SETD2 regulates chromatin accessibility and transcription to suppress lung tumorigenesis.

SETD2, a H3K36 trimethyltransferase, is the most frequently mutated epigenetic modifier in lung adenocarcinoma, with a mutation frequency of approximately 9%. However, how SETD2 loss of function promotes tumorigenesis remains unclear. Using conditional Setd2-KO mice, we demonstrated that Setd2 deficiency accelerated the initiation of KrasG12D-driven lung tumorigenesis, increased tumor burden, and significantly reduced mouse survival. An integrated chromatin accessibility and transcriptome analysis revealed a potentially novel tumor suppressor model of SETD2 in which SETD2 loss activates intronic enhancers to drive oncogenic transcriptional output, including the KRAS transcriptional signature and PRC2-repressed targets, through regulation of chromatin accessibility and histone chaperone recruitment. Importantly, SETD2 loss sensitized KRAS-mutant lung cancer to inhibition of histone chaperones, the FACT complex, or transcriptional elongation both in vitro and in vivo. Overall, our studies not only provide insight into how SETD2 loss shapes the epigenetic and transcriptional landscape to promote tumorigenesis, but they also identify potential therapeutic strategies for SETD2 mutant cancers.

Targeting Aurora B kinase prevents and overcomes resistance to EGFR inhibitors in lung cancer by enhancing BIM- and PUMA-mediated apoptosis.

The clinical success of EGFR inhibitors in EGFR-mutant lung cancer is limited by the eventual development of acquired resistance. We hypothesize that enhancing apoptosis through combination therapies can eradicate cancer cells and reduce the emergence of drug-tolerant persisters. Through high-throughput screening of a custom library of ∼1,000 compounds, we discover Aurora B kinase inhibitors as potent enhancers of osimertinib-induced apoptosis. Mechanistically, Aurora B inhibition stabilizes BIM through reduced Ser87 phosphorylation, and transactivates PUMA through FOXO1/3. Importantly, osimertinib resistance caused by epithelial-mesenchymal transition (EMT) activates the ATR-CHK1-Aurora B signaling cascade and thereby engenders hypersensitivity to respective kinase inhibitors by activating BIM-mediated mitotic catastrophe. Combined inhibition of EGFR and Aurora B not only efficiently eliminates cancer cells but also overcomes resistance beyond EMT.

An Assessment of Anthropogenic CO2 Emissions by Satellite-Based Observations in China.

Carbon dioxide (CO2) is the most important anthropogenic greenhouse gas and its concentration in atmosphere has been increasing rapidly due to the increase of anthropogenic CO2 emissions. Quantifying anthropogenic CO2 emissions is essential to evaluate the measures for mitigating climate change. Satellite-based measurements of greenhouse gases greatly advance the way of monitoring atmospheric CO2 concentration. In this study, we propose an approach for estimating anthropogenic CO2 emissions by an artificial neural network using column-average dry air mole fraction of CO2 (XCO2) derived from observations of Greenhouse gases Observing SATellite (GOSAT) in China. First, we use annual XCO2 anomalies (dXCO2) derived from XCO2 and anthropogenic emission data during 2010⁻2014 as the training dataset to build a General Regression Neural Network (GRNN) model. Second, applying the built model to annual dXCO2 in 2015, we estimate the corresponding emission and verify them using ODIAC emission. As a results, the estimated emissions significantly demonstrate positive correlation with that of ODIAC CO2 emissions especially in the areas with high anthropogenic CO2 emissions. Our results indicate that XCO2 data from satellite observations can be applied in estimating anthropogenic CO2 emissions at regional scale by the machine learning. This developed method can estimate carbon emission inventory in a data-driven way. In particular, it is expected that the estimation accuracy can be further improved when combined with other data sources, related CO2 uptake and emissions, from satellite observations.

Phosphorylation of bacterial L9 and its functional implication in response to starvation stress.

The bacterial L9 (bL9) protein expressed and purified from Escherichia coli is stably phosphorylated. We mapped seven Ser/Thr phosphorylation sites, all of which but one are located at the carboxyl-terminal domain (CTD). When a histidine tag is fused to the C-terminus, bL9 is no longer phosphorylated. Phosphorylation of bL9 causes complete disordering of its CTD and helps cell survival under nutrient-limiting conditions. Previous structural studies of the ribosome have shown that bL9 exhibits two distinct conformations, one of which competes with binding of RelA to the 30s rRNA and prevents RelA activation. Taken together, we suggest that the flexibility of the bL9 CTD enabled by phosphorylation would remove the steric hindrance, serving as a previously unknown mechanism to regulate RelA function and help cell survival under starvation stress.

Characterization of C-terminal structure of MinC and its implication in evolution of bacterial cell division.

Proper cell division at the mid-site of Gram-negative bacteria reflects stringent regulation by the min system (MinC, MinD and MinE). Herein we report crystal structure of the C-terminal domain of MinC from Escherichia coli (EcMinCCTD). The MinCCTD beta helical domain is engaged in a tight homodimer, similar to Thermotoga maritima MinCCTD (TmMinCCTD). However, both EcMinCCTD and TmMinCCTD lack an α-helix (helix3) at their C-terminal tail, in comparison to Aquifex aerolicu MinCCTD (AaMinCCTD) which forms an extra interaction interface with MinD. To understand the role of this extra binding element in MinC/MinD interactions, we fused this helix (Aahelix3) to the C-terminus of EcMinC and examined its effect on cell morphology and cell growth. Our results revealed that Aahelix3 impaired normal cell division in vivo. Furthermore, results of a co-pelleting assay and binding free energy calculation suggested that Aahelix3 plays an essential role in AaMinCD complex formation, under the circumstance of lacking MinE in A. aerolicu. Combining these results with sequence analysis of MinC and MinD in different organisms, we propose an evolutionary relationship to rationalize different mechanisms in cell division positioning in various organisms.

Characterization of DicB by partially masking its potent inhibitory activity of cell division.

DicB, a protein encoded by the Kim (Qin) prophage in Escherichia coli, inhibits cell division through interaction with MinC. Thus far, characterization of DicB has been severely hampered owing to its potent activity which ceases cell division and leads to cell death. In this work, through fusing maltose-binding protein to the N-terminus of DicB (MBP-DicB), we successfully expressed and purified recombinant DicB that enabled in vitro analysis for the first time. More importantly, taking advantage of the reduced inhibitory activity of MBP-DicB, we were able to study its effects on cell growth and morphology. Inhibition of cell growth by MBP-DicB was systematically evaluated using various DicB constructs, and their corresponding effects on cell morphology were also investigated. Our results revealed that the N-terminal segment of DicB plays an essential functional role, in contrast to its C-terminal tail. The N-terminus of DicB is of critical importance as even the first amino acid (following the initial Met) could not be removed, although it could be mutated. This study provides the first glimpse of the molecular determinants underlying DicB's function.

A new autoinhibited kinase conformation reveals a salt-bridge switch in kinase activation.

In the structure of autoinhibited EphA2 tyrosine kinase reported herein, we have captured the entire activation segment, revealing a previously unknown role of the conserved Arg762 in kinase autoinhibition by interacting with the essential Mg(2+)-chelating Asp757. While it is well known that this Arg residue is involved in an electrostatic interaction with the phospho-residue of the activation loop to stabilize the active conformation, our structure determination revealed a new role for the Arg, acting as a switch between the autoinhibited and activated conformations. Mutation of Arg762 to Ala in EphA2 sensitized Mg(2+) response, resulting in enhanced kinase catalytic activity and Mg(2+) cooperativity. Furthermore, mutation of the corresponding Arg/Lys to Ala in PKA and p38MAPK also exhibited similar behavior. This new salt bridge-mediated switch may thus be an important mechanism of activation on a broader scope for kinases which utilize autophosphorylation.

CX3CR1 polymorphisms and the risk of age-related macular degeneration.

BACKGROUND: Age-related macular degeneration (AMD), a most common eye disease, can lead to irreversible visual impairment. Age, genetic and environmental factors have been implicated in AMD. Chemokine (C-X3-C motif) receptor 1 (CX3CR1) gene polymorphisms could influence the susceptibility of AMD. METHODS: We tested the association between AMD and single nocleotide polymorphisms (SNPs) of CX3CR1 gene (rs3732378 and rs3732379) in 102 cases and 115 controls from China. Genotypes were determined by MassArray genotyping assay method. Association between CX3CR1 gene polymorphisms and AMD were examined by χ(2) test and logistic regression. RESULTS: Genotype distribution of CX3CR1 gene polymorphisms were in accordance with HWE examination. No obvious differences were observed in the genotypes of rs3732378 polymorphism between case and control groups (P>0.05), but A allele of it could increase the risk of AMD (P=0.025, OR=2.391, 95% CI=1.092-5.237). Both TT genotype and T allele of rs3732379 were significantly associated with the susceptibility of AMD (P=8.663, OR=8.663, 95% CI=1.044-71.874; P=0.021, OR=2.076, 95% CI=1.104-3.903). Age, gender and smoking status were used as common confounders to adjust the association between CX3CR1 gene polymorphism and AMD risk. Then we found that rs3732378 had no obvious association with AMD susceptibility. TT genotype of rs3732379 related to the occurrence of AMD, but the association was not significant (P=0.050, OR=8.274, 95% CI=1.002-69.963). T allele of rs3732379 might increase the susceptibility of AMD (P=0.029, OR=2.033, 95% CI=1.077-3.838). CONCLUSION: T allele of rs3732379 might have a positive association with the susceptibility of AMD.

Insights into the cellular function of YhdE, a nucleotide pyrophosphatase from Escherichia coli.

YhdE, a Maf-like protein in Escherichia coli, exhibits nucleotide pyrophosphatase (PPase) activity, yet its cellular function remains unknown. Here, we characterized the PPase activity of YhdE on dTTP, UTP and TTP and determined two crystal structures of YhdE, revealing 'closed' and 'open' conformations of an adaptive active site. Our functional studies demonstrated that YhdE retards cell growth by prolonging the lag and log phases, particularly under stress conditions. Morphology studies showed that yhdE-knockout cells transformed the normal rod shape of wild-type cells to a more spherical form, and the cell wall appeared to become more flexible. In contrast, YhdE overexpression resulted in filamentous cells. This study reveals the previously unknown involvement of YhdE in cell growth inhibition under stress conditions, cell-division arrest and cell-shape maintenance, highlighting YhdE's important role in E. coli cell-cycle checkpoints.

[Estimating Winter Wheat Nitrogen Vertical Distribution Based on Bidirectional Canopy Reflected Spectrum].

The vertical distribution of crop nitrogen is increased with plant height, timely and non-damaging measurement of crop nitrogen vertical distribution is critical for the crop production and quality, improving fertilizer utilization and reducing environmental impact. The objective of this study was to discuss the method of estimating winter wheat nitrogen vertical distribution by exploring bidirectional reflectance distribution function (BRDF) data using partial least square (PLS) algorithm. The canopy reflectance at nadir, +/-50 degrees and +/- 60 degrees; at nadir, +/- 30 degrees and +/- 40 degrees; and at nadir, +/- 20 degrees and +/- 30 degrees were selected to estimate foliage nitrogen density (FND) at upper layer, middle layer and bottom layer, respectively. Three PLS analysis models with FND as the dependent variable and vegetation indices at corresponding angles as the explicative variables were. established. The impact of soil reflectance and the canopy non-photosynthetic materials, was minimized by seven kinds of modifying vegetation indices with the ratio R700/R670. The estimated accuracy is significant raised at upper layer, middle layer and bottom layer in modeling experiment. Independent model verification selected the best three vegetation indices for further research. The research result showed that the modified Green normalized difference vegetation index (GNDVI) shows better performance than other vegetation indices at each layer, which means modified GNDVI could be used in estimating winter wheat nitrogen vertical distribution

Estimation of nitrogen vertical distribution by bi-directional canopy reflectance in winter wheat.

Timely measurement of vertical foliage nitrogen distribution is critical for increasing crop yield and reducing environmental impact. In this study, a novel method with partial least square regression (PLSR) and vegetation indices was developed to determine optimal models for extracting vertical foliage nitrogen distribution of winter wheat by using bi-directional reflectance distribution function (BRDF) data. The BRDF data were collected from ground-based hyperspectral reflectance measurements recorded at the Xiaotangshan Precision Agriculture Experimental Base in 2003, 2004 and 2007. The view zenith angles (1) at nadir, 40° and 50°; (2) at nadir, 30° and 40°; and (3) at nadir, 20° and 30° were selected as optical view angles to estimate foliage nitrogen density (FND) at an upper, middle and bottom layer, respectively. For each layer, three optimal PLSR analysis models with FND as a dependent variable and two vegetation indices (nitrogen reflectance index (NRI), normalized pigment chlorophyll index (NPCI) or a combination of NRI and NPCI) at corresponding angles as explanatory variables were established. The experimental results from an independent model verification demonstrated that the PLSR analysis models with the combination of NRI and NPCI as the explanatory variables were the most accurate in estimating FND for each layer. The coefficients of determination (R2) of this model between upper layer-, middle layer- and bottom layer-derived and laboratory-measured foliage nitrogen density were 0.7335, 0.7336, 0.6746, respectively.

Prevalence and risk factors for pterygium in rural older adults in Shandong Province of China: a cross-sectional study.

To investigate the prevalence and risk factors for pterygium in rural older adults in Shandong Province, eastern China, a population-based, cross-sectional study was performed from April to July 2008. By means of cluster random sampling methods, a total of 19,583 people aged 50 years or above were randomly selected from four rural counties. Out of 19,583 people, 1,767 residents were excluded mainly because they were migrant workers when this study was performed. Finally, 17,816 (90.98%) people were included as eligible subjects. They received a comprehensive eye examination and a structured questionnaire voluntarily. Patients with pterygium were defined as having pterygium at the time of survey or pterygium surgery had been performed. 1,876 people were diagnosed as pterygium, either unilateral (1,083) or bilateral (793), which is equivalent to a prevalence of 10.53% (95% CI, 10.08-10.98). The multivariate logistic regression analysis showed that pterygium was independently associated with older age, areas, outdoor time, educational level, and use of hat and/or sunglasses. The prevalence of pterygium increased with age and hours spent under sunshine per day. Meanwhile, the higher the educational level and the more use of hat and/or sunglasses, the lower the pterygium prevalence.

[Causes of moderate to severe visual impairment and blindness in population aged 50 years or more in rural Shandong province].

OBJECTIVE: To investigate the etiological spectrum of moderate to severe visual impairment and blindness in population aged 50 years or more in rural Shandong province, China. METHODS: A population based, random cluster sampling was used to screening the adults aged 50 years or more living in rural Shandong Province from April to July 2008. Three counties and one suburb representing the different levels of socioeconomic development within Shandong area were selected as the investigated areas. Geographically defined cluster sampling was used in randomly selecting a cross-section of residents aged ≥ 50 years from each county. Best corrected visual acuity and intra-ocular pressure were evaluated in those with presenting visual acuity ≤ 0.5 and suspected glaucoma respectively. The major causes of visual impairment and blindness were diagnosed in those with presenting visual acuity ≤ 0.3. According to the results of presenting visual acuity and best corrected visual acuity, the etiology constituent ratios of the moderate to severe visual impairment and blindness were analyzed respectively. RESULTS: According to the number of people, the first three principal causes for blindness based on the presenting visual acuity were cataract (59.8%, 168/281), fundus disease (12.1%, 34/281) and corneal opacity (4.3%, 12/281) or ametropia (4.3%, 12/281). The first three principal causes for moderate to severe visual impairment and blindness were cataract (55.2%, 844/1530), uncorrected refractive error (18.2%, 278/1530) and fundus disease (11.9%, 182/1530). Based on the best corrected visual acuity, the first three principal causes for blindness were cataract (64.6%, 153/237), fundus disease (10.5%, 25/237) and corneal opacity (4.7%, 11/237), respectively. The first three principal causes for moderate to severe visual impairment and blindness were cataract (66.4%, 590/889), fundus disease (16.0%, 142/889) and optic nerve atrophy (3.0%, 27/889). According to number of the eyes, proportion of cataract in cases with moderate to severe visual impairment and blindness had positive relation with age, the proportion of ametropia and fundus disease had negative relation with age. The etiology constituent ratio had no difference between male and female. The proportion of cataract in cases with moderate to severe visual impairment and blindness in Huaiyin District of Jinan was slightly lower than those in other areas, however, the proportion ratio of ametropia and fundus disease was slightly higher than those in other areas. CONCLUSION: Cataract, uncorrected refractive error, and fundus diseases are ranked in the top three causes of moderate to severe visual impairment and blindness in adults aged 50 years or more in rural Shandong Province.

[Prevalence of visual impairment and blindness in older adults in rural Shandong Province].

OBJECTIVE: To describe the prevalence of visual impairment/blindness among older adults aged > or = 50 years in rural populations in Shandong Province, China. METHODS: Population-based, cross-sectional study was designed in this survey. Three counties and one suburbs representative of the different levels of socioeconomic development were selected as the study areas within the province from April to July 2008. Geographically defined cluster sampling was used in randomly selecting a cross-section of residents aged > or = 50 years from each county. Eligible persons were invited to local examination sites for visual acuity (VA) testing and eye examination. Those presenting with VA < or = 0.5 in either eye were refracted to achieve best-corrected VA. Chi2-test was used to compare the prevalence of blindness and visual impairment in the different groups. Multiple logistic regressions were used to investigate the association of age, gender, education, and county with presenting and best-corrected visual impairment and blindness. Adjusted odds ratio was used to compare the prevalence of blindness and visual impairment in the different counties. RESULTS: Of 19 583 enumerated eligible persons, 17 816 (90.98%) were examined and tested for VA. The prevalence of presenting visual impairment (0.05- < 0.3) in the better-seeing eye was 7.01% (the age-standardized rate was 6.56%) and presenting blindness (< 0.05) was 1.58% (the age-standardized rate was 1.48%). Across the 4 counties, presenting visual impairment ranged from 4.51% to 8.65%, and presenting blindness from 1.35% to 1.77%. With best-corrected VA, the prevalence of visual impairment was 3.66% (the age-standardized rate was 3.38%), and 1.33% for blindness (the age-standardized rate was 1.24%). The ranges across the 4 counties were 2.63% to 4.38% for visual impairment and 1.06%-1.54% for blindness. The prevalence of visual impairment with presenting VA was higher than that with best-corrected VA (2 = 201.262, P = 0.000). There was no significant difference between the prevalence of blindness with presenting VA and that with best-corrected VA (Chi2 = 0.117, P = 0.732). Based on both presenting and best-corrected VA, visual impairment and blindness were associated with older age, female gender, lack of education, and county (P < or = 0.05). CONCLUSIONS: Visual impairment and blindness are important public health problems in rural older adults aged > or = 50 years in Shandong Province. Un-corrected refractive error is one of the main causes of visual impairment.