Biogeochemical Cycling of 99Tc in Alkaline Sediments

99Tc will be present in significant quantities in radioactive wastes including intermediate-level waste (ILW). The internationally favored concept for disposing of higher activity radioactive wastes including ILW is via deep geological disposal in an underground engineered facility located ∼200–1000 m deep. Typically, in the deep geological disposal environment, the subsurface will be saturated, cement will be used extensively as an engineering material, and iron will be ubiquitous. This means that understanding Tc biogeochemistry in high pH, cementitious environments is important to underpin safety case development. Here, alkaline sediment microcosms (pH 10) were incubated under anoxic conditions under “no added Fe(III)” and “with added Fe(III)” conditions (added as ferrihydrite) at three Tc concentrations (10–11, 10–6, and 10–4 mol L–1). In the 10–6 mol L–1 Tc experiments with no added Fe(III), ∼35% Tc(VII) removal occurred during bioreduction. Solvent extraction of the residual solution phase indicated that ∼75% of Tc was present as Tc(IV), potentially as colloids. In both biologically active and sterile control experiments with added Fe(III), Fe(II) formed during bioreduction and >90% Tc was removed from the solution, most likely due to abiotic reduction mediated by Fe(II). X-ray absorption spectroscopy (XAS) showed that in bioreduced sediments, Tc was present as hydrous TcO2-like phases, with some evidence for an Fe association. When reduced sediments with added Fe(III) were air oxidized, there was a significant loss of Fe(II) over 1 month (∼50%), yet this was coupled to only modest Tc remobilization (∼25%). Here, XAS analysis suggested that with air oxidation, partial incorporation of Tc(IV) into newly forming Fe oxyhydr(oxide) minerals may be occurring. These data suggest that in Fe-rich, alkaline environments, biologically mediated processes may limit Tc mobility.Peer reviewe

Retargeted adenoviruses for radiation-guided gene delivery

The combination of radiation with radiosensitizing gene delivery or oncolytic viruses promises to provide an advantage that could improve the therapeutic results for glioblastoma. X-rays can induce significant molecular changes in cancer cells. We isolated the GIRLRG peptide that binds to radiation-inducible 78 kDa glucose-regulated protein (GRP78), which is overexpressed on the plasma membranes of irradiated cancer cells and tumor-associated microvascular endothelial cells. The goal of our study was to improve tumor-specific adenovirus-mediated gene delivery by selectively targeting the adenovirus binding to this radiation-inducible protein. We employed an adenoviral fiber replacement approach to conduct a study of the targeting utility of GRP78-binding peptide. We have developed fiber-modified adenoviruses encoding the GRP78-binding peptide inserted into the fiber-fibritin. We have evaluated the reporter gene expression of fiber-modified adenoviruses in vitro using a panel of glioma cells and a human D54MG tumor xenograft model. The obtained results demonstrated that employment of the GRP78-binding peptide resulted in increased gene expression in irradiated tumors following infection with fiber-modified adenoviruses, compared with untreated tumor cells. These studies demonstrate the feasibility of adenoviral retargeting using the GRP78-binding peptide that selectively recognizes tumor cells responding to radiation treatment

Microbial interactions with phosphorus containing glasses representative of vitrified radioactive waste

The presence of phosphorus in borosilicate glass (at 0.1 – 1.3 mol% P2O5) and in iron-phosphate glass (at 53 mol% P2O5) stimulated the growth and metabolic activity of anaerobic bacteria in model systems. Dissolution of these phosphorus containing glasses was either inhibited or accelerated by microbial metabolic activity, depending on the solution chemistry and the glass composition. The breakdown of organic carbon to volatile fatty acids increased glass dissolution. The interaction of microbially reduced Fe(II) with phosphorus-containing glass under anoxic conditions decreased dissolution rates, whereas the interaction of Fe(III) with phosphorus-containing glass under oxic conditions increased glass dissolution. Phosphorus addition to borosilicate glasses did not significantly affect the microbial species present, however, the diversity of the microbial community was enhanced on the surface of the iron phosphate glass. Results demonstrate the potential for microbes to influence the geochemistry of radioactive waste disposal environments with implication for wasteform durability

Creating the cultures of the future: cultural strategy, policy and institutions in Gramsci. Part one: Gramsci and cultural policy studies: some methodological reflections

Gramsci’s writings have rarely been discussed and used systematically by scholars in cultural policy studies, despite the fact that in cultural studies, from which the field emerged, Gramsci has been a major source of theoretical concepts. Cultural policy studies were, in fact, theorised as an anti-Gramscian project between the late 1980s and the early 1990s, when a group of scholars based in Australia advocated a major political and theoretical reorientation of cultural studies away from hegemony theory and radical politicisation, and towards reformist-technocratic engagement with the policy concerns of contemporary government and business. Their criticism of the ‘Gramscian tradition’ as inadequate for the study of cultural policy and institutions has remained largely unexamined in any detail for almost twenty years and seems to have had a significant role in the subsequent neglect of Gramsci’s contribution in this area of study. This essay, consisting of three parts, is an attempt to challenge such criticism and to provide an analysis of Gramsci’s writings, with the aim of proposing a more systematic contribution of his work to the theoretical development of cultural policy studies. In Part One, I question the use of the notion of ‘Gramscian tradition’ made by its critics and challenge the claim that it was inadequate for the study of cultural policy and institutions. In parts Two and Three, I consider Gramsci’s specific writings on questions of cultural strategy, policy and institutions, which have so far been overlooked by scholars, arguing that they provide further analytical insights to those offered by his more general concepts. More specifically, in Part Two, I consider Gramsci’s pre-prison writings and political practice in relation to questions of cultural strategy and institutions. I argue that the analysis of these early texts, which were written in the years in which Gramsci was active in party organisation and leadership, is fundamental not only for understanding the nature of Gramsci’s early and continued involvement with questions of cultural strategy and institutions, but also as a key for deciphering and interpreting cultural policy themes that he later developed in the prison notebooks, and which originated in earlier debates. Finally, in Part Three, I carry out a detailed analysis of Gramsci’s prison notes on questions of cultural strategy, policy and institutions, which enrich the theoretical underpinnings for critical frameworks of analysis as well as for radical practices of cultural strategy, cultural policy-making and cultural organisation. I then answer the question of whether Gramsci’s insights amount to a theory of cultural policy

Endoplasmic Reticulum Stress-Induced JNK Activation Is a Critical Event Leading to Mitochondria-Mediated Cell Death Caused by β-Lapachone Treatment

β-lapachone (β-lap) is a bioreductive agent that is activated by the two-electron reductase NAD(P)H quinone oxidoreductase 1 (NQO1). Although β-lap has been reported to induce apoptosis in various cancer types in an NQO1-dependent manner, the signaling pathways by which β-lap causes apoptosis are poorly understood.β-lap-induced apoptosis and related molecular signaling pathways in NQO1-negative and NQO1-overexpressing MDA-MB-231 cells were investigated. Pharmacological inhibitors or siRNAs against factors involved in β-lap-induced apoptosis were used to clarify the roles played by such factors in β-lap-activated apoptotic signaling pathways. β-lap leads to clonogenic cell death and apoptosis in an NQO1- dependent manner. Treatment of NQO1-overexpressing MDA-MB-231 cells with β-lap causes rapid disruption of mitochondrial membrane potential, nuclear translocation of AIF and Endo G from mitochondria, and subsequent caspase-independent apoptotic cell death. siRNAs targeting AIF and Endo G effectively attenuate β-lap-induced clonogenic and apoptotic cell death. Moreover, β-lap induces cleavage of Bax, which accumulates in mitochondria, coinciding with the observed changes in mitochondria membrane potential. Pretreatment with Salubrinal (Sal), an endoplasmic reticulum (ER) stress inhibitor, efficiently attenuates JNK activation caused by β-lap, and subsequent mitochondria-mediated cell death. In addition, β-lap-induced generation and mitochondrial translocation of cleaved Bax are efficiently blocked by JNK inhibition.Our results indicate that β-lap triggers induction of endoplasmic reticulum (ER) stress, thereby leading to JNK activation and mitochondria-mediated apoptosis. The signaling pathways that we revealed in this study may significantly contribute to an improvement of NQO1-directed tumor therapies

XRN2 Links Transcription Termination to DNA Damage and Replication Stress

We thank the Proteomics Core Facility. We thank Dr. Robert J. Crouch for providing us with GFP- and GFP-RNase H expression plasmids. We also thank Dr. Stephen H. Leppla for providing us with antibodies directed against RNA:DNA hybrids (R loops) (S9.6). We thank Novus Biologicals for generously providing XRN2 and Rrp45 antibodies. We also thank the members of the Boothman lab for critical reading of this manuscript.Author Summary Genomic instability is one of the primary causes of disease states, in particular cancer. One major cause of genomic instability is the formation of DNA double strand breaks (DSBs), which are one of the most dangerous types of DNA lesions the cell can encounter. If not repaired in a timely manner, one DSB can lead not only to cell death. If misrepaired, one DSB can lead to a hazardous chromosomal aberration, such as a translocation, that can eventually lead to cancer. The cell encounters and repairs DSBs that arise from naturally occurring cellular processes on a daily basis. A number of studies have demonstrated that aberrant structures that form during transcription under certain circumstances, in particular RNA:DNA hybrids (R loops), can lead to DSB formation and genomic instability, especially during DNA synthesis. Thus, it is important to understand how the cell responds and repairs transcription-mediated DNA damage in general and R loop-related DNA damage in particular. This paper both demonstrates that the XRN transcription termination factor links transcription and DNA damage, but also provides a better understanding of how the cell prevents transcription-related DNA damage.Yeshttp://www.plosgenetics.org/static/editorial#pee