From Marx to Gramsci to us: Laboratory to prison, and back

Marx and Gramsci remain two of the most constant presences and inspirations for those on the left. Yet there is a persistent sense that we have still to get them right. Perhaps this indicates that sources like this are now fully classics, to be returned, and returned to. In the case of Marx and Gramsci, a series of major works published in the Brill Historical Materialism series breaks new ground as well as returning to older controversies, both resolved and unresolved. Apart from remaining arguments concerning the status of materials unpublished in their own lifetimes, the major tension that emerges here is that between the task of immanent, contextual philology and the challenge of reading ‘Marx for today’ or ‘Gramsci for today’. The tension between text and context, and the question of what travels, conceptually persists

Extracting Gene Networks for Low-Dose Radiation Using Graph Theoretical Algorithms

Genes with common functions often exhibit correlated expression levels, which can be used to identify sets of interacting genes from microarray data. Microarrays typically measure expression across genomic space, creating a massive matrix of co-expression that must be mined to extract only the most relevant gene interactions. We describe a graph theoretical approach to extracting co-expressed sets of genes, based on the computation of cliques. Unlike the results of traditional clustering algorithms, cliques are not disjoint and allow genes to be assigned to multiple sets of interacting partners, consistent with biological reality. A graph is created by thresholding the correlation matrix to include only the correlations most likely to signify functional relationships. Cliques computed from the graph correspond to sets of genes for which significant edges are present between all members of the set, representing potential members of common or interacting pathways. Clique membership can be used to infer function about poorly annotated genes, based on the known functions of better-annotated genes with which they share clique membership (i.e., “guilt-by-association”). We illustrate our method by applying it to microarray data collected from the spleens of mice exposed to low-dose ionizing radiation. Differential analysis is used to identify sets of genes whose interactions are impacted by radiation exposure. The correlation graph is also queried independently of clique to extract edges that are impacted by radiation. We present several examples of multiple gene interactions that are altered by radiation exposure and thus represent potential molecular pathways that mediate the radiation response

Targeting NAD+ Metabolism to Enhance Radiation Therapy Responses

Nicotinamide adenine dinucleotide (NAD+) metabolism is integrally connected with the mechanisms of action of radiation therapy and is altered in many radiation-resistant tumors. This makes NAD+ metabolism an ideal target for therapies that increase radiation sensitivity and improve patient outcomes. This review provides an overview of NAD+ metabolism in the context of the cellular response to ionizing radiation, as well as current therapies that target NAD+ metabolism to enhance radiation therapy responses. Additionally, we summarize state-of-the-art methods for measuring, modeling, and manipulating NAD+ metabolism, which are being used to identify novel targets in the NAD+ metabolic network for therapeutic interventions in combination with radiation therapy

Oncogene advance online publication

Inadvertent mammalian tissue exposures to low doses of ionizing radiation (IR) after radiation accidents, remediation of radioactive-contaminated areas, space travel or a dirty bomb represent an interesting trauma to an organism. Possible low-dose IR-induced bystander effects could impact our evaluation of human health effects, as cells within tissue are not equally damaged after doses of IR p10 cGy. To understand tissue responses after low IR doses, we generated a reporter system using the human clusterin promoter fused to firefly luciferase (hCLUp-Luc). Secretory clusterin (sCLU), an extracellular molecular chaperone, induced by low doses of cytotoxic agents, clears cell debris. Low-dose IR (X2 cGy) exposure induced hCLUp-Luc activity with peak levels at 96 h, consistent with endogenous sCLU levels. As doses increased (X1 Gy), sCLU induction amplitudes increased and time-to-peak response decreased. sCLU expression was stimulated by insulin-like growth factor-1, but suppressed by p53. Responses in transgenic hCLUp-Luc reporter mice after low IR doses showed that specific tissues (that is, colon, spleen, mammary, thymus and bone marrow) of female mice induced hCLUp-Luc activity more than male mice after whole body (X10 cGy) irradiation. Tissue-specific, non-linear dose-and time-responses of hCLUp-Luc and endogenous sCLU levels were noted. Colon maintained homeostatic balance after 10 cGy. Bone marrow responded with delayed, but prolonged and elevated expression. Intraperitoneal administration of a-transforming growth factor (TGF)b1 (1D11), but not control (13C4) antibodies, immediately following IR exposure abrogated CLU induction responses. Induction in vivo also correlated with Smad signaling by activated TGFb1 after IR. Mechanistically, media with elevated sCLU levels suppressed signaling, blocked apoptosis and increased survival of TGFb1-exposed tumor or normal cells. Thus, sCLU is a pro-survival bystander factor that abrogates TGFb1 signaling and most likely promotes wound healing

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

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

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