Radiation Quality Effects on Transcriptome Profiles in 3-d Cultures After Particle Irradiation

In this work, we evaluate the differential effects of low- and high-LET radiation on 3-D organotypic cultures in order to investigate radiation quality impacts on gene expression and cellular responses. Reducing uncertainties in current risk models requires new knowledge on the fundamental differences in biological responses (the so-called radiation quality effects) triggered by heavy ion particle radiation versus low-LET radiation associated with Earth-based exposures. We are utilizing novel 3-D organotypic human tissue models that provide a format for study of human cells within a realistic tissue framework, thereby bridging the gap between 2-D monolayer culture and animal models for risk extrapolation to humans. To identify biological pathway signatures unique to heavy ion particle exposure, functional gene set enrichment analysis (GSEA) was used with whole transcriptome profiling. GSEA has been used extensively as a method to garner biological information in a variety of model systems but has not been commonly used to analyze radiation effects. It is a powerful approach for assessing the functional significance of radiation quality-dependent changes from datasets where the changes are subtle but broad, and where single gene based analysis using rankings of fold-change may not reveal important biological information. We identified 45 statistically significant gene sets at 0.05 q-value cutoff, including 14 gene sets common to gamma and titanium irradiation, 19 gene sets specific to gamma irradiation, and 12 titanium-specific gene sets. Common gene sets largely align with DNA damage, cell cycle, early immune response, and inflammatory cytokine pathway activation. The top gene set enriched for the gamma- and titanium-irradiated samples involved KRAS pathway activation and genes activated in TNF-treated cells, respectively. Another difference noted for the high-LET samples was an apparent enrichment in gene sets involved in cycle cycle/mitotic control. It is plausible that the enrichment in these particular pathways results from the complex DNA damage resulting from high-LET exposure where repair processes are not completed during the same time scale as the less complex damage resulting from low-LET radiation

Methane selective oxidation on metal oxide catalysts at low temperatures with O₂ using an NO/NO₂ oxygen atom shuttle

Methane oxidation using O2 over transition metal oxides often requires severe conditions ( >500 °C) to achieve detectable conversion. In this study, NO was used to transfer oxygen atoms from O2, through the facile gas-phase formation of NO2 at moderate conditions (0.1 MPa and 300–400 °C), to oxidize methane over silica-supported transition metal oxides (VOx, CrOx, MnOx, NbOx, MoOx, and WOx). In situ infrared spectroscopy measurements indicated that the reaction likely proceeded by the formation of surface monodentate nitrate intermediates. These nitrate species were formed by the interaction between adsorbed NO2 and the supported metal oxides. During the reaction, the oxides of vanadium, molybdenum, and tungsten formed formaldehyde and CO2, whereas the oxides of chromium, manganese, and niobium produced only CO2. These results are consistent with the known hydrocarbon oxidation chemistry of the metal oxides. Contact time measurements on VOx/SiO2 indicated that formaldehyde was a primary product and CO2 was the final product; conversely, analogous measurements on MnOx/SiO2 showed that CO2 was the sole product. The formaldehyde production rate on VOx/SiO2, MoOx/SiO2, and WOx/SiO2, based on surface sites measured by high temperature oxygen chemisorption, compared favorably to oxygenate production rates for stronger oxidants (N2O and H2O2) reported in the literature

Advanced Measurement and Modeling Techniques for Improved SOFC Cathodes

The goal of this project was to develop an improved understanding of factors governing performance and degradation of mixed-conducting SOFC cathodes. Two new diagnostic tools were developed to help achieve this goal: (1) microelectrode half-cells for improved isolation of cathode impedance on thin electrolytes, and (2) nonlinear electrochemical impedance spectroscopy (NLEIS), a variant of traditional impedance that allows workers to probe nonlinear rates as a function of frequency. After reporting on the development and efficacy of these tools, this document reports on the use of these and other tools to better understand performance and degradation of cathodes based on the mixed conductor La{sub 1-x}Sr{sub x}CoO{sub 3-{delta}} (LSC) on gadolinia or samaria-doped ceria (GDC or SDC). We describe the use of NLEIS to measure O{sub 2} exchange on thin-film LSC electrodes, and show that O{sub 2} exchange is most likely governed by dissociative adsorption. We also describe parametric studies of porous LSC electrodes using impedance and NLEIS. Our results suggest that O{sub 2} exchange and ion transport co-limit performance under most relevant conditions, but it is O{sub 2} exchange that is most sensitive to processing, and subject to the greatest degradation and sample-to-sample variation. We recommend further work that focuses on electrodes of well-defined or characterized geometry, and probes the details of surface structure, composition, and impurities. Parallel work on primarily electronic conductors (LSM) would also be of benefit to developers, and to improved understanding of surface vs. bulk diffusion

Creation and luminescence of size-selected gold nanorods

Fluorescent metal nanoparticles have attracted great interest in recent years for their unique properties and potential applications. Their optical behaviour depends not only on size but also on shape, and will only be useful if the morphology is stable. In this work, we produce stable size-selected gold nanorods (aspect ratio 1-2) using a size-selected cluster source and correlate their luminescence behaviour with the particle shape. Thermodynamic modelling is used to predict the preferred aspect ratio of 1.5, in agreement with the observations, and confirms that the double-icosahedron observed in experiments is significantly lower in energy than the alternatives. Using these samples a fluorescence lifetime imaging microscopy study observed two photon luminescence from nanoparticle arrays and a fast decay process (<100 ps luminescence lifetime), which are similar to those found from ligand stabilized gold nanorods under the same measurement conditions, indicating that a surface plasmon enhanced two-photon excitation process is still active at these small sizes. By further reducing the nanoparticle size, this approach has the potential to investigate size-dependent luminescence behaviour at smaller sizes than has been possible before

Abrupt boundaries of intermediate phases and space filling in oxide glasses

Modulated DSC measurements on bulk (Na2O)x(GeO2)1-x glasses show a sharp reversibility window in the 14% < x < 19% soda range, which correlates well with a broad global minimum in molar volumes. Raman and IR reflectance TO and LO mode frequencies exhibit anomalies between xc(1) = 14% (stress transition) and xc(2) = 19% (rigidity transition), with optical elasticity power-laws confirming the nature of the transitions . Birefringence measurements dramatize the macroscopically stress-free nature of the Intermediate Phase in the reversibility window

Muonium Decay

Modifications of the mu+ lifetime in matter due to muonium (M = mu+ e-) formation and other medium effects are examined. Muonium and free mu+ decay spectra are found to differ at O(alpha m_e/m_mu) from Doppler broadening and O(alpha^2 m_e/m_mu) from the Coulomb bound state potential. However, both types of corrections are shown to cancel in the total decay rate due to Lorentz and gauge invariance respectively, leaving a very small time dilation lifetime difference, (tau_M - tau_mu+)/tau_mu+ = alpha^2 m_e^2/ 2m_mu^2 \simeq 6\times 10^-10, as the dominant bound state effect. It is argued that other medium effects on the stopped mu+ lifetime are similarly suppressed.Comment: 14 pages, revte

PEG Branched Polymer for Functionalization of Nanomaterials with Ultralong Blood Circulation

Nanomaterials have been actively pursued for biological and medical applications in recent years. Here, we report the synthesis of several new poly(ethylene glycol) grafted branched-polymers for functionalization of various nanomaterials including carbon nanotubes, gold nanoparticles (NP) and gold nanorods (NRs), affording high aqueous solubility and stability for these materials. We synthesize different surfactant polymers based upon poly-(g-glutamic acid) (gPGA) and poly(maleic anhydride-alt-1-octadecene) (PMHC18). We use the abundant free carboxylic acid groups of gPGA for attaching lipophilic species such as pyrene or phospholipid, which bind to nanomaterials via robust physisorption. Additionally, the remaining carboxylic acids on gPGA or the amine-reactive anhydrides of PMHC18 are then PEGylated, providing extended hydrophilic groups, affording polymeric amphiphiles. We show that single-walled carbon nanotubes (SWNTs), Au NPs and NRs functionalized by the polymers exhibit high stability in aqueous solutions at different pHs, at elevated temperatures and in serum. Morever, the polymer-coated SWNTs exhibit remarkably long blood circulation (t1/2 22.1 h) upon intravenous injection into mice, far exceeding the previous record of 5.4 h. The ultra-long blood circulation time suggests greatly delayed clearance of nanomaterials by the reticuloendothelial system (RES) of mice, a highly desired property for in vivo applications of nanomaterials, including imaging and drug delivery

Baylisascaris procyonis in the Metropolitan Atlanta Area

Baylisascaris procyonis, the raccoon roundworm responsible for fatal larva migrans in humans, has long been thought to be absent from many regions in the southeastern United States. During spring 2002, 11 (22%) of 50 raccoons trapped in DeKalb County, Georgia, had B. procyonis infection. The increasing number of cases highlight this emerging zoonotic infection

Peroxisome proliferator-activated receptor δ agonist GW1516 attenuates diet-induced aortic inflammation, insulin resistance, and atherosclerosis in low-density lipoprotein receptor knockout mice

OBJECTIVE - The peroxisome proliferator-activated receptor (PPAR) δ regulates systemic lipid homeostasis and inflammation. However, the ability of PPARδ agonists to improve the pathology of pre-established lesions and whether PPARδ activation is atheroprotective in the setting of insulin resistance have not been reported. Here, we examine whether intervention with a selective PPARδ agonist corrects metabolic dysregulation and attenuates aortic inflammation and atherosclerosis. APPROACH AND RESULTS - Low-density lipoprotein receptor knockout mice were fed a chow or a high-fat, high-cholesterol (HFHC) diet (42% fat, 0.2% cholesterol) for 4 weeks. For a further 8 weeks, the HFHC group was fed either HFHC or HFHC plus GW1516 (3 mg/kg per day). GW1516 significantly attenuated pre-established fasting hyperlipidemia, hyperglycemia, and hyperinsulinemia, as well as glucose and insulin intolerance. GW1516 intervention markedly reduced aortic sinus lesions and lesion macrophages, whereas smooth muscle α-actin was unchanged and collagen deposition enhanced. In aortae, GW1516 increased the expression of the PPARδ-specific gene Adfp but not PPARα- or γ-specific genes. GW1516 intervention decreased the expression of aortic proinflammatory M1 cytokines, increased the expression of the anti-inflammatory M2 cytokine Arg1, and attenuated the iNos/Arg1 ratio. Enhanced mitogen-activated protein kinase signaling, known to induce inflammatory cytokine expression in vitro, was enhanced in aortae of HFHC-fed mice. Furthermore, the HFHC diet impaired aortic insulin signaling through Akt and forkhead box O1, which was associated with elevated endoplasmic reticulum stress markers CCAAT-enhancer-binding protein homologous protein and 78kDa glucose regulated protein. GW1516 intervention normalized mitogen-activated protein kinase activation, insulin signaling, and endoplasmic reticulum stress. CONCLUSIONS - Intervention with a PPARδ agonist inhibits aortic inflammation and attenuates the progression of pre-established atherosclerosis. © 2013 American Heart Association, Inc

Membrane-targeting potentiates guanine nucleotide exchange factor CDC25 and SOS1 activation of Ras transforming activity.

Growth factor-triggered activation of Ras proteins is believed to be mediated by guanine nucleotide exchange factors (CDC25/GRF and SOS1/2) that promote formation of the active Ras GTP-bound state. Although the mechanism(s) of guanine nucleotide exchange factor regulation is unclear, recent studies suggest that translocation of SOS1 to the plasma membrane, where Ras is located, might be responsible for Ras activation. To evaluate this model, we generated constructs that encode the catalytic domains of human CDC25 or mouse SOS1, either alone (designated cCDC25 and cSOS1, respectively) or terminating in the carboxyl-terminal CAAX membrane-targeting sequence from K-Ras4B (designated cCDC25-CAAX and cSOS1-CAAX, respectively; in CAAX, C is Cys, A is an aliphatic amino acid, and X is Ser or Met). We then compared the transforming potential of cCDC25 and cSOS1 with their membrane-targeted counterparts. We observed that addition of the Ras plasma membrane-targeting sequence to the catalytic domains of CDC25 and SOS1 greatly enhanced their focus-forming activity (10- to 50-fold) in NIH 3T3 transfection assays. Similarly, we observed that the membrane-targeted versions showed a 5- to 10-fold enhanced ability to induce transcriptional activation from the Ets/AP-1 Ras-responsive element. Furthermore, whereas cells that stably expressed cCDC25 or cSOS1 exhibited the same morphologies as untransformed NIH 3T3 cells, cells expressing cCDC25-CAAX or cSOS1-CAAX displayed transformed morphologies that were indistinguishable from the elongated and refractile morphology of oncogenic Ras-transformed cells. Thus, these results suggest that membrane translocation alone is sufficient to potentiate guanine nucleotide exchange factor activation of Ras