Association of the -112A>C polymorphism of the uncoupling protein 1 gene with insulin resistance in Japanese individuals with type 2 diabetes

The -112A>C polymorphism (rs10011540) of the gene for uncoupling protein 1 (UCP1) has been associated with type 2 diabetes mellitus in Japanese individuals. The aim of the present study was to investigate the effects of this polymorphism, as well as the well-known -3826A>G polymorphism (rs1800592), on clinical characteristics of type 2 diabetes. We determined the genotypes of the two polymorphisms in 93 Japanese patients with type 2 diabetes. Intramyocellular lipid content and hepatic lipid content (HLC) were measured by magnetic resonance spectroscopy. No significant differences in age, sex, BMI, or HbA1c level were detected between type 2 diabetic patients with the -112C allele and those without it. However, homeostasis model assessment for insulin resistance (p=0.0089) and HLC (p=0.012) was significantly greater in patients with the -112C allele. We did not detect an association of the -3826A>G polymorphism (rs1800592) of UCP1 gene with any measured parameters. These results suggest that insulin resistance caused by the -112C allele influences the susceptibility to type 2 diabetes.     

Retrovirus-mediated conditional immortalization and analysis of established cell lines of osteoclast precursor cells

Osteoclast precursor cells (OPCs) have previously been established from bone marrow cells of SV40 temperature-sensitive T antigen-expressing transgenic mice. Here, we use retrovirus-mediated gene transfer to conditionally immortalize OPCs by expressing temperature-sensitive large T antigen (tsLT) from wild type bone marrow cells. The immortalized OPCs proliferated at the permissive temperature of 33.5 degrees C, but stopped growing at the non-permissive temperature of 39 degrees C. In the presence of receptor activator of NFkappaB ligand (RANKL), the OPCs differentiated into tartrate-resistant acid phosphatase (TRAP)-positive cells and formed multinucleate osteoclasts at 33.5 degrees C. From these OPCs, we cloned two types of cell lines. Both differentiated into TRAP-positive cells, but one formed multinucleate osteoclasts while the other remained unfused in the presence of RANKL. These results indicate that the established cell lines are useful for analyzing mechanisms of differentiation, particularly multinucleate osteoclast formation. Retrovirus-mediated conditional immortalization should be a useful method to immortalize OPCs from primary bone marrow cells.     

Reduced responsiveness is an essential feature of chronic fatigue syndrome: A fMRI study

Background  

Although the neural mechanism of chronic fatigue syndrome has been investigated by a number of researchers, it remains poorly understood.     

Learning to simulate others' decisions

A fundamental challenge in social cognition is how humans learn another person's values to predict their decision-making behavior. This form of learning is often assumed to require simulation of the other by direct recruitment of one's own valuation process to model the other's process. However, the cognitive and neural mechanism of simulation learning is not known. Using behavior, modeling, and fMRI, we show that simulation involves two learning signals in a hierarchical arrangement. A simulated-other's reward prediction error processed in ventromedial prefrontal cortex mediated simulation by direct recruitment, being identical for valuation of the self and simulated-other. However, direct recruitment was insufficient for learning, and also required observation of the other's choices to generate?a simulated-other's action prediction error encoded in dorsomedial/dorsolateral prefrontal cortex. These findings show that simulation uses a core prefrontal circuit for modeling the other's valuation to generate prediction and an adjunct circuit for tracking behavioral variation to refine prediction.     

Roles of Ataxin-2 in Pathological Cascades Mediated by TAR DNA-binding Protein 43 (TDP-43) and Fused in Sarcoma (FUS)

The RNA-binding proteins TDP-43 and Fused in Sarcoma (FUS) play central roles in neurodegeneration associated with amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Both proteins are components of messenger ribonucleoprotein (mRNP) granules and show cytoplasmic mislocalization in affected tissues. Recently, ataxin-2 was identified as a potent modifier of TDP-43 toxicity in an RNA-dependent manner. This study investigated to clarify how ataxin-2 modifies the TDP-43 and FUS pathological pathway. The expression of cytoplasmic TDP-43, the 35-kDa C-terminal fragment (TDP-p35f), and mutant FUS recruited ataxin-2 to mRNP granules, whereas increased ataxin-2 inhibited the mRNP granule formation of the 35-kDa C-terminal fragment and mutant FUS. A subcellular compartment analysis showed that the overexpressed ataxin-2 increased the cytoplasmic concentrations of both proteins, whereas it decreased their nuclear distributions. These data indicate that increased ataxin-2 impairs the assembly of TDP-43 and FUS into mRNP granules, leading to an aberrant distribution of RNA-binding proteins. Consequently, these sequences may exacerbate the impairment of the RNA-quality control system mediated by amyotrophic lateral sclerosis/frontotemporal lobar degeneration-associated RNA-binding proteins, which forms the core of the degenerative cascade.     

Comparative expression analysis of the H3K27 demethylases, JMJD3 and UTX, with the H3K27 methylase, EZH2, in Xenopus

The regulated removal of the gene-silencing epigenetic mark, trimethylation of lysine 27 of histone H3 (H3K27me3), has been shown to be critical for tissue-specific activation of developmental genes; however, the extent of embryonic expression of its demethylases, JMJD3 and UTX, has remained unclear. In this study, we investigated the expression of jmjd3 and utx genes in Xenopus embryos in parallel with that of the H3K27 methylase gene, ezh2. At the blastula stage, jmjd3, utx and ezh2 showed similar expression patterns in the animal cap and marginal zone that give rise to the ectoderm and mesoderm, respectively. The three genes maintained similar expression patterns in the neural plate, preplacodal ectoderm and axial mesoderm during the gastrula and neurula stages. Later, expression was maintained in the developing brain and cranial sensory tissues, such as the eye and ear, of tailbud embryos. These findings suggest that the H3K27 demethylases and methylase may function continuously for progressive switching of genetic programs during neural development, a model involving the simultaneous action of both of the demethylases for the de-repression of silent genes and the methylase for the silencing of active genes.     

Self-interaction, nucleic acid binding, and nucleic acid chaperone activities are unexpectedly retained in the unique ORF1p of zebrafish LINE

Long interspersed elements (LINEs) are mobile elements that comprise a large proportion of many eukaryotic genomes. Although some LINE-encoded open reading frame 1 proteins (ORF1ps) were suggested to be required for LINE mobilization through binding to their RNA, their general role is not known. The ZfL2-1 ORF1p, which belongs to the esterase-type ORF1p, is especially interesting because it has no known RNA-binding domain. Here we demonstrate that ZfL2-1 ORF1p has all the canonical activities associated with known ORF1ps, including self-interaction, nucleic acid binding, and nucleic acid chaperone activities. In particular, we showed that its chaperone activity is reversible, suggesting that the chaperone activities of many other ORF1ps are also reversible. From this discovery, we propose that LINE ORF1ps play a general role in LINE integration by forming a complex with LINE RNA and rearranging its conformation.     

Discovery of novel 5-alkynyl-4-anilinopyrimidines as potent, orally active dual inhibitors of EGFR and Her-2 tyrosine kinases

5-Alkenyl or 5-alkynyl-4-anilinopyrimidines were prepared and evaluated for in vitro inhibition of EGFR/Her-2 kinase activity and the growth of tumor cell lines (BT474 and N87). Several of these compounds inhibited the growth of BT474 and N87 at concentrations below 200nM. Structure-activity relationship studies revealed a critical role for the 5-alkynyl moieties. The representative compound 19 exhibited significant antitumor potency in a mouse xenograft model.