (odds ratio, 3.83; 95% confidence interval, 2.37-6.19). Multivariate logistic regression analysis indicated that higher monthly household income, being a National Health Insurance holder, and having private health insurance were related to more frequent use of eye care services in young children. For the older population and women, those living in an urban area and those with a best-corrected visual acuity less than 20 / 40 in the worse-seeing eye were more likely to have had an eye examination during their lifetime. Low education level was associated with low lifetime use of eye care services in the older population. CONCLUSIONS: There are sociodemographic disparities with use of eye care services in South Korea. This population-based study provides information that is useful for determining different intervention programs based on sociodemographic disparities to promote eye care service utilization in South Korea.

LPS-induced NFκB enhanceosome requires TonEBP/NFAT5 without DNA binding.

NFκB is a central mediator of inflammation. Present inhibitors of NFκB are mostly based on inhibition of essential machinery such as proteasome and protein kinases, or activation of nuclear receptors; as such, they are of limited therapeutic use due to severe toxicity. Here we report an LPS-induced NFκB enhanceosome in which TonEBP is required for the recruitment of p300. Increased expression of TonEBP enhances the NFκB activity and reduced TonEBP expression lowers it. Recombinant TonEBP molecules incapable of recruiting p300 do not stimulate NFκB. Myeloid-specific deletion of TonEBP results in milder inflammation and sepsis. We discover that a natural small molecule cerulenin specifically disrupts the enhanceosome without affecting the activation of NFκB itself. Cerulenin suppresses the pro-inflammatory activation of macrophages and sepsis without detectable toxicity. Thus, the NFκB enhanceosome offers a promising target for useful anti-inflammatory agents.

TonEBP suppresses IL-10-mediated immunomodulation.

TonEBP is a key transcriptional activator of M1 phenotype in macrophage, and its high expression is associated with many inflammatory diseases. During the progression of the inflammatory responses, the M1 to M2 phenotypic switch enables the dual role of macrophages in controlling the initiation and resolution of inflammation. Here we report that in human and mouse M1 macrophages TonEBP suppresses IL-10 expression and M2 phenotype. TonEBP knockdown promoted the transcription of the IL-10 gene by enhancing chromatin accessibility and Sp1 recruitment to its promoter. The enhanced expression of M2 genes by TonEBP knockdown was abrogated by antagonism of IL-10 by either neutralizing antibodies or siRNA-mediated silencing. In addition, pharmacological suppression of TonEBP leads to similar upregulation of IL-10 and M2 genes. Thus, TonEBP suppresses M2 phenotype via downregulation of the IL-10 in M1 macrophages.