The Elg1-RFC Clamp-Loading Complex Performs a Role in Sister Chromatid Cohesion

It is widely accepted that of the four Replication Factor C (RFC) complexes (defined by the associations of either Rfc1p, Ctf18p, Elg1p or Rad24p with Rfc2p-Rfc5p), only Ctf18-RFC functions in sister chromatid cohesion. This model is based on findings that CTF18 deletion is lethal in combination with mutations in either CTF7ECO1 or MCD1 sister chromatid cohesion genes and that ctf18 mutant cells exhibit cohesion defects. Here, we report that Elg1-RFC not only participates in cohesion but performs a function that is distinct from that of Ctf18-RFC. The results show that deletion of ELG1 rescues both ctf7eco1 mutant cell temperature sensitivity and cohesion defects. Moreover, over-expression of ELG1 enhances ctf7eco1 mutant cell phenotypes. These findings suggest that the balance of Ctf7pEco1p activity depends on both Ctf18-RFC and Elg1-RFC. We also report that ELG1 deletion produces cohesion defects and intensifies the conditional phenotype of mcd1 mutant cells, further supporting a role for Elg1-RFC in cohesion. Attesting to the specificity of these interactions, deletion of RAD24 neither suppressed nor exacerbated cohesion defects in either ctf7eco1 or mcd1 mutant cells. While parallel analyses failed to uncover a similar role in cohesion for Rad24-RFC, it is well known that Rad24-RFC, Elg1-RFC and Ctf18-RFC play key roles in DNA damage responses. We tested and found that Ctf7pEco1p plays a significant role in Rad24-RFC-based DNA response pathways. In combination, these findings challenge current views and document new and distinct roles for RFC complexes in cohesion and for Ctf7pEco1p in DNA repair

Integration of Gene Dosage and Gene Expression in Non-Small Cell Lung Cancer, Identification of HSP90 as Potential Target

BACKGROUND: Lung cancer causes approximately 1.2 million deaths per year worldwide, and non-small cell lung cancer (NSCLC) represents 85% of all lung cancers. Understanding the molecular events in non-small cell lung cancer (NSCLC) is essential to improve early diagnosis and treatment for this disease. METHODOLOGY AND PRINCIPAL FINDINGS: In an attempt to identify novel NSCLC related genes, we performed a genome-wide screening of chromosomal copy number changes affecting gene expression using microarray based comparative genomic hybridization and gene expression arrays on 32 radically resected tumor samples from stage I and II NSCLC patients. An integrative analysis tool was applied to determine whether chromosomal copy number affects gene expression. We identified a deletion on 14q32.2-33 as a common alteration in NSCLC (44%), which significantly influenced gene expression for HSP90, residing on 14q32. This deletion was correlated with better overall survival (P = 0.008), survival was also longer in patients whose tumors had low expression levels of HSP90. We extended the analysis to three independent validation sets of NSCLC patients, and confirmed low HSP90 expression to be related with longer overall survival (P = 0.003, P = 0.07 and P = 0.04). Furthermore, in vitro treatment with an HSP90 inhibitor had potent antiproliferative activity in NSCLC cell lines. CONCLUSIONS: We suggest that targeting HSP90 will have clinical impact for NSCLC patients

Tradition as a Peacebuilding Tool

The concept of tradition, rather like that of secularism, has come to mean different things to different people in a variety of contexts. This Chapter explores an understanding of tradition as that group of rules or practices which sits alongside core governing texts of groups within civil society. It identifies tradition as that which facilitates the contextualisation of civil society groups over time. It then examines how tradition could be used as a tool for engendering peaceful civil society relations. To do this it first explains the rationale for identifying plural religious traditions as important for strong civil society building, including for the protection of fundamental rights and the socio-economic well-being of a nation. Tradition is then proposed as a means of countering the exclusion of plural religious voices from the public square arising both as a result of the secular narrative manifesting itself in extreme forms of Laïcité and as a result of forms of theocracy and confessionalism. The chapter does this by identifying the development of the concept of tradition, setting out dictionary definitions, definitions within the discipline of law and their interaction and links with definitions within the three Abrahamic faiths. The overarching thesis drawing these threads together is that the various methods of forming and using tradition by intermediate institutions of civil society could inform the creation of a platform as a dialogical basis to build consensus amongst individuals, institutions of civil society and governments. This envisages a plurality of religious voices not as a threat but rather as a richly diverse canvas upon which to paint the interactions of civic life and formulate the law that governs those interactions