Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. We sequenced and analyzed the whole genomes of 27 HCCs, 25 of which were associated with hepatitis B or C virus infections, including two sets of multicentric tumors. Although no common somatic mutations were identified in the multicentric tumor pairs, their whole-genome substitution patterns were similar, suggesting that these tumors developed from independent mutations, although their shared etiological backgrounds may have strongly influenced their somatic mutation patterns. Statistical and functional analyses yielded a list of recurrently mutated genes. Multiple chromatin regulators, including ARID1A, ARID1B, ARID2, MLL and MLL3, were mutated in ～50% of the tumors. Hepatitis B virus genome integration in the TERT locus was frequently observed in a high clonal proportion. Our whole-genome sequencing analysis of HCCs identified the influence of etiological background on somatic mutation patterns and subsequent carcinogenesis, as well as recurrent mutations in chromatin regulators in HCCs.     

A genome-wide approach accounting for body mass index identifies genetic variants influencing fasting glycemic traits and insulin resistance

Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology.     

Large-scale genome-wide association studies in East Asians identify new genetic loci influencing metabolic traits

To identify the genetic bases for nine metabolic traits, we conducted a meta-analysis combining Korean genome-wide association results from the KARE project (n = 8,842) and the HEXA shared control study (n = 3,703). We verified the associations of the loci selected from the discovery meta-analysis in the replication stage (30,395 individuals from the BioBank Japan genome-wide association study and individuals comprising the Health2 and Shanghai Jiao Tong University Diabetes cohorts). We identified ten genome-wide significant signals newly associated with traits from an overall meta-analysis. The most compelling associations involved 12q24.11 (near MYL2) and 12q24.13 (in C12orf51) for high-density lipoprotein cholesterol, 2p21 (near SIX2-SIX3) for fasting plasma glucose, 19q13.33 (in RPS11) and 6q22.33 (in RSPO3) for renal traits, and 12q24.11 (near MYL2), 12q24.13 (in C12orf51 and near OAS1), 4q31.22 (in ZNF827) and 7q11.23 (near TBL2-BCL7B) for hepatic traits. These findings highlight previously unknown biological pathways for metabolic traits investigated in this study.     

Cycles of juvenile hormone esterase activity during the juvenile hormone-driven cycles of oxygen consumption in pupal diapause of flesh flies

Summary During diapause O₂ consumption in fly pupae is a cyclic event (4-day periodicity at 25°C) driven by cycles of juvenile hormone activity. Levels of juvenile hormone esterase activity change systematically during the cycle, with highest activity observed at the nadir of the O₂ consumption cycle.Supported in part by grant 88-37153-3473 from the USDA Competitive Grants Office and grant 23-088 from the USDA Forest Service. Thanks to Dr Ming Tu Chang for her helpful advice.     

Columns for visual features of objects in monkey inferotemporal cortex.

At early stages of the mammalian visual cortex, neurons with similar stimulus selectivities are vertically arrayed through the thickness of the cortical sheet and clustered in patches or bands across the surface. This organization, referred to as a 'column', has been found with respect to one-dimensional stimulus parameters such as orientation of stimulus contours, eye dominance of visual inputs, and direction of stimulus motion. It is unclear, however, whether information with extremely high dimensions, such as visual shape, is organized in a similar columnar fashion or in a different manner in the brain. Here we report that the anterior inferotemporal area of the monkey cortex, the final station of the visual cortical stream crucial for object recognition, consists of columns, each containing cells responsive to similar visual features of objects.     

3-A resolution structure of a protein with histone-like properties in prokaryotes

The 3-A structure of DNA-binding protein II, which exhibits histone-like properties in bacteria, has been determined. The molecule is dimeric and appears to bind to the phosphate backbone of DNA through two symmetry-related arms. A mechanism by which the protein induces DNA supercoiling is proposed.     

Inhibition of aldose reductase by dihydroflavonols inEngelhardtia chrysolepis and effects on other enzymes

Astilbin and neoastilbin, dihydroflavonol rhamnosides fromEngelhardtia chrysolepis, showed potent inhibition of lens aldose reductase. Kinetic analysis showed astilbin exhibited uncompetitive inhibition against bothdl-glyceraldehyde and NADPH. These taxifolin glycosides were selective inhibitors of aldose reductase with no inhibition of NADH oxidase.     

The increase of thiobarbituric acid reacting substances in rats with experimental chronic hypoxia

Summary Feeding under conditions of reduced oxygen supply prompted an increase in serum, arterial and brain tissue levels of thiobarbituric acid (TBA)-reacting substances. These observations indicated the possibility that hypoxia might be one of the factors predisposing to the accumulation of lipid peroxide.