Craig Rhos-y-felin: A Welsh bluestone megalith quarry for Stonehenge

The long-distance transport of the bluestones from south Wales to Stonehenge is one of the most remarkable achievements of Neolithic societies in north-west Europe. Where precisely these stones were quarried, when they were extracted and how they were transported has long been a subject of speculation, experiment and controversy. The discovery of a megalithic bluestone quarry at Craig Rhos-y-felin in 2011 marked a turning point in this research. Subsequent excavations have provided details of the quarrying process along with direct dating evidence for the extraction of bluestone monoliths at this location, demonstrating both Neolithic and Early Bronze Age activity

Functional and genetic analysis of the v-src oncogene

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The coupling of TEL/PDGF R to distinct functional responses is modulated by the presence of cytokine: involvement of mitogen-activated protein kinases

The TEL/PDGF{beta}R oncogenic fusion protein is the product of the t(5;12)(q33; p13) translocation recurrently found in patients with chronic myelomonocytic leukemia (CMML). To investigate the coupling of molecular signaling events activated by TEL/PDGF{beta}R to functional responses, we expressed TEL/PDGF{beta}R in interleukin 3 (IL-3)–dependent BaF/3 cells using the tetracycline-regulated expression system. Induction of TEL/PDGF{beta}R expression led to increased cell survival following IL-3 withdrawal and constitutive activation of protein kinase B (PKB), signal transducer and activator of transcription 5 (STAT5), extracellular signal-regulated kinases 1/2 (ERK1/2), Jun N-terminal kinases 1/2 (JNK1/2), and p38 mitogenactivated protein kinase (MAPK) pathways. However, inducible expression of TEL/PDGF{beta}R failed to generate factor-independent cells, whereas constitutive expression of TEL/PDGF{beta}R did, albeit at low frequency, suggesting the duration of TEL/PDGF{beta}R expression is important for transformation. Surprisingly, in cells induced to express TEL/PDGF{beta}R, IL-3–dependent growth was dramatically reduced as a result of increased apoptosis of cells receiving combined IL-3 and TEL/PDGF{beta}R signals. We demonstrate that TEL/PDGF{beta}R expression augmented IL-3–induced activation of PKB, STAT5, ERK1/2, p38, and JNK1/2. Inhibition of neither phosphoinositide-3 kinases nor p38 MAPKs reduced the inhibition of IL-3–driven proliferation observed when TEL/PDGF{beta}R was expressed. However, inhibition of MEKs or JNKs partially reversed the combined inhibitory effects of TEL/PDGF{beta}R and IL-3 on proliferation and survival. These results suggest that the combination of TEL/PDGF{beta}R and IL-3–induced signals activate apoptosis through ERK and JNK MAPK-dependent pathways. Given that in vivo hematopoietic cells are in contact with a variety of cytokines, our results have important implications for cellular responses in the pathogenesis of CMML

Molecular interactions of SHP1 and SHP2 in IL-3-signalling

SHP1 and SHP2 tyrosine phosphatases have both been implicated in signalling pathways downstream of the interleukin-3 (IL-3) receptor. We have investigated the co-association of SHP1 and SHP2 with tyrosine-phosphorylated proteins in IL-3-dependent BaF/3 cells. We demonstrate that both SHP1 and SHP2 associate with Aic2A (β chain of the IL-3 receptor), Gab2 and the paired inhibitory receptor B (PIR-B). The individual SH2 domains of SHP2 can independently bind Gab2, potentially important for the adapter function of SHP2. Association of both phosphatases with Aic2A and Gab2 increases upon IL-3 treatment. Recruitment of SHP1 to PIR-B also increases in response to IL-3, suggesting a functional link between inhibitory and cytokine receptor signalling. Aic2A is a rapid target for dephosphorylation following IL-3 stimulation and substrate-trapping versions of both phosphatases identify Aic2A and Gab2 as substrates for SHP1 and SHP2. These studies suggest that SH2–domain interactions are important for targetting these phosphatases to their substrates