Response to Pervasive Sequence Patents Cover the Entire Human Genome

In a widely reported article by Jeffrey Rosenfeld and Christopher Mason published in Genome Medicine, significant misstatements were made, because the authors did not sufficiently review the claims – which define the legal scope of a patent – in the patents they analyzed. Specifically, the authors do not provide an adequate basis for their assertion that 41% of the genes in the human genome have been claimed

Critical Role of the Virus-Encoded MicroRNA-155 Ortholog in the Induction of Marek's Disease Lymphomas

Notwithstanding the well-characterised roles of a number of oncogenes in neoplastic transformation, microRNAs (miRNAs) are increasingly implicated in several human cancers. Discovery of miRNAs in several oncogenic herpesviruses such as KSHV has further highlighted the potential of virus-encoded miRNAs to contribute to their oncogenic capabilities. Nevertheless, despite the identification of several possible cancer-related genes as their targets, the direct in vivo role of virus-encoded miRNAs in neoplastic diseases such as those induced by KSHV is difficult to demonstrate in the absence of suitable models. However, excellent natural disease models of rapid-onset Marek's disease (MD) lymphomas in chickens allow examination of the oncogenic potential of virus-encoded miRNAs. Using viruses modified by reverse genetics of the infectious BAC clone of the oncogenic RB-1B strain of MDV, we show that the deletion of the six-miRNA cluster 1 from the viral genome abolished the oncogenicity of the virus. This loss of oncogenicity appeared to be primarily due to the single miRNA within the cluster, miR-M4, the ortholog of cellular miR-155, since its deletion or a 2-nucleotide mutation within its seed region was sufficient to inhibit the induction of lymphomas. The definitive role of this miR-155 ortholog in oncogenicity was further confirmed by the rescue of oncogenic phenotype by revertant viruses that expressed either the miR-M4 or the cellular homolog gga-miR-155. This is the first demonstration of the direct in vivo role of a virus-encoded miRNA in inducing tumors in a natural infection model. Furthermore, the use of viruses deleted in miRNAs as effective vaccines against virulent MDV challenge, enables the prospects of generating genetically defined attenuated vaccines

Herpesvirus Telomerase RNA(vTR)-Dependent Lymphoma Formation Does Not Require Interaction of vTR with Telomerase Reverse Transcriptase (TERT)

Telomerase is a ribonucleoprotein complex involved in the maintenance of telomeres, a protective structure at the distal ends of chromosomes. The enzyme complex contains two main components, telomerase reverse transcriptase (TERT), the catalytic subunit, and telomerase RNA (TR), which serves as a template for the addition of telomeric repeats (TTAGGG)n. Marek's disease virus (MDV), an oncogenic herpesvirus inducing fatal lymphoma in chickens, encodes a TR homologue, viral TR (vTR), which significantly contributes to MDV-induced lymphomagenesis. As recent studies have suggested that TRs possess functions independently of telomerase activity, we investigated if the tumor-promoting properties of MDV vTR are dependent on formation of a functional telomerase complex. The P6.1 stem-loop of TR is known to mediate TR-TERT complex formation and we show here that interaction of vTR with TERT and, consequently, telomerase activity was efficiently abrogated by the disruption of the vTR P6.1 stem-loop (P6.1mut). Recombinant MDV carrying the P6.1mut stem-loop mutation were generated and tested for their behavior in the natural host in vivo. In contrast to viruses lacking vTR, all animals infected with the P6.1mut viruses developed MDV-induced lymphomas, but onset of tumor formation was significantly delayed. P6.1mut viruses induced enhanced metastasis, indicating functionality of non-complexed vTR in tumor dissemination. We discovered that RPL22, a cellular factor involved in T-cell development and virus-induced transformation, directly interacts with wild-type and mutant vTR and is, consequently, relocalized to the nucleoplasm. Our study provides the first evidence that expression of TR, in this case encoded by a herpesvirus, is pro-oncogenic in the absence of telomerase activity

Different expressions of the same mode: a recent dialogue between archaeological and contemporary drawing practices

In this article we explore what we perceive as pertinent features of shared experience at the excavations of an Iron Age Hillfort at Bodfari, North Wales, referencing artist, archaeologist and examples of seminal art works and archaeological records resulting through inter-disciplinary collaboration. We explore ways along which archaeological and artistic practices of improvisation become entangled and productive through their different modes of mark-making. We contend that marks and memories of artist and archaeologist alike emerge interactively, through the mutually constituting effects of the object of study, the tools of exploration, and the practitioners themselves, when they are enmeshed in the cross-modally bound activities. These include, but are not limited to, remote sensing, surveying, mattocking, trowelling, drawing, photographing, videoing and sound recording. These marks represent the co-signatories: the gesture of the often anonymous practitioners, the voice of the deposits, as well as the imprint of the tools, and their interplay creates a multi-threaded narrative documenting their modes of intra-action, in short our practices. They occupy the conceptual space of paradata, and in the process of saturating the interstices of digital cognitive prosthetics they lend probity to their translations in both art form and archive

Clonal Structure of Rapid-Onset MDV-Driven CD4+ Lymphomas and Responding CD8+ T Cells

Lymphoid oncogenesis is a life threatening complication associated with a number of persistent viral infections (e.g. EBV and HTLV-1 in humans). With many of these infections it is difficult to study their natural history and the dynamics of tumor formation. Marek's Disease Virus (MDV) is a prevalent α-herpesvirus of poultry, inducing CD4+ TCRαβ+ T cell tumors in susceptible hosts. The high penetrance and temporal predictability of tumor induction raises issues related to the clonal structure of these lymphomas. Similarly, the clonality of responding CD8 T cells that infiltrate the tumor sites is unknown. Using TCRβ repertoire analysis tools, we demonstrated that MDV driven CD4+ T cell tumors were dominated by one to three large clones within an oligoclonal framework of smaller clones of CD4+ T cells. Individual birds had multiple tumor sites, some the result of metastasis (i.e. shared dominant clones) and others derived from distinct clones of transformed cells. The smaller oligoclonal CD4+ cells may represent an anti-tumor response, although on one occasion a low frequency clone was transformed and expanded after culture. Metastatic tumor clones were detected in the blood early during infection and dominated the circulating T cell repertoire, leading to MDV associated immune suppression. We also demonstrated that the tumor-infiltrating CD8+ T cell response was dominated by large oligoclonal expansions containing both “public” and “private” CDR3 sequences. The frequency of CD8+ T cell CDR3 sequences suggests initial stimulation during the early phases of infection. Collectively, our results indicate that MDV driven tumors are dominated by a highly restricted number of CD4+ clones. Moreover, the responding CD8+ T cell infiltrate is oligoclonal indicating recognition of a limited number of MDV antigens. These studies improve our understanding of the biology of MDV, an important poultry pathogen and a natural infection model of virus-induced tumor formation

Some cultural consequences in Spain of the Spanish Invasion of Morocco 1859-60

This article argues is a contribution to the study of interrelationships between colonialism, art, and literature in the nineteenth century. The article argues that the Spanish invasion of Morocco in 1859 led to contradictions and tensions within liberal nationalism, not least because of concerns about the tensions between the need for military reassertion of Spain and the respect for the independence of nations. This led to some reconfiguration of Spanish intellectuals' already complex relationship with North Africa and Islam. A major, perhaps surprising consequence of this reconfiguration, was some equation of Moroccan identity with a monotonous surface that was resistant to the gaze. In consequence, the Catalan painter Fortuny's crucial experience of Morocco led him to value near blank surfaces, and thus to make a major contribution to the origins of modern art

A direct comparison of strategies for combinatorial RNA interference

<p>Abstract</p> <p>Background</p> <p>Combinatorial RNA interference (co-RNAi) is a valuable tool for highly effective gene suppression of single and multiple-genes targets, and can be used to prevent the escape of mutation-prone transcripts. There are currently three main approaches used to achieve co-RNAi in animal cells; multiple promoter/shRNA cassettes, long hairpin RNAs (lhRNA) and miRNA-embedded shRNAs, however, the relative effectiveness of each is not known. The current study directly compares the ability of each co-RNAi method to deliver pre-validated siRNA molecules to the same gene targets.</p> <p>Results</p> <p>Double-shRNA expression vectors were generated for each co-RNAi platform and their ability to suppress both single and double-gene reporter targets were compared. The most reliable and effective gene silencing was achieved from the multiple promoter/shRNA approach, as this method induced additive suppression of single-gene targets and equally effective knockdown of double-gene targets. Although both lhRNA and microRNA-embedded strategies provided efficient gene knockdown, suppression levels were inconsistent and activity varied greatly for different siRNAs tested. Furthermore, it appeared that not only the position of siRNAs within these multi-shRNA constructs impacted upon silencing activity, but also local properties of each individual molecule. In addition, it was also found that the insertion of up to five promoter/shRNA cassettes into a single construct did not negatively affect the efficacy of each individual shRNA.</p> <p>Conclusions</p> <p>By directly comparing the ability of shRNAs delivered from different co-RNA platforms to initiate knockdown of the same gene targets, we found that multiple U6/shRNA cassettes offered the most reliable and predictable suppression of both single and multiple-gene targets. These results highlight some important strengths and pitfalls of the currently used methods for multiple shRNA delivery, and provide valuable insights for the design and application of reliable co-RNAi.</p

Post-identity politics and the social weightlessness of radical gender theory

This paper analysis current forms of post-identity politics within contemporary gender theory, notably the works of Rosi Braidotti, Elizabeth Grosz and Bobby Noble. Although these thinkers offer some important insights, I argue that their theories ultimately suffer from what Lois McNay has labelled ‘social weightlessness’. This is because their models of subjectivity and agency are severed from the everyday realities of social subjects. I indicate two ways that this social weightlessness is manifested in radical gender theories which offer a post-identity politics: (1) they underappreciate the social and political importance to many people of establishing stable, coherent identities; (ii) they are unable to offer a satisfactory account of agency. I suggest that these issues result, at least partly, from the anti-recognition stance adopted by these theorists. By incorporating an adequate model of recognition back into their theories, I claim, will equip their accounts with a properly-grounded model of the subject, which is responsive to the inequalities and oppressions that infuse the particular concrete contexts in which we experience and live out our identities