The OXR domain defines a conserved family of eukaryotic oxidation resistance proteins

BACKGROUND: The NCOA7 gene product is an estrogen receptor associated protein that is highly similar to the human OXR1 gene product, which functions in oxidation resistance. OXR genes are conserved among all sequenced eukaryotes from yeast to humans. In this study we examine if NCOA7 has an oxidation resistance function similar to that demonstrated for OXR1. We also examine NCOA7 expression in response to oxidative stress and its subcellular localization in human cells, comparing these properties with those of OXR1. RESULTS: We find that NCOA7, like OXR1 can suppress the oxidative mutator phenotype when expressed in an E. coli strain that exhibits an oxidation specific mutator phenotype. Moreover, NCOA7's oxidation resistance function requires expression of only its carboxyl-terminal domain and is similar in this regard to OXR1. We find that, in human cells, NCOA7 is constitutively expressed and is not induced by oxidative stress and appears to localize to the nucleus following estradiol stimulation. These properties of NCOA7 are in striking contrast to those of OXR1, which is induced by oxidative stress, localizes to mitochondria, and appears to be excluded, or largely absent from nuclei. CONCLUSION: NCOA7 most likely arose from duplication. Like its homologue, OXR1, it is capable of reducing the DNA damaging effects of reactive oxygen species when expressed in bacteria, indicating the protein has an activity that can contribute to oxidation resistance. Unlike OXR1, it appears to localize to nuclei and interacts with the estrogen receptor. This raises the possibility that NCOA7 encodes the nuclear counterpart of the mitochondrial OXR1 protein and in mammalian cells it may reduce the oxidative by-products of estrogen metabolite-mediated DNA damage

Descope of the ALIA mission

The present work reports on a feasibility study commissioned by the Chinese Academy of Sciences of China to explore various possible mission options to detect gravitational waves in space alternative to that of the eLISA/LISA mission concept. Based on the relative merits assigned to science and technological viability, a few representative mission options descoped from the ALIA mission are considered. A semi-analytic Monte Carlo simulation is carried out to understand the cosmic black hole merger histories starting from intermediate mass black holes at high redshift as well as the possible scientific merits of the mission options considered in probing the light seed black holes and their coevolution with galaxies in early Universe. The study indicates that, by choosing the armlength of the interferometer to be three million kilometers and shifting the sensitivity floor to around one-hundredth Hz, together with a very moderate improvement on the position noise budget, there are certain mission options capable of exploring light seed, intermediate mass black hole binaries at high redshift that are not readily accessible to eLISA/LISA, and yet the technological requirements seem to within reach in the next few decades for China

Genomic sequencing of colorectal adenocarcinomas identifies a recurrent VTI1A-TCF7L2 fusion

Prior studies have identified recurrent oncogenic mutations in colorectal adenocarcinoma1 and have surveyed exons of protein-coding genes for mutations in 11 affected individuals2,3. Here we report whole-genome sequencing from nine individuals with colorectal cancer, including primary colorectal tumors and matched adjacent non-tumor tissues, at an average of 30.7× and 31.9× coverage, respectively. We identify an average of 75 somatic rearrangements per tumor, including complex networks of translocations between pairs of chromosomes. Eleven rearrangements encode predicted in-frame fusion proteins, including a fusion of VTI1A and TCF7L2 found in 3 out of 97 colorectal cancers. Although TCF7L2 encodes TCF4, which cooperates with β-catenin4 in colorectal carcinogenesis5,6, the fusion lacks the TCF4 β-catenin–binding domain. We found a colorectal carcinoma cell line harboring the fusion gene to be dependent on VTI1A-TCF7L2 for anchorage-independent growth using RNA interference-mediated knockdown. This study shows previously unidentified levels of genomic rearrangements in colorectal carcinoma that can lead to essential gene fusions and other oncogenic events

Retinoic acid responsiveness and resistance in acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is characterized by reciprocal chromosomal translocations invariably involving the retinoic acid receptor alpha (RARalpha) gene on chromosome 17. In the vast majority of APL cases, the RARalpha gene is fused to the PML gene on chromosome 15, generating the fusion PML-RARalpha. The chimeric PML-RARalpha protein plays a critical role in APL leukemogenesis. Retinoic acid (RA) can overcome the differentiation block conferred by PML-RARalpha and induce APL cells to terminally maturate into granulocytes. However, resistance to RA develops both in vitro and in patients. We have developed RA-resistant subclones derived from the human APL cell line, NB4. These resistant subclones display altered RA-binding and reduced transactivation of retinoid response elements (RAREs) upon RA treatment. In the subclone R4, we identified a point mutation changing a leucine to praline in the ligand binding domain of the fusion PML-RARalpha protein that causes a loss of ligand binding. The mutant PML-RARalpha protein retains its ability to heterodimerize with RXRalpha and bind to RAREs. Thus, it functions as a dominant negative transcriptional inhibitor of the coexpressed wild-type RARalpha. The mutant PML-RARalpha has impaired RA-dependent interaction with receptor coregulatory factors, SMRT and ACTR. Histone deacetylase inhibitor, Trichostatin A (TSA), in combination with RA can overcome the dominant negative activity of the mutant PML-RARalpha in R4 and relieve transcriptional inhibition on RAREs. Further, TSA potentiates and partially restores RA-induced differentiation of NB4 and R4 cells respectively. When we examined the interaction of specific cofactors with retinoid receptors in NB4 cells compared to that in RA-resistant cell lines, we isolated the DRIP/TRAP protein complex. The ligand-inducible interaction between the DRIP/TRAP complex and retinoid receptors is independent of RA sensitivity and the expression of PML-RARalpha, supporting the gl

Research on deep exploiting technology of power transformer load capacity

Exploiting the load capacity of operating transformers is an important measure to ensure the safe operation of the power grid under emergency load conditions. Based on the typical methods for top oil temperature measurement and hot-spot temperature measurement， this paper proposes an optimal measurement of R×K2 and gr for special transformers to exert the original load capacity of the transformer still further. Meanwhile， to improve the cooling capacity of transformers， a series of solutions including installing extra fans， replacing low-speed fans， and frequency conversion of power supply for fans. Thus， the load capacity of the operating transformers is improved. The paper analyzes the transformers’ safety risks during the high-load operating condition， and proposes a new safety management method based on the online monitoring of oil levels and combustible gas， providing technical support for ensuring the high-load operation safety of transformers

ERAP140, a Conserved Tissue-Specific Nuclear Receptor Coactivator

We report here the identification and characterization of a novel nuclear receptor coactivator, ERAP140. ERAP140 was isolated in a screen for ERα-interacting proteins using the ERα ligand binding domain as a probe. The ERAP140 protein shares no sequence and has little structural homology with other nuclear receptor cofactors. However, homologues of ERAP140 have been identified in mouse, Drosophila, and Caenorhabditis elegans. The expression of ERAP140 is cell and tissue type specific and is most abundant in the brain, where its expression is restricted to neurons. In addition to interacting with ERα, ERAP140 also binds ERβ, TRβ, PPARγ, and RARα. ERAP140 interacts with ERα via a noncanonical interaction motif. The ERα-ERAP140 association can be competed by coactivator NR boxes, indicating ERAP140 binds ERα on a surface similar to that of other coactivators. ERAP140 can enhance the transcriptional activities of nuclear receptors with which it interacts. In vivo, ERAP140 is recruited by estrogen-bound ERα to the promoter region of endogenous ERα target genes. Furthermore, the E(2)-induced recruitment of ERAP140 to the promoter follows a cyclic pattern similar to that of other coactivators. Our results suggest that ERAP140 represents a distinct class of nuclear receptor coactivators that mediates receptor signaling in specific target tissues