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.     

Cloning of adiponectin receptors that mediate antidiabetic metabolic effects

Adiponectin (also known as 30-kDa adipocyte complement-related protein; Acrp30) is a hormone secreted by adipocytes that acts as an antidiabetic and anti-atherogenic adipokine. Levels of adiponectin in the blood are decreased under conditions of obesity, insulin resistance and type 2 diabetes. Administration of adiponectin causes glucose-lowering effects and ameliorates insulin resistance in mice. Conversely, adiponectin-deficient mice exhibit insulin resistance and diabetes. This insulin-sensitizing effect of adiponectin seems to be mediated by an increase in fatty-acid oxidation through activation of AMP kinase and PPAR-alpha. Here we report the cloning of complementary DNAs encoding adiponectin receptors 1 and 2 (AdipoR1 and AdipoR2) by expression cloning. AdipoR1 is abundantly expressed in skeletal muscle, whereas AdipoR2 is predominantly expressed in the liver. These two adiponectin receptors are predicted to contain seven transmembrane domains, but to be structurally and functionally distinct from G-protein-coupled receptors. Expression of AdipoR1/R2 or suppression of AdipoR1/R2 expression by small-interfering RNA supports our conclusion that they serve as receptors for globular and full-length adiponectin, and that they mediate increased AMP kinase and PPAR-alpha ligand activities, as well as fatty-acid oxidation and glucose uptake by adiponectin.     

Mechanisms of ciliogenesis suppression in dividing cells

The primary cilium is a non-motile and microtubule-enriched protrusion ensheathed by plasma membrane. Primary cilia function as mechano/chemosensors and signaling hubs and their disorders predispose to a wide spectrum of human diseases. Most types of cells assemble their primary cilia in response to cellular quiescence, whereas they start to retract the primary cilia upon cell-cycle reentry. The retardation of ciliary resorption process has been shown to delay cell-cycle progression to the S or M phase after cell-cycle reentry. Apart from this conventional concept of ciliary disassembly linked to cell-cycle reentry, recent studies have led to a novel concept, suggesting that cells can suppress primary cilia assembly during cell proliferation. Accumulating evidence has also demonstrated the importance of Aurora-A (a protein originally identified as one of mitotic kinases) not only in ciliary resorption after cell-cycle reentry but also in the suppression of ciliogenesis in proliferating cells, whereas Aurora-A activators are clearly distinct in both phenomena. Here, we summarize the current knowledge of how cycling cells suppress ciliogenesis and compare it with mechanisms underlying ciliary resorption after cell-cycle reentry. We also discuss a reciprocal relationship between primary cilia and cell proliferation.     

Identification by mutagenesis of a Mg(2+)-block site of the NMDA receptor channel.

The N-methyl-D-aspartate (NMDA) receptor channel is highly permeable to Ca2+ but is blocked by Mg2+ in a voltage-dependent manner. These characteristics are essential for the NMDA receptor channel to mediate the induction of long-term potentiation of synaptic efficacy, a form of activity-dependent synaptic plasticity thought to underlie memory, learning and development. Recent studies have revealed the molecular and functional diversity of the NMDA receptor channel subunits, which are classified into the epsilon and zeta families according to the amino-acid sequence homology. Here we report that replacement by glutamine of asparagine 598 in putative transmembrane segment M2 of the zeta 1 subunit, strongly reduces the sensitivity of the heteromeric epsilon 2/zeta 1 NMDA receptor channel to Mg2+ block. The corresponding mutation of the epsilon 2 subunit has a similar effect. Furthermore, the heteromeric epsilon 2/zeta 1 NMDA receptor channel with the mutation on both subunits shows greatly reduced sensitivity to MK-801, a channel blocker of the NMDA receptor channel, but is still susceptible to inhibition by Zn2+. These findings suggest that the conserved asparagine residue in segment M2 constitutes a Mg(2+)-block site of the NMDA receptor channel, and that the MK-801 site overlaps the Mg2+ site.     

Elevation of plasma dopamine-β-hydroxylase activity during insulin-induced hypoglycemia in man

Résumé Nous avons étudié l'activité de la dopamine--hydroxylase du plasma humain. Elle a été remarquablement accure par l'administration de grandes quantités d'insuline. Les corrélations entre cette activité et celle des systèmes nerveux sympathiques sont également discutées.     

A functional SNP in CILP, encoding cartilage intermediate layer protein, is associated with susceptibility to lumbar disc disease

Lumbar disc disease (LDD) is caused by degeneration of intervertebral discs of the lumbar spine. One of the most common musculoskeletal disorders, LDD has strong genetic determinants. Using a case-control association study, we identified a functional SNP (1184T --> C, resulting in the amino acid substitution I395T) in CILP, which encodes the cartilage intermediate layer protein, that acts as a modulator of LDD susceptibility. CILP was expressed abundantly in intervertebral discs, and its expression increased as disc degeneration progressed. CILP colocalized with TGF-beta1 in clustering chondrocytes and their territorial matrices in intervertebral discs. CILP inhibited TGF-beta1-mediated induction of cartilage matrix genes through direct interaction with TGF-beta1 and inhibition of TGF-beta1 signaling. The susceptibility-associated 1184C allele showed increased binding and inhibition of TGF-beta1. Therefore, we conclude that the extracellular matrix protein CILP regulates TGF-beta signaling and that this regulation has a crucial role in the etiology and pathogenesis of LDD. Our study also adds to the list of connective tissue diseases that are associated with TGF-beta.     

Effect of lower bainite/martensite/retained austenite triplex microstructure on the mechanical properties of a low-carbon steel with quenching and partitioning process

We present a study concerning Fe–0.176C–1.31Si–1.58Mn–0.26Al–0.3Cr (wt%) steel subjected to a quenching and partitioning (Q&P) process. The results of scanning electron microscopy, transmission electron microscopy, X-ray diffraction, and tensile tests demonstrate that the microstructures primarily consist of lath martensite, retained austenite, lower bainite (LB), and a small amount of tempered martensite; moreover, few twin austenite grains were observed. In the microstructure, three types of retained austenite with different sizes and morphologies were observed: blocky retained austenite (~300 nm in width), film-like retained austenite (80–120 nm in width), and ultra- fine film-like retained austenite (30–40 nm in width). Because of the effect of the retained austenite/martensite/LB triplex microstructure, the specimens prepared using different quenching temperatures exhibit high ultimate tensile strength and yield strength. Furthermore, the strength effect of LB can partially counteract the decreasing strength effect of martensite. The formation of LB substantially reduces the amount of retained austenite. Analyses of the retained austenite and the amount of blocky retained austenite indicated that the carbon content is critical to the total elongation of Q&P steel.     

6H-anthra[1,9-bc]thiophene derivatives from a bryozoan,Dakaira subovoidea

Separation of a lipophilic extract of the bryozoan,Dakaira subovoidea, a common fouling organism of underwater structures, guided by inhibition of lipid peroxide formation in rat liver microsomes, gave 5,7-dihydroxy-1-hydroxymethyl-6-oxo-6H-anthra[1,9-bc]thiophene (1a) and its 1-methoxycarbonyl derivative (1c), together with the known 1,8-dihydroxyanthraquinone (2). The structures were determined by spectral and crystallographic analyses.     

Royalactin induces queen differentiation in honeybees

The honeybee (Apis mellifera) forms two female castes: the queen and the worker. This dimorphism depends not on genetic differences, but on ingestion of royal jelly, although the mechanism through which royal jelly regulates caste differentiation has long remained unknown. Here I show that a 57-kDa protein in royal jelly, previously designated as royalactin, induces the differentiation of honeybee larvae into queens. Royalactin increased body size and ovary development and shortened developmental time in honeybees. Surprisingly, it also showed similar effects in the fruitfly (Drosophila melanogaster). Mechanistic studies revealed that royalactin activated p70 S6 kinase, which was responsible for the increase of body size, increased the activity of mitogen-activated protein kinase, which was involved in the decreased developmental time, and increased the titre of juvenile hormone, an essential hormone for ovary development. Knockdown of epidermal growth factor receptor (Egfr) expression in the fat body of honeybees and fruitflies resulted in a defect of all phenotypes induced by royalactin, showing that Egfr mediates these actions. These findings indicate that a specific factor in royal jelly, royalactin, drives queen development through an Egfr-mediated signalling pathway.