Ring-opening polymerization of some aryl substituted polycyclic alkenes

The work described in this thesis is concerned with an investigation of the polymerizability of aryl substituted polycyclic alkenes by ring-opening using metathesis catalyst systems. The synthesis, purification and characterization of the monomers required for this work are described in Chapter 2. Successful ring-open polymerizations are described in Chapter 3 together with the unsuccessful attempts to ring open polymerize some heteroatom substituted compounds. The characterization of the new polymers is discussed in Chapter 4 together with some preliminary results concerning the susceptibility of these polymers to the photo-oxidative degradation

Loss of TAF8 causes TFIID dysfunction and p53-mediated apoptotic neuronal cell death

Mutations in genes encoding general transcription factors cause neurological disorders. Despite clinical prominence, the consequences of defects in the basal transcription machinery during brain development are unclear. We found that loss of the TATA-box binding protein-associated factor TAF8, a component of the general transcription factor TFIID, in the developing central nervous system affected the expression of many, but notably not all genes. Taf8 deletion caused apoptosis, unexpectedly restricted to forebrain regions. Nuclear levels of the transcription factor p53 were elevated in the absence of TAF8, as were the mRNAs of the pro-apoptotic p53 target genes Noxa, Puma and Bax. The cell death in Taf8 forebrain regions was completely rescued by additional loss of p53, but Taf8 and p53 brains failed to initiate a neuronal expression program. Taf8 deletion caused aberrant transcription of promoter regions and splicing anomalies. We propose that TAF8 supports the directionality of transcription and co-transcriptional splicing, and that failure of these processes causes p53-induced apoptosis of neuronal cells in the developing mouse embryo.Farrah El-Saafin, Maria I. Bergamasco, Yunshun Chen, Rose E. May, Prabagaran Esakky, Soroor Hediyeh-zadeh, Mathew Dixon, Stephen Wilcox, Melissa J. Davis, Andreas Strasser, Gordon K. Smyth, Tim Thomas, and Anne K. Vos

The site of breast cancer metastases dictates their clonal composition and reversible transcriptomic profile

Intratumoral heterogeneity is a driver of breast cancer progression, but the nature of the clonal interactive network involved in this process remains unclear. Here, we optimized the use of optical barcoding to visualize and characterize 31 cancer subclones in vivo. By mapping the clonal composition of thousands of metastases in two clinically relevant sites, the lungs and liver, we found that metastases were highly polyclonal in lungs but not in the liver. Furthermore, the transcriptome of the subclones varied according to their metastatic niche. We also identified a reversible niche-driven signature that was conserved in lung and liver metastases collected during patient autopsies. Among this signature, we found that the tumor necrosis factor-α pathway was up-regulated in lung compared to liver metastases, and inhibition of this pathway affected metastasis diversity. These results highlight that the cellular and molecular heterogeneity observed in metastases is largely dictated by the tumor microenvironment