RMI1 is Essential for Early Embryonic Development and Attenuation of Tumor Development

RMI1 (BLM-Associated Protein 75 or Blap75) is highly conserved from yeast to human. Previous studies have shown that hRMI1 is required for BLM/TopoIIIα/RMI1 complex stability and function. However, in vivo functions of RMI1 remain elusive. To address this question, I generated RMI1 knockout mice by homologous replacement targeting. While RMI1+/- mice showed no obvious phenotype, deletion of both RMI1 alleles leads to early embryonic lethality before implantation. I then generated RMI1/p53 double knockout mice. After ionizing radiation treatment at 4Gy, RMI1/p53 double-heterzygous mice showed shortened tumor latency and aggressive tumor types when comparing with wild type, RMI1+/- and p53+/- control cohorts. My study suggests a dual-functional role of RMI1 in early embryonic development and tumor suppression.

Attenuation of fibrosis in vitro and in vivo with SPARC siRNA.

INTRODUCTION: SPARC is a matricellular protein, which, along with other extracellular matrix components including collagens, is commonly over-expressed in fibrotic diseases. The purpose of this study was to examine whether inhibition of SPARC can regulate collagen expression in vitro and in vivo, and subsequently attenuate fibrotic stimulation by bleomycin in mouse skin and lungs. METHODS: In in vitro studies, skin fibroblasts obtained from a Tgfbr1 knock-in mouse (TBR1CA; Cre-ER) were transfected with SPARC siRNA. Gene and protein expressions of the Col1a2 and the Ctgf were examined by real-time RT-PCR and Western blotting, respectively. In in vivo studies, C57BL/6 mice were induced for skin and lung fibrosis by bleomycin and followed by SPARC siRNA treatment through subcutaneous injection and intratracheal instillation, respectively. The pathological changes of skin and lungs were assessed by hematoxylin and eosin and Masson's trichrome stains. The expression changes of collagen in the tissues were assessed by real-time RT-PCR and non-crosslinked fibrillar collagen content assays. RESULTS: SPARC siRNA significantly reduced gene and protein expression of collagen type 1 in fibroblasts obtained from the TBR1CA; Cre-ER mouse that was induced for constitutively active TGF-beta receptor I. Skin and lung fibrosis induced by bleomycin was markedly reduced by treatment with SPARC siRNA. The anti-fibrotic effect of SPARC siRNA in vivo was accompanied by an inhibition of Ctgf expression in these same tissues. CONCLUSIONS: Specific inhibition of SPARC effectively reduced fibrotic changes in vitro and in vivo. SPARC inhibition may represent a potential therapeutic approach to fibrotic diseases.

Modeling Englacial Radar Attenuation at Siple Dome, West Antarctica, Using Ice Chemistry and Temperature Data

The radar reflectivity of an ice-sheet bed is a primary measurement for discriminating between thawed and frozen beds. Uncertainty in englacial radar attenuation and its spatial variation introduces corresponding uncertainty in estimates of basal reflectivity. Radar attenuation is proportional to ice conductivity, which depends on the concentrations of acid and sea-salt chloride and the temperature of the ice. We synthesize published conductivity measurements to specify an ice-conductivity model and find that some of the dielectric properties of ice at radar frequencies are not yet well constrained. Using depth profiles of ice-core chemistry and borehole temperature and an average of the experimental values for the dielectric properties, we calculate an attenuation rate profile for Siple Dome, West Antarctica. The depth-averaged modeled attenuation rate at Siple Dome (20.0 +/- 5.7 dB km(-1)) is somewhat lower than the value derived from radar profiles (25.3 +/- 1.1 dB km(-1)). Pending more experimental data on the dielectric properties of ice, we can match the modeled and radar-derived attenuation rates by an adjustment to the value for the pure ice conductivity that is within the range of reported values. Alternatively, using the pure ice dielectric properties derived from the most extensive single data set, the modeled depth-averaged attenuation rate is 24.0 +/- 2.2 dB km(-1). This work shows how to calculate englacial radar attenuation using ice chemistry and temperature data and establishes a basis for mapping spatial variations in radar attenuation across an ice sheet.

The Forensic Reference Phantom-a new tool for quality assurance of attenuation measurements in forensic radiology

Introduction The purpose of this paper is to present the technical specifications of the Forensic Reference Phantom (FRP), to test its behavior relative to organic test materials, and discuss potential applications of the phantom in forensic radiology. Materials and method The FRP prototype is made of synthetic materials designed to simulate the computed tomography (CT) attenuation of water. It has six bore holes that accommodate multiuse containers. These containers were filled with test materials and scanned at 80 kVp, 120 kVp, and 140 kVp. X-ray attenuation was measured by two readers. Intra- and inter-reader reliability was assessed using the intra-class correlation coefficient (ICC). Significance levels between mean CT numbers at 80 kVp, 120 kVp, and 140 kVp were assessed with the Friedman-test. The T-test was used to assess significance levels between the FRP and water. Results Overall mean CT numbers ranged from −3.0–3.7HU for the FRP; −1000.3–−993.5HU for air; −157.7– −108.1HU for oil; 35.5–42.0HU for musle tissue; and 1301.5–2354.8HU for cortical bone. Inter-reader and intra-reader reliability were excellent (ICC>0.994; and ICC=0.999 respectively). CT numbers were significantly different at different energy levels. There was no significant difference between the attenuation of the FRP and water. Conclusions The FRP is a new tool for quality assurance and research in forensic radiology. The mean CT attenuation of the FRP is equivalent to water. The phantom can be scanned during routine post-mortem CT to assess the composition of unidentified objects. In addition, the FRP may be used to investigate new imaging algorithms and scan protocols in forensic radiology.

Metabolomics Reveals Aging-associated Attenuation of Noninvasive Radiation Biomarkers in Mice: Potential Role of Polyamine Catabolism and Incoherent DNA Damage-repair

Development of methods for rapid screening and stratification of subjects after exposure is an integral part of countermeasures against radiation. The potential demographic and exposure history-related heterogeneity of exposed populations warrants robust biomarkers that withstand and reflect such differences. In this study, the effect of aging and repeated exposure on the metabolic response to sublethal irradiation was examined in mice using UPLC-ESI-QTOF mass spectrometry. Aging attenuated postexposure elevation in excretions of DNA damage biomarkers as well as N(1)-acetylspermidine. Although N(1)-acetylspermidine and 2'-deoxyuridine elevation was highly correlated in all age groups, xanthine and N(1)-acetylspermidine elevation was poorly correlated in older mice. These results may reflect the established decline in DNA damage-repair efficiency associated with aging and indicate a novel role for polyamine metabolism in the process. Although repeated irradiation at long intervals did not affect the elevation of N(1)-acetylspermidine, 2'-deoxyuridine, and xanthine, it did significantly attenuate the elevation of 2'-deoxycytidine and thymidine compared to a single exposure. However, these biomarkers were found to identify exposed subjects with accuracy ranging from 82% (xanthosine) to 98% (2'-deoxyuridine), irrespective of their age and exposure history. This indicates that metabolic biomarkers can act as robust noninvasive signatures of sublethal radiation exposure.

Benchmark problems for reactive transport modeling of the generation and attenuation of acid rock drainage

Acid rock drainage (ARD) is a problem of international relevance with substantial environmental and economic implications. Reactive transport modeling has proven a powerful tool for the process-based assessment of metal release and attenuation at ARD sites. Although a variety of models has been used to investigate ARD, a systematic model intercomparison has not been conducted to date. This contribution presents such a model intercomparison involving three synthetic benchmark problems designed to evaluate model results for the most relevant processes at ARD sites. The first benchmark (ARD-B1) focuses on the oxidation of sulfide minerals in an unsaturated tailing impoundment, affected by the ingress of atmospheric oxygen. ARD-B2 extends the first problem to include pH buffering by primary mineral dissolution and secondary mineral precipitation. The third problem (ARD-B3) in addition considers the kinetic and pH-dependent dissolution of silicate minerals under low pH conditions. The set of benchmarks was solved by four reactive transport codes, namely CrunchFlow, Flotran, HP1, and MIN3P. The results comparison focused on spatial profiles of dissolved concentrations, pH and pE, pore gas composition, and mineral assemblages. In addition, results of transient profiles for selected elements and cumulative mass loadings were considered in the intercomparison. Despite substantial differences in model formulations, very good agreement was obtained between the various codes. Residual deviations between the results are analyzed and discussed in terms of their implications for capturing system evolution and long-term mass loading predictions.

Observations of the Sensitivity of Beam Attenuation to Particle Size in a Coastal Bottom Boundary Layer

The goal of this study was to test the hypothesis that the aggregated state of natural marine particles constrains the sensitivity of optical beam attenuation to particle size. An instrumented bottom tripod was deployed at the 12-m node of the Martha's Vineyard Coastal Observatory to monitor particle size distributions, particle size-versus-settling-velocity relationships, and the beam attenuation coefficient (c(p)) in the bottom boundary layer in September 2007. An automated in situ filtration system on the tripod collected 24 direct estimates of suspended particulate mass (SPM) during each of five deployments. On a sampling interval of 5 min, data from a Sequoia Scientific LISST 100x Type B were merged with data from a digital floc camera to generate suspended particle volume size distributions spanning diameters from approximately 2 mu m to 4 cm. Diameter-dependent densities were calculated from size-versus-settling-velocity data, allowing conversion of the volume size distributions to mass distributions, which were used to estimate SPM every 5 min. Estimated SPM and measured c(p) from the LISST 100x were linearly correlated throughout the experiment, despite wide variations in particle size. The slope of the line, which is the ratio of c(p) to SPM, was 0.22 g m(-2). Individual estimates of c(p):SPM were between 0.2 and 0.4 g m(-2) for volumetric median particle diameters ranging from 10 to 150 mu m. The wide range of values in c(p):SPM in the literature likely results from three factors capable of producing factor-of-two variability in the ratio: particle size, particle composition, and the finite acceptance angle of commercial beam-transmissometers.

A LAPLACE TRANSFORM PAIR MODEL TO DETERMINE BREMSSTRAHLUNG SPECTRA FROM ATTENUATION DATA (RADIATION, X-RAY, SPECTRAL MODELING)

Every x-ray attenuation curve inherently contains all the information necessary to extract the complete energy spectrum of a beam. To date, attempts to obtain accurate spectral information from attenuation data have been inadequate.^ This investigation presents a mathematical pair model, grounded in physical reality by the Laplace Transformation, to describe the attenuation of a photon beam and the corresponding bremsstrahlung spectral distribution. In addition the Laplace model has been mathematically extended to include characteristic radiation in a physically meaningful way. A method to determine the fraction of characteristic radiation in any diagnostic x-ray beam was introduced for use with the extended model.^ This work has examined the reconstructive capability of the Laplace pair model for a photon beam range of from 50 kVp to 25 MV, using both theoretical and experimental methods.^ In the diagnostic region, excellent agreement between a wide variety of experimental spectra and those reconstructed with the Laplace model was obtained when the atomic composition of the attenuators was accurately known. The model successfully reproduced a 2 MV spectrum but demonstrated difficulty in accurately reconstructing orthovoltage and 6 MV spectra. The 25 MV spectrum was successfully reconstructed although poor agreement with the spectrum obtained by Levy was found.^ The analysis of errors, performed with diagnostic energy data, demonstrated the relative insensitivity of the model to typical experimental errors and confirmed that the model can be successfully used to theoretically derive accurate spectral information from experimental attenuation data. ^