Clustered DNA damage on subcellular level: effect of scavengers

Clustered DNA damages are induced by ionizing radiation, particularly of high linear energy transfer (LET). Compared to isolated DNA damage sites, their biological effects can be more severe. We investigated a clustered DNA damage induced by high LET radiation (C 290 MeV u(-1) and Fe 500 MeV u(-1)) in pBR322 plasmid DNA. The plasmid is dissolved in pure water or in aqueous solution of one of the three scavengers (coumarin-3-carboxylic acid, dimethylsulfoxide, and glycylglycine). The yield of double strand breaks (DSB) induced in the DNA plasmid-scavenger system by heavy ion radiation was found to decrease with increasing scavenging capacity due to reaction with hydroxyl radical, linearly with high correlation coefficients. The yield of non-DSB clusters was found to occur twice as much as the DSB. Their decrease with increasing scavenging capacity had lower linear correlation coefficients. This indicates that the yield of non-DSB clusters depends on more factors, which are likely connected to the chemical properties of individual scavengers

Differential interaction of estrogen receptor and thyroid hormone receptor isoforms on the rat oxytocin receptor promoter leads to differences in transcriptional regulation

Both the estrogen receptor (ER) and thyroid hormone receptor (TR) are members of the nuclear receptor superfamily. Two isoforms of the ER, alpha and beta, exist. The TRalpha and beta isoforms are products of two distinct genes that are further differentially spliced to give TRalpha1 and alpha2, TRbeta1 and beta2. The TRs have been shown to interfere with ER-mediated transcription from both the consensus estrogen response element (ERE) and the rat preproenkephalin (PPE) promoter, possibly by competing with ER binding to the ERE or by squelching coactivators essential for ER-mediated transcription. The rat oxytocin receptor (OTR) gene is thought to be involved in several facets of reproductive and affiliative behaviors. 17beta-Estradiol-bound ERs upregulate the OTR gene in the ventromedial hypothalamus, a region critical for the induction of lordosis behavior in several species. We investigated the effects of the ligand-binding TR isoforms on the ER-mediated transcription from a physiological promoter of a behaviorally relevant gene such as the OTR. Only ERalpha could induce the OTR gene in two cell lines tested, the CV-1 and the SK-N-BE2C neuroblastoma cell lines. ERbeta was incapable of inducing the gene in either cell line. ERalpha is therefore not equivalent to ERbeta on this physiological promoter. Indeed, in the neural cell line, ERbeta can inhibit ERalpha-mediated induction from the OTR promoter. While the TRalpha1 isoform inhibited ERalpha-mediated induction in the neural cell line, the TRbeta1 isoform stimulated induction, thus demonstrating isoform specificity in the interaction. The use of a DNA-binding mutant, the TR P box mutant, showed that inhibition of ERalpha-mediated induction of the rat OTR gene promoter by the TRalpha1 isoform does not require DNA-binding ability. SRC-1 overexpression relieved TRalpha1-mediated inhibition in both cell lines, suggesting that squelching for coactivators is an important molecular mechanism in TRalpha-mediated inhibition. Such interactions between TR and ER isoforms on the rat OTR promoter provide a mechanism to achieve neuroendocrine integration

Mitral annular systolic velocity as a marker of preclinical systolic dysfunction among patients with arterial hypertension

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to investigate early changes in left ventricular longitudinal systolic function in patients with hypertension (HTN) with and without concomitant diastolic dysfunction (DD) and the clinical implications of these findings.</p> <p>Method</p> <p>We enrolled 299 patients with HTN and 297 age-matched patients with HTN and DD and compared both groups with an age-matched control group consisting of 100 healthy subjects. The long axis systolic function was investigated by determining the average peak systolic velocity of the septal and lateral mitral sites (Sm_avg) using spectral pulsed wave tissue Doppler imaging (TDI).</p> <p>Results</p> <p>We found a strong negative trend toward the reduction of velocity, which is dependent on the grade of HTN, on the magnitude of DD, and also on the gender and age of the subjects (r=−0.891/-0.580; p<0.0001). The data showed that the beginning and evolution of HTN are related to a slight but significant reduction in the long axis systolic function (10.2-10.0 cm/s; p<0.0001), and DD worsens this initial finding (9.8-8.8 cm/s; p<0.0001).</p> <p>Conclusion</p> <p>The strength of the study is the analysis of incremental changes in longitudinal contraction in patients with different stage of HTN but not so many the classification of the degree of systolic dysfunction. The importance of our results lies in the fact that these initial changes in systolic contraction could be used as an early sign that should prompt optimization of the treatment of HTN.</p

Simulating radial dose of ion tracks in liquid water simulated with Geant4-DNA: A comparative study

An accurate modeling of radial energy deposition around ion tracks is a key requirement of radiation transport software used for simulations in radiobiology at the sub-cellular scale. The work presented in this paper is part of the on-going benchmarking of the "Geant4-DNA" physics processes and models, which are available in the Geant4 Monte Carlo simulation toolkit for the low energy transport of particles in liquid water. We present for the first time radial dose distributions of incident ion tracks simulated with "Geant4-DNA". Simulation results are compared to other results available in the literature, obtained from analytical calculations, step-by-step Monte Carlo simulations and measurements. They show a reasonable agreement with reference data. © 2014 Elsevier B.V. All rights reserved