Time transfer by IRIG-B time code via dedicated telephone link

Measurements were made of the stability of time transfer by the IRIG-B code over a dedicated telephone link on a microwave system. The short and long term Allan Variance was measured on both types of microwave system, one of which is synchronized, the other having free local oscillators. The results promise a time transfer accuracy of 10 microns. The paper also describes a prototype slave clock designed to detect interference in the IRIG-B code to ensure local time is kept during such interference

Polarization of Broad Absorption Line QSOs I. A Spectropolarimetric Atlas

We present a spectropolarimetric survey of 36 broad absorption line quasi-stellar objects (BAL QSOs). The continuum, absorption trough, and emission line polarization of BAL QSOs yield clues about their structure. We confirm that BAL QSOs are in general more highly polarized than non-BAL QSOs, consistent with a more equatorial viewing direction for the former than the latter. We have identified two new highly-polarized QSOs in our sample (1232+1325 and 1333+2840). The polarization rises weakly to the blue in most objects, perhaps due to scattering and absorption by dust particles. We find that a polarization increase in the BAL troughs is a general property of polarized BAL QSOs, indicating an excess of scattered light relative to direct light, and consistent with the unification of BAL QSOs and non-BAL QSOs. We have also discovered evidence of resonantly scattered photons in the red wing of the C IV broad emission lines of a few objects. In most cases, the broad emission lines have lower polarization and a different position angle than the continuum. The polarization characteristics of low-ionization BAL QSOs are similar to those of high-ionization BAL QSOs, suggesting a similar BAL wind geometry.Comment: 39 pages, 6 figures (20 .gif files), accepted for publication in The Astrophysical Journal Supplement

Epigenetic aspects of genotoxic and non-genotoxic hepatocarcinogenesis: Studies in rodents

Hepatocellular carcinoma, which is one of the most prevalent life-threatening human cancers, is showing an increased incidence worldwide. Recent evidence indicates that the development of hepatocellular carcinoma is associated with not only genetic alterations, but also with profound epigenetic changes. This review summarizes the current knowledge about epigenetic alterations during rodent hepatocarcinogenesis, considers the similarities and differences in epigenetic effects of genotoxic and non-genotoxic rodent liver carcinogens, and discusses the possible role of these effects in the causality of liver tumor development

The masses of the millisecond pulsar J1012+5307 and its white-dwarf companion

We report on spectroscopy of the white-dwarf companion of the millisecond radio pulsar PSR J1012+5307. We find strong Balmer absorption lines, as would be expected for a cool DA white dwarf. The profiles are much narrower than usual, however, and lines are seen up to H12, indicating that the companion has a low gravity and hence a low mass. This is consistent with the expectation---based on evolutionary considerations and on the mass function---that it is a low-mass white dwarf with a helium core. By comparing the spectra to model atmospheres, we derive an effective temperature $T_{\rm{}eff}=8550\pm25\,$K and a surface gravity $\log{}g=6.75\pm0.07$ (cgs units). Using the Hamada-Salpeter mass-radius relation for helium white dwarfs, with an approximate correction for finite-temperature effects, we infer a mass \mwd=0.16\pm0.02\,\msun. This is the lowest mass among all spectroscopically identified white dwarfs. We determine radial velocities from our spectra, and find a radial-velocity amplitude of 280\pm15\,\kms. With the pulsar's radial-velocity amplitude, the mass ratio \mpsr/\mwd=13.3\pm0.7. From all constraints, we find that with 95\% confidence 1.5<\mpsr/\msun<3.2.Comment: 6 pages of text and figures. Refereed version, resubmitted to ApJL. Needs aas2pp4.sty, epsf.st

Chronic administration of ethanol leads to an increased incidence of hepatocellular adenoma by promoting H-ras-mutated cells

This study used tissue samples from male B6C3F1 mice treated with ethanol in drinking water (0, 2.5, or 5%) for 4 or 104 weeks. We tested whether chronic alcohol drinking promotes oxidative stress in the liver and characterized the mutation profile of spontaneous and ethanol-induced tumors. We show that ethanol does not cause detectable oxidative stress in the liver at any time point and acts by promoting H-ras mutated cells

Gene Expression and DNA Methylation Alterations During Non-alcoholic Steatohepatitis-Associated Liver Carcinogenesis

Hepatocellular carcinoma (HCC) is one of the most aggressive human cancers. HCC is characterized by an acquisition of multiple abnormal phenotypes driven by genetic and epigenetic alterations, especially abnormal DNA methylation. Most of the existing clinical and experimental reports provide only a snapshot of abnormal DNA methylation patterns in HCC rather than their dynamic changes. This makes it difficult to elucidate the significance of these changes in the development of HCC. In the present study, we investigated hepatic gene expression and gene-specific DNA methylation alterations in mice using the Stelic Animal Model (STAM) of non-alcoholic steatohepatitis (NASH)-derived liver carcinogenesis. Analysis of the DNA methylation status in aberrantly expressed epigenetically regulated genes showed the accumulation of DNA methylation abnormalities during the development of HCC, with the greatest number of aberrantly methylated genes being found in full-fledged HCC. Among these genes, only one gene, tubulin, beta 2B class IIB (Tubb2b), was increasingly hypomethylated and over-expressed during the progression of the carcinogenic process. Furthermore, the TUBB2B gene was also over-expressed and hypomethylated in poorly differentiated human HepG2 cells as compared to well-differentiated HepaRG cells. The results of this study indicate that unique gene-expression alterations mediated by aberrant DNA methylation of selective genes may contribute to the development of HCC and may have diagnostic value as the disease-specific indicator

Activation pathway to amino acid adducts

Funding: This work was supported in part by Fundação para a Ciência e a Tecnologia (FCT), Portugal (PTDC/QUI-QUI/113910/2009, RECI/QEQ-MED/0330/2012, UID/QUI/00100/2013 and IF/ 01091/2013/CP1163/CT0001), and by Interagency Agreement Y1ES1027 between the National Center for Toxicological Research/Food and Drug Administration and the National Institute of Environmental Health Sciences/National Toxicology Program. The opinions expressed in this paper do not necessarily represent those of the U.S. Food and Drug Administration. RW, ALG, ILM and SGH thank FCT for postdoctoral and doctoral fellowships (SFRH/BPD/70953/2010, SFRH/BD/72301/2010, SFRH/BD/75426/2010 and SFRH/BD/ 80690/2011, respectively). AMM also acknowledges Programa Operacional Potencial Humano from FCT and the European Social Fund (IF/01091/2013), and the LRI Innovative Science Award. We thank the Portuguese NMR and MS networks (IST nodes) for providing access to the facilities.Nevirapine (NVP) is the non-nucleoside HIV-1 reverse transcriptase inhibitor most commonly used in developing countries, both as a component of combined antiretroviral therapy and to prevent mother-to-child transmission of the virus; however, severe hepatotoxicity and serious adverse cutaneous effects raise concerns about its safety. NVP metabolism yields several phenolic derivatives conceivably capable of undergoing further metabolic oxidation to electrophilic quinoid derivatives prone to react with bionucleophiles and initiate toxic responses. We investigated the ability of two phenolic NVP metabolites, 2-hydroxy-NVP and 3-hydroxy-NVP, to undergo oxidation and subsequent reaction with bionucleophiles. Both metabolites yielded the same ring-contraction product upon oxidation with Frémy's salt in aqueous medium. This is consistent with the formation of a 2,3-NVP-quinone intermediate, which upon stabilization by reduction was fully characterized by mass spectrometry and nuclear magnetic resonance spectroscopy. Additionally, we established that the oxidative activation of 2-hydroxy-NVP involved the transient formation of both the quinone and a quinone-imine, whereas 3-hydroxy-NVP was selectively converted into 2,3-NVP-quinone. The oxidations of 2-hydroxy-NVP and 3-hydroxy-NVP in the presence of the model amino acids ethyl valinate (to mimic the highly reactive N-terminal valine of hemoglobin) and N-acetylcysteine were also investigated. Ethyl valinate reacted with both 2,3-NVP-quinone and NVP-quinone-imine, yielding covalent adducts. By contrast, neither 2,3-NVP-quinone nor NVP-derived quinone-imine reacted with N-acetylcysteine. The product profile observed upon Frémy's salt oxidation of 2-hydroxy-NVP in the presence of ethyl valinate was replicated with myeloperoxidase-mediated oxidation. Additionally, tyrosinase-mediated oxidations selectively yielded 2,3-NVP-quinone-derived products, while quinone-imine-derived products were obtained upon lactoperoxidase catalysis. These observations suggest that the metabolic conversion of phenolic NVP metabolites into quinoid electrophiles is biologically plausible. Moreover, the lack of reaction with sulfhydryl groups might hamper the in vivo detoxification of NVP-derived quinone and quinone-imine metabolites via glutathione conjugation. As a result, these metabolites could be available for reaction with nitrogen-based bionucleophiles (e.g., lysine residues of proteins) ultimately eliciting toxic events.publishersversionpublishe

Difference in expression of hepatic microRNAs miR-29c, miR-34a, miR-155 and miR-200b is associated with strain-specific susceptibility to dietary nonalcoholic steatohepatitis in mice

The importance of dysregulation of microRNA (miRNA) expression in nonalcoholic steatohepatitis (NASH) has been increasingly recognized; however, the association between altered expression of miRNAs and pathophysiological features of NASH and whether or not there is a connection between susceptibility to NASH and altered expression of miRNAs are largely unknown. In the present study, male inbred C57BL/6J and DBA/2J mice were fed a lipogenic methyl-deficient diet that causes liver injury similar to human NASH, and the expression of miRNAs and the level of proteins targeted by these miRNAs in the livers were determined. The administration of the methyl-deficient diet triggered NASH-specific changes in the livers of C57BL/6J and DBA/2J mice with a magnitude being more severe in DBA/2J mice. This was evidenced by a greater extent of expression of fibrosis-related genes in the livers of methyl-deficient DBA/2J mice. The development of NASH was accompanied by prominent changes in the expression of miRNAs, including miR-29c, miR-34a, miR-155, and miR-200b. Interestingly, changes in the expression of these miRNAs and protein levels of their targets, including Cebp-β, Socs 1, Zeb-1, and E-cadherin, in the livers of DBA/2J mice fed a methyl-deficient diet were more pronounced as compared to the C57BL/6J mice. These results demonstrate that alterations in expression of miRNAs are a prominent event during development of NASH induced by methyl deficiency and strongly suggest that severity of NASH and susceptibility to NASH may be determined by variations in miRNA expression response. More importantly, our data provide a mechanistic link between alterations in miRNA expression and pathophysiological and pathomorphological features of NASH