A novel type 2 diabetes risk allele increases the promoter activity of the muscle-specific small ankyrin 1 gene

Genome-wide association studies have identified Ankyrin-1 (ANK1) as a common type 2 diabetes (T2D) susceptibility locus. However, the underlying causal variants and functional mechanisms remain unknown. We screened for 8 tag single nucleotide polymorphisms (SNPs) in ANK1 between 2 case-control studies. Genotype analysis revealed significant associations of 3 SNPs, rs508419 (first identified here), rs515071, and rs516946 with T2D (P 0.80); subsequent analysis indicated that the CCC haplotype associated with increased T2D susceptibility (OR 1.447, P < 0.001). Further mapping showed that rs508419 resides in the muscle-specific ANK1 gene promoter. Allele-specific mRNA and protein level measurements confirmed association of the C allele with increased small ANK1 (sAnk1) expression in human skeletal muscle (P = 0.018 and P < 0.001, respectively). Luciferase assays showed increased rs508419-C allele transcriptional activity in murine skeletal muscle C2C12 myoblasts, and electrophoretic mobility-shift assays demonstrated altered rs508419 DNA-protein complex formation. Glucose uptake was decreased with excess sAnk1 expression upon insulin stimulation. Thus, the ANK1 rs508419-C T2D-risk allele alters DNA-protein complex binding leading to increased promoter activity and sAnk1 expression; thus, increased sAnk1 expression in skeletal muscle might contribute to T2D susceptibility

Quantified mass loss of the Laohugou ice core and its precipitation signal during 1961–2005 at high elevation in the northeastern Tibetan Plateau

Ice records provide a qualitative rather than a quantitative indication of the trend of climate change. Using the bulk aerodynamic method and degree day model, this study quantified ice mass loss attributable to sublimation/evaporation (S/E) and meltwater on the basis of integrated observations (1960–2006) of glacier-related and atmospheric variables in the northeastern Tibetan Plateau. During 1961–2005, the average annual mass loss in the ice core was 95.33 ± 20.56 mm w.e. (minimum: 78.97 mm w.e. in 1967, maximum: 146.67 mm w.e. in 2001), while the average ratio of the revised annual ice accumulation was 21.2 ± 7.7% (minimum: 11.0% in 1992, maximum 44.8% in 2000). A quantitative formula expressing the relationship between S/E and air temperature at the monthly scale was established, which could be extended to estimation of S/E changes of other glaciers in other regions. The elevation effect on alpine precipitation determined using revised ice accumulation and instrumental data was found remarkable. This work established a method for quantitative assessment of the temporal variation in ice core mass loss, and advanced the reconstruction of long-term precipitation at high elevations. Importantly, the formula established for reconstruction of S/E from temperature time series data could be used in other regions

The Blue Light-Dependent Polyubiquitination and Degradation of Arabidopsis Cryptochrome2 Requires Multiple E3 Ubiquitin Ligases

Cryptochromes are blue light receptors regulated by light-dependent ubiquitination and degradation in both plant and animal lineages. The Arabidopsis genome encodes two cryptochromes, CRY1 and CRY2, of which CRY2 undergoes blue light-dependent ubiquitination and 26S proteasome-dependent degradation. The molecular mechanism regulating blue light-dependent proteolysis of CRY2 is still not fully understood. We found that the F-box proteins ZEITLUPE (ZTL) and Lov Kelch Protein2 (LKP2), which mediate blue light suppression of degradation of the CRY2 signaling partner CIB1, are not required for the blue light-dependent CRY2 degradation. We further showed that the previously reported function of the COP1-SPA1 protein complex in blue light-dependent CRY2 degradation is more likely to be attributable to its cullin 4 (CUL4)-based E3 ubiquitin ligase activity than its activity as the cryptochrome signaling partner. However, the blue light-dependent CRY2 degradation is only partially impaired in the cul4 mutant, the cop1-5 null mutant and the spa1234 quadruple mutant, suggesting a possible involvement of additional E3 ubiquitin ligases in the regulation of CRY2. Consistent with this hypothesis, we demonstrated that the blue light-dependent CRY2 degradation is significantly impaired in the temperature-sensitive cul1 mutant allele (axr6-3), especially under the non-permissive temperature. Based on these and other results presented, we propose that photoexcited CRY2 undergoes Lys48-linked polyubiquitination catalyzed by the CUL4- and CUL1-based E3 ubiquitin ligases

Identification of the ADPR binding pocket in the NUDT9 homology domain of TRPM2

Activation of the transient receptor potential melastatin 2 (TRPM2) channel occurs during the response to oxidative stress under physiological conditions as well as in pathological processes such as ischemia and diabetes. Accumulating evidence indicates that adenosine diphosphate ribose (ADPR) is the most important endogenous ligand of TRPM2. However, although it is known that ADPR binds to the NUDT9 homology (NUDT9-H) domain in the intracellular C-terminal region, the molecular mechanism underlying ADPR binding and activation of TRPM2 remains unknown. In this study, we generate a structural model of the NUDT9-H domain and identify the binding pocket for ADPR using induced docking and molecular dynamics simulation. We find a subset of 11 residues—H1346, T1347, T1349, L1379, G1389, S1391, E1409, D1431, R1433, L1484, and H1488—that are most likely to directly interact with ADPR. Results from mutagenesis and electrophysiology approaches support the predicted binding mechanism, indicating that ADPR binds tightly to the NUDT9-H domain, and suggest that the most significant interactions are the van der Waals forces with S1391 and L1484, polar solvation interaction with E1409, and electronic interactions (including π–π interactions) with H1346, T1347, Y1349, D1431, and H1488. These findings not only clarify the roles of a range of newly identified residues involved in ADPR binding in the TRPM2 channel, but also reveal the binding pocket for ADPR in the NUDT9-H domain, which should facilitate structure-based drug design for the TRPM2 channel

Associations of Educational Attainment, Occupation, Social Class and Major Depressive Disorder among Han Chinese Women

Background The prevalence of major depressive disorder (MDD) is higher in those with low levels of educational attainment, the unemployed and those with low social status. However the extent to which these factors cause MDD is unclear. Most of the available data comes from studies in developed countries, and these findings may not extrapolate to developing countries. Examining the relationship between MDD and socio economic status in China is likely to add to the debate because of the radical economic and social changes occurring in China over the last 30 years. Principal findings We report results from 3,639 Chinese women with recurrent MDD and 3,800 controls. Highly significant odds ratios (ORs) were observed between MDD and full time employment (OR = 0.36, 95% CI = 0.25–0.46, logP = 78), social status (OR = 0.83, 95% CI = 0.77–0.87, logP = 13.3) and education attainment (OR = 0.90, 95% CI = 0.86–0.90, logP = 6.8). We found a monotonic relationship between increasing age and increasing levels of educational attainment. Those with only primary school education have significantly more episodes of MDD (mean 6.5, P-value = 0.009) and have a clinically more severe disorder, while those with higher educational attainment are likely to manifest more comorbid anxiety disorders. Conclusions In China lower socioeconomic position is associated with increased rates of MDD, as it is elsewhere in the world. Significantly more episodes of MDD occur among those with lower educational attainment (rather than longer episodes of disease), consistent with the hypothesis that the lower socioeconomic position increases the likelihood of developing MDD. The phenomenology of MDD varies according to the degree of educational attainment: higher educational attainment not only appears to protect against MDD but alters its presentation, to a more anxious phenotype

Wenchuan Earthquake Surface Fault Rupture and Disaster: A Lesson on Seismic Hazard Assessment and Mitigation

The Ms 8.0 Wenchuan earthquake occurred along the Longmenshan Faults in China and was a great disaster. Most of the damage and casualties during the quake were concentrated along surface rupture zones: the 240-km-long Beichuan-Yingxiu Fault and the 70-km-long Jiangyou-Guanxian Fault. Although the Longmenshan Faults are well known and studied, the surface Fault ruptures were not considered in mitigation planning, and the associated ground-motion hazard was therefore underestimated. Not considering Fault rupture and underestimating ground-motion hazard contributed to the disastrous effects of the earthquake. The lesson from the Wenchuan earthquake disaster is that the fault rupture hazard must be assessed and considered in mitigation. Furthermore, the deterministic approach is more appropriate for fault rupture hazard assessment than the probabilistic approach

Sedimentary characteristics and sedimentary model of the Upper Permian-Lower Triassic shallow braided river delta in the hinterland of the Junggar Basin

The lower play of the Junggar Basin has huge oil and gas potential, which is the most important strategic succession field for oil and gas exploration. Large-scale delta sand bodies are developed in Permian and Triassic in the four sags in the hinterland, in which new discoveries of oil and gas have been made in succession. In order to reveal the sedimentary characteristics, sedimentary model, and distribution patterns of sand bodies in the hinterland, the studies on basin prototype, sequence framework, paleogeomorphic restoration and sedimentary system were systematically carried out based on a large number of newly drilled cores, logging and geophysical data. The results show that: the development background of large depression lake basin can be identified in the development period of the Upper Permian-Lower Triassic shallow water braided river delta in the hinterland of the basin, and the study area has the characteristics of flat terrain, small slope, sufficient material supply, extremely shallow and frequently turbulent water bodies, alternating oxidation and reduction environments, and overall oxidation environment during the sedimentation period. The shallow braided river delta is characterized by coarse grain size, low impurity content, medium texture maturity, long distance transportation, strong hydrodynamic scouring, cross bedding and parallel bedding. The advantageous water system in the sedimentation period of the Upper Wuerhe and Baikouquan formations in the hinterland mainly comes from the northwest and northeast, and extends from north to south as a whole, with three provenance systems developed, namely Wuerhe provenance, Karamay provenance and Kelameily provenance. The terrain within the basin has obvious zoning characteristics, forming four facies belts namely fan delta area, braided river delta plain area, front area and lake area, thus forming a shallow water braided river delta sedimentary pattern of "large plain, small front" in the hinterland, where plain area and front area are favorable sand body development zones

A splice mutation and mRNA decay of EXT2 provoke hereditary multiple exostoses.

BACKGROUND: Hereditary multiple exostoses (HME) is an autosomal dominant disease. The classical paradigm of mutation screening seeks to relate alterations in the exostosin glycosyltransferase genes, EXT1 and EXT2, which are responsible for over 70% of HME cases. However, the pathological significance of the majority of these mutations is often unclear. METHODS: In a Chinese family with HME, EXT1 and EXT2 genes were screened by direct sequencing. The consequence of a detected mutant was predicted by in silico analysis and confirmed by mRNA analysis. The EXT1 and EXT2 mRNA and protein levels and the HS patterns in the HME patients were compared with those in healthy controls. RESULTS: A heterozygous transition (c.743+1G>A) in the EXT2 gene, which co-segregated with the HME phenotype in this family, was identified. The G residue at position +1 in intron 4 of EXT2 was predicted to be a 5' donor splice site. The mRNA analysis revealed an alternative transcript with a cryptic splice site 5 bp downstream of the wild-type site, which harbored a premature stop codon. However, the predicted truncated protein was not detected by western blot analysis. Decay of the mutant mRNA was shown by clone sequencing and quantification analysis. The corresponding downregulation of the EXT2 mRNA will contribute to the abnormal EXT1/EXT2 ratio and HS pattern that were detected in the patients with HME. CONCLUSION: The heterozygous mutation c.743+1G>A in the EXT2 gene causes HME as a result of abnormal splicing, mRNA decay, and the resulting haploinsufficiency of EXT2

The Blue Light-Dependent Polyubiquitination and Degradation of Arabidopsis Cryptochrome2 Requires Multiple E3 Ubiquitin Ligases.

Cryptochromes are blue light receptors regulated by light-dependent ubiquitination and degradation in both plant and animal lineages. The Arabidopsis genome encodes two cryptochromes, CRY1 and CRY2, of which CRY2 undergoes blue light-dependent ubiquitination and 26S proteasome-dependent degradation. The molecular mechanism regulating blue light-dependent proteolysis of CRY2 is still not fully understood. We found that the F-box proteins ZEITLUPE (ZTL) and Lov Kelch Protein2 (LKP2), which mediate blue light suppression of degradation of the CRY2 signaling partner CIB1, are not required for the blue light-dependent CRY2 degradation. We further showed that the previously reported function of the COP1-SPA1 protein complex in blue light-dependent CRY2 degradation is more likely to be attributable to its cullin 4 (CUL4)-based E3 ubiquitin ligase activity than its activity as the cryptochrome signaling partner. However, the blue light-dependent CRY2 degradation is only partially impaired in the cul4 mutant, the cop1-5 null mutant and the spa1234 quadruple mutant, suggesting a possible involvement of additional E3 ubiquitin ligases in the regulation of CRY2. Consistent with this hypothesis, we demonstrated that the blue light-dependent CRY2 degradation is significantly impaired in the temperature-sensitive cul1 mutant allele (axr6-3), especially under the non-permissive temperature. Based on these and other results presented, we propose that photoexcited CRY2 undergoes Lys48-linked polyubiquitination catalyzed by the CUL4- and CUL1-based E3 ubiquitin ligases