Tetramerization of upstream stimulating factor USF2 requires the elongated bent leucine zipper of the bHLH-LZ domain.

Upstream stimulating factors (USFs), including USF1 and USF2, are key components of the transcription machinery that recruit coactivators and histone-modifying enzymes. Using the classic basic helix-loop-helix leucine zipper (bHLH-LZ) domain, USFs bind the E-box DNA and form tetramers that promote DNA looping for transcription initiation. The structural basis by which USFs tetramerize and bind DNA, however, remains unknown. Here, we report the crystal structure of the complete bHLH-LZ domain of USF2 in complex with E-box DNA. We observed that the leucine zipper (LZ) of USF2 is longer than that of other bHLH-LZ family transcription factors and that the C-terminus of USF2 forms an additional α-helix following the LZ region (denoted as LZ-Ext). We also found the elongated LZ-Ext facilitates compact tetramer formation. In addition to the classic interactions between the basic region and DNA, we show a highly conserved basic residue in the loop region, Lys271, participates in DNA interaction. Together, these findings suggest that USF2 forms a tetramer structure with a bent elongated LZ-Ext region, providing a molecular basis for its role as a key component of the transcription machinery.

A small-molecule drug inhibits autophagy gene expression through the central regulator TFEB.

Autophagy supports the fast growth of established tumors and promotes tumor resistance to multiple treatments. Inhibition of autophagy is a promising strategy for tumor therapy. However, effective autophagy inhibitors suitable for clinical use are currently lacking. There is a high demand for identifying novel autophagy drug targets and potent inhibitors with drug-like properties. The transcription factor EB (TFEB) is the central transcriptional regulator of autophagy, which promotes lysosomal biogenesis and functions and systematically up-regulates autophagy. Despite extensive evidence that TFEB is a promising target for autophagy inhibition, no small molecular TFEB inhibitors were reported. Here, we show that an United States Food and Drug Administration (FDA)-approved drug Eltrombopag (EO) binds to the basic helix-loop-helix-leucine zipper domain of TFEB, specifically the bottom surface of helix-loop-helix to clash with DNA recognition, and disrupts TFEB-DNA interaction in vitro and in cellular context. EO selectively inhibits TFEB's transcriptional activity at the genomic scale according to RNA sequencing analyses, blocks autophagy in a dose-dependent manner, and increases the sensitivity of glioblastoma to temozolomide in vivo. Together, this work reveals that TFEB is targetable and presents the first direct TFEB inhibitor EO, a drug compound with great potential to benefit a wide range of cancer therapies by inhibiting autophagy.

The use of progressive addition lenses to improve the daily visual function of children receiving topical atropine treatment.

PURPOSE: To evaluate the changes in visual function when progressive addition lenses (PAL) are added in children using topical atropine as a myopia control therapy. Daily visual complaints and the determination of their near correction were studied. METHODS: Forty children aged 7-12 years were recruited. Distance and near visual acuity, accommodative lag, heterophoria, near point of convergence and stereopsis were examined, and a questionnaire of daily visual complaints was administered. RESULTS: Significant differences in visual functions were found after the near correction was prescribed. Significant improvements in distance and near visual acuity, lag of accommodation and binocular visual function were observed, and fewer visual complaints were reported at the Harmon distance. CONCLUSION: The use of PAL is helpful for children undergoing topical atropine treatment for myopia control, particularly those receiving medium to high doses. This combination therapy could also be applied to younger children who have a low tolerance to contact lenses, with less risk of ocular adverse effects.

Fine Particulate Matter Exposure Levels in Patients with Normal-Tension Glaucoma and Primary Open-Angle Glaucoma: A Population-Based Study from Taiwan.

Patients with NTG or POAG with more than one outpatient or discharge diagnosis from the ophthalmology department were included in the study. These data were merged with the PM2.5 data from the Air Quality Monitoring Network for analysis. This was a case−control study, with 1006 participants in the NTG group and 2533 in the POAG group. To investigate fine particulate matter (PM2.5) exposure levels in patients with normal-tension glaucoma (NTG) and primary open-angle glaucoma (POAG), patient data were obtained from Taiwan's Longitudinal Health Insurance Database 2000 for the 2008 to 2013 period. We used a multivariate logic regression model to assess the risk for each participant. The PM2.5 exposure levels were divided into four groups: <25th percentile (Q1), <617 µg/mm3; 25th to 50th percentile (Q2), 617 to 1297 µg/mm3; 50th to 75th percentile (Q3), 1297 to 2113 µg/mm3; and >75th percentile (Q4), >2113 µg/mm3. The results are expressed in terms of odds ratio (OR) and 95% CI. A multiple logistic regression was used to compare the results of the NTG group with those of the POAG group. Compared with the PM2.5 Q1 level, the OR of the PM2.5 Q2 level was 1.009 (95% CI 0.812−1.254), the PM2.5 Q3 level was 1.241 (95% CI 1.241−1.537, p < 0.05), and the PM2.5 Q4 level was 1.246 (95% CI 1.008−1.539, p < 0.05). Our research reveals that compared with POAG, the risk of developing NTG is more closely related with PM2.5 exposure, and PM2.5 has a concentration−dose effect. It is hoped that in the future, in the clinical judgment of NTG and POAG, the level of PM2.5 in the environment can be taken as a risk factor.

Bisphenol A induced apoptosis via oxidative stress generation involved Nrf2/HO-1 pathway and mitochondrial dependent pathways in human retinal pigment epithelium (ARPE-19) cells.

Bisphenol A (BPA) is an estrogen-like compound, and an environmental hormone, that is commonly used in daily life. Therefore, it may enter the human body through food or direct contact, causing BPA residues in blood and urine. Because most studies focused on the analysis of BPA in reproductive cells or tissues, regarding evidence the effect of BPA on human retinal pigment epithelium (ARPE-19) cells unavailable. Accordingly, the present study explored the cytotoxicity of BPA on ARPE-19 cells. After BPA treatment, the expression of Bcl-XL an antiapoptotic protein, in the mitochondria decreased, and the expression of Bax, a proapoptotic protein increased. Then the mitochondrial membrane potential was affected. BPA changed in mitochondrial membrane potential led to the release of cytochrome C, which activated caspase-9 to promote downstream caspase-3 leading to cytotoxicity. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and heme oxygenase 1 (HO-1) pathway play a major role in age-related macular degeneration. Our results showed that expression of HO-1 and Nrf2 suppressed by BPA. Superoxide dismutase and catalase, which Nrf2 downstream antioxidants, were degraded by BPA. AMP-activated kinase (AMPK), which can regulate the phosphorylation of Nrf2, and the phosphorylation of AMPK expression was reduced by BPA. Finally, BPA-induced ROS generation and cytotoxicity were reduced by N-acetyl-l-cysteine. Taken together, these results suggest that BPA induced ARPE-19 cells via oxidative stress, which was associated with down regulated Nrf2/HO-1 pathway, and the mitochondria dependent apoptotic signaling pathway.

Comparison of Medical Comorbidity between Patients with Normal-Tension Glaucoma and Primary Open-Angle Glaucoma: A Population-Based Study in Taiwan.

The objective was to investigate different comorbidities developed in normal-tension glaucoma (NTG) and primary open-angle glaucoma (POAG) patients. This was a case-control study, with 1489 people in the NTG group and 5120 people in the POAG group. Patient data were obtained from the Longitudinal Health Insurance Database 2010 (LHID2010) of Taiwan for the 2008-2013 period. The chi-square test was used to compare categorical variables, such as gender, income and urbanisation level, between NTG and POAG patients, and the two-tailed t test was used to compare continuity between the two groups. We use a multivariate logic regression model to assess the risk of each participant. The results are expressed in terms of odds ratio (OR) and 95% confidence intervals (CI). Patients with NTG had significantly higher proportions of hypotension (adjusted OR, 1.984; 95% CI, 1.128-3.490), sleep disturbances (adjusted OR, 1.323; 95% CI, 1.146-1.528), peptic ulcers (adjusted OR, 1.383; 95% CI, 1.188-1.609) and allergic rhinitis (adjusted OR, 1.484; 95% CI, 1.290-1.707) than those with POAG. Conversely, arterial hypertension (adjusted OR, 0.767; 95% CI, 0.660-0.893), diabetes (adjusted OR, 0.850; 95% CI, 0.728-0.993) and atopic dermatitis (adjusted OR, 0.869; 95% CI, 0.763-0.990) had a lower risk in the NTG group than in the POAG group. We found that comorbidities such a hypotension, sleep disturbances and peptic ulcer and allergic rhinitis are more highly associated to NTG than POAG.

The Impact of Clinical Atropine Use in Taiwanese Schoolchildren: Changes in Physiological Characteristics and Visual Functions.

Taiwan is commonly noted for its high prevalence of myopia, as well as a long history of more than 20 years of using atropine to control myopia. However, the clinical implications are rarely discussed. This is a cross-sectional study investigating the influence of topical atropine instillation on ocular physiology, visual function, and visual discomfort in children. Aged 7 to 12 years, 212 schoolchildren were recruited and divided into the atropine group and the non-atropine group. Physiological characteristics such as pupil size and intraocular pressure were measured, and a variety of visual functions was also evaluated. A questionnaire was used to investigate the side effects and visual complaints caused by atropine treatment. There was a significant difference in pupil size (OD: 5.40 ± 0.90 vs. 6.60 ± 1.01 mm; OS: 5.42 ± 0.87 vs. 6.64 ± 1.00 mm, p < 0.001) between the two groups. Reductions in near visual acuity, accommodation, convergence ability, and stereopsis were observed in the atropine group. The horizontal pupil diameter enlarged, and visual functions were greatly affected after administration of topical atropine. The changes in visual function during atropine therapy need to be carefully monitored by clinicians, while patient compliance is usually the key to success.

The Correlations between Horizontal and Vertical Peripheral Refractions and Human Eye Shape Using Magnetic Resonance Imaging in Highly Myopic Eyes.

The aim of this study was to determine the relationship between relative peripheral refraction and retinal shape by 2-D magnetic resonance imaging in high myopes. Thirty-five young adults aged 20 to 30 years participated in this study with 16 high myopes (spherical equivalent < -6.00 D) and 19 emmetropes (+0.50 to -0.50 D). An open field autorefractor was used to measure refractions from the center out to 60° in the horizontal meridian and out to around 20° in the vertical meridian, with a step of 3 degrees. Axial length was measured by using A-scan ultrasonography. In addition, images of axial, sagittal, and tangential sections were obtained using 2-D magnetic resonance imaging. The highly myopic group had a significantly relative peripheral hyperopic refraction and showed a prolate ocular shape compared to the emmetropic group. The highly myopic group had relative peripheral hyperopic refraction and showed a prolate ocular form. Significant differences in the ratios of height/axial (1.01 ± 0.02 vs. 0.94 ± 0.03) and width/axial (0.99 ± 0.17 vs. 0.93 ± 0.04) were found from the MRI images between the emmetropic and the highly myopic eyes (p < 0.001). There was a negative correlation between the retina's curvature and relative peripheral refraction for both temporal (Pearson r = -0.459; p < 0.01) and nasal (Pearson r = -0.277; p = 0.011) retina. For the highly myopic eyes, the amount of peripheral hyperopic defocus is correlated to its ocular shape deformation. This could be the first study investigating the relationship between peripheral refraction and ocular dimension in high myopes, and it is hoped to provide useful knowledge of how the development of myopia changes human eye shape.

Association Between PM2.5 Exposure Level and Primary Open-Angle Glaucoma in Taiwanese Adults: A Nested Case-Control Study.

Primary open-angle glaucoma (POAG) is the most common type of glaucoma. However, little is known about POAG in adults and exposure to air pollution. The current study aims to investigate whether exposure to particulate matter with a mass median aerodynamic diameter of ≤2.5 µm (PM2.5) is associated with POAG diagnosis. Patient data were obtained from the Longitudinal Health Insurance Database 2010 (LHID2010) of Taiwan for the 2008-2013 period. PM2.5 concentration data, collected from the Ambient Air Quality Monitoring Network established by the Environmental Protection Administration of Taiwan, were categorized into four groups according to World Health Organization (WHO) exposure standards for PM2.5. We estimated the odds ratios (ORs) and 95% CIs for risk factors for POAG with logistic regression. The OR of per WHO standard level increase was 1.193 (95% CI 1.050-1.356). Compared with the normal level, the OR of WHO 2.0 level was 1.668 (95% CI 1.045-2.663, P < 0.05). After excluding confounding risk factors for POAG in this study, we determined that increased PM2.5 exposure is related to POAG risk (ORs > 1, P < 0.05). In this study, PM2.5 was an independent factor associated with open-angle glaucoma. Further research is required to better understand the mechanisms connecting PM2.5 and open-angle glaucoma.

Peripheral Refraction in Myopic Children with and without Atropine Usage.

PURPOSE: To compare the patterns of relative peripheral refractions of myopic children who were currently on atropine treatment for myopia control and myopic children who did not use atropine. METHODS: Chinese children (n = 209) aged 7 to 12 years participated in the study, 106 used atropine and 103 did not. Participants were also classified into three groups: emmetropes (SE: +0.50 to -0.50 D), low myopes (SE: -0.50 to -3.00 D), and moderate myopes (SE: -3.00 to -6.00 D). The central and peripheral refractions along the horizontal meridians (for both nasal and temporal fields) were measured in 10-degree steps to 30 degrees. RESULTS: There were no statistically significant differences in spherical equivalent and astigmatism of the three refractive groups in either the nasal or temporal retina. The atropine group showed a significant relative myopia in the temporal 30° field in spherical equivalent compared to the emmetropic group (t 49 = 3.36, P=0.02). In eyes with low myopia, the atropine group had significant relative myopia in the nasal 30° and temporal 30° fields (t 118 = 2.59, P=0.01; t 118 = 2.06, P=0.04), and it is also observed at 20° and 30° of the nasal field for the moderate myopic group (t 36 = 2.37, P=0.02; t 2.84 = 2.84, P=0.01). CONCLUSION: Significant differences in relative peripheral refraction were found between the atropine group and its controls. The findings suggested that the eyes that received atropine may have a less prolate shape and thus explain why using atropine is effective in controlling myopia progression.

Progressive rear-view mirror for motorcycles.

In this work, we present the design and fabrication of a progressive rear-view mirror for motorcycles. In the context of physiological and physical background knowledge, we first analyze the geometric relationships among the profile of the mirror, the blind spot, the field of view, and the reflected image size. On the basis of Walker's eye model, the binocular disparity is further calculated according to the image size on each retina. We present the polynomial expansion that specifies our progressive mirror's profile, as well as the fused deposition modeling process for fabricating physical mirrors. Compared with a conventional aspheric or flat mirror, this progressive mirror can achieve a wider horizontal viewing angle and shows a more stable image, thus enhancing riding safety.

Reconstruction of the optical system of personalized eye models by using magnetic resonance imaging.

This study presents a practical method for reconstructing the optical system of personalized eye models by using magnetic resonance imaging (MRI). Monocular images were obtained from a young (20-year-old) healthy subject viewing at a near point (10 cm). Each magnetic resonance image was first analyzed using several commercial software to capture the profile of each optical element of the human eye except for the anterior lens surface, which could not be determined because it overlapped the ciliary muscle. The missing profile was substituted with a modified profile from a generic eye model. After the data-including the refractive indices from a generic model-were input in ZEMAX, we obtained a reasonable initial layout. By further considering the resolution of the MRI, the model was optimized to match the optical performance of a healthy eye. The main benefit of having a personalized eye model is the ability to quantitatively identify wide-angle ocular aberrations, which were corrected by the designed free-form spectacle lens.

[Impact of different tillage practices on soil organic carbon and water use efficiency under continuous wheat-maize binary cropping system].

Base on an 8-year field experiment, the effects of tillage practices coupled with or without straw return on the soil organic carbon (SOC) and water use efficiency (WUE) were investigated in Guanzhong Plain during the growing seasons from 2008 to 2009. The results showed that conservation tillage practices (sub-soiling, SS; rotary tillage, RT; no-till, NT) improved the SOC, WUE and crop yield compared with conventional tillage (CT), among which, SS coupled with straw return had the highest increment, with increase in SOC content of the 0-30 cm soil layer, WUE and crop yield by 19.5%, 16.9% and 20.5%, respectively. The NT practice effectively increased the SOC content of the 0-10 cm soil layer. Conclusively, under the current soil and climatic conditions in Guanzhong Plain, sub-soiling coupled with straw return is the most efficient tillage practice for promoting SOC accumulation, increasing water-use efficiency and yield.

Noncontact intraocular pressure reading prediction after Laser-assisted in situ Keratomileusis by the finite element method.

The finite element method with linear elastic assumption for predicting the intraocular pressure (IOP) readings after reshaping of the corneal structure is demonstrated in the present study. Twelve effective eye measurements in seven subjects were examined using the TOPCON LX-10, a noncontact intraocular pressure measurement technique, before and after laser-assisted in situ Keratomileusis surgery. A linear elastic model was introduced to reduce possible errors from a complicated anisotropic model with uncertain tissue parameters. Linear relationship between the simplified removal depth of laser-assisted in situ Keratomileusis and predicted IOP was expected, and the comparisons between measurements and the predicted model were made. The results indicated that the expected IOP readings are close to the measurement IOP values, while larger errors occur at smaller IOP conditions. In conclusion, the linear elastic finite element approach can already reveal parameters that influence measurement data the most, and the interaction between parameters was higher than we had expected. This helps us to build the confidence on implementing the anisotropic model.

Characterising visual deficits in children of an urban elementary school in Taiwan.

PURPOSE: The aim was to screen children from Grades 1 to 6 in an urban elementary school in Central Taiwan for visual deficits and associated parameters and, as an extension, to examine the acceptance of cycloplegic therapy as well as the lag in optimal vision correction. METHODS: Of 900 students in one school, 731 participated in the study, with parental consent. Data from 694 students, who had also completed a vision correction history were analysed. In addition to body height and weight, the screening included vision, non-cycloplegic autorefraction and distance retinoscopy, axial length and functional testing. RESULTS: There was a decrease in students with vision of 1.0 or better from 55.8 per cent in Grade 1 to 20.0 per cent in Grade 6. The decreases between Grades 2 and 3 and Grades 5 and 6 were significant. These trends were in general agreement with those based on refractive error and axial length. The students had abnormal functional findings including: stereoscopic vision, 9.2 per cent; cover tests, 14.1 per cent; pupillary responses, 13.8 per cent; and less commonly in extraocular muscular functions (3.0 per cent) and colour vision (5.2 per cent). A full 40 per cent of students received cycloplegic therapy with 25 per cent dropping out for various reasons. These cases were generally associated with lower vision and higher myopia. A lag between subnormal vision and optical correction was also observed with 55.1 per cent apparently not optimally corrected. Other parameters, including body height, weight and body mass index were not correlated with vision or refractive error. CONCLUSIONS: Age-dependent increase in the prevalence of myopia appears to continue despite the common practice of topical cycloplegic therapy in Taiwan. Timely correction of the refractive error is also lacking. While maintaining a visual acuity of 1.0 or better for all students at all times is not possible, this lag might be shortened by more frequent screening and/or direct provision of optical aids.