41 research outputs found

    Regulation of polarized morphogenesis by protein kinase C iota in oncogenic epithelial spheroids.

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    Protein kinase C iota (PKCĪ¹), a serine/threonine kinase required for cell polarity, proliferation and migration, is commonly up- or downregulated in cancer. PKCĪ¹ is a human oncogene but whether this is related to its role in cell polarity and what repertoire of oncogenes acts in concert with PKCĪ¹ is not known. We developed a panel of candidate oncogene expressing Madin-Darby canine kidney (MDCK) cells and demonstrated that H-Ras, ErbB2 and phosphatidylinositol 3-kinase transformation led to non-polar spheroid morphogenesis (dysplasia), whereas MDCK spheroids expressing c-Raf or v-Src were largely polarized. We show that small interfering RNA (siRNA)-targeting PKCĪ¹ decreased the size of all spheroids tested and partially reversed the aberrant polarity phenotype in H-Ras and ErbB2 spheroids only. This indicates distinct requirements for PKCĪ¹ and moreover that different thresholds of PKCĪ¹ activity are required for these phenotypes. By manipulating PKCĪ¹ function using mutant constructs, siRNA depletion or chemical inhibition, we have demonstrated that PKCĪ¹ is required for polarization of parental MDCK epithelial cysts in a 3D matrix and that there is a threshold of PKCĪ¹ activity above and below which, disorganized epithelial morphogenesis results. Furthermore, treatment with a novel PKCĪ¹ inhibitor, CRT0066854, was able to restore polarized morphogenesis in the dysplastic H-Ras spheroids. These results show that tightly regulated PKCĪ¹ is required for normal-polarized morphogenesis in mammalian cells and that H-Ras and ErbB2 cooperate with PKCĪ¹ for loss of polarization and dysplasia. The identification of a PKCĪ¹ inhibitor that can restore polarized morphogenesis has implications for the treatment of Ras and ErbB2 driven malignancies.Cancer Research UK; Royal Marsden/Institute of Cancer Research National Institute for Health Research Biomedical Research Centre (M.L.)

    Does dog ownership reduce anxiety in humans?

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    The purpose of this project is to gain insight into the affects dog ownership has on anxiety and mental health in humans

    Sulfur isotope constraints on the petrogenesis of the Kimberley kimberlites

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    This work was funded by the Ambizione fellowship awarded to AG by the Swiss National Science Foundation (grant n. PZ00P2_180126/1).Cretaceous kimberlites in southern Africa have been suggested to host deeply subducted material in their mantle sources based on radiogenic isotope systematics. However, potential subducted material contributions to the volatile budget, including sulfur, of these kimberlites is unclear. Here we report new petrographic, geochemical, and isotopic data on sulfides and sulfates in sub-volcanic kimberlites from Kimberley, South Africa. The examined kimberlites were divided into four groups based on their sulfide mineralogy, sulfur contents, and isotopic compositions. None of these groups exhibit clear signs of mass-independent fractionation. Three samples contain sphalerite, have moderate bulk-sulfide S concentrations (203-329 Āµg/g) and highly negative bulk-sulfide Ī“34S values (-10 to -13ā€°). Four samples have moderate-to-high bulk-sulfide S contents (220-745 Āµg/g), positive Ī“34Ssulfide values (+0.2 to +14ā€°), and contain galena, pyrite or secondary Cu-sulfides as the dominant sulfides. These groups of S-rich kimberlites were probably contaminated by fluids sourced from local country rocks. The remaining eight samples contain negligible amounts of crustal sulfides (e.g., sphalerite, galena), have lower bulk-sulfide S concentrations (ā‰¤111 Āµg/g), and display a different Ī“34Ssulfide range (-5.7 to +1.1ā€°) compared to the S-rich groups. By considering only the five samples with fresh primary Cu-Fe-Ni sulfides, the Ī“34S range contracts to between -5.7 and -3.4ā€°, which is considered representative of the mantle source composition. This range indicates the presence of a deeply recycled sedimentary component in the melt source. The combination of detailed sulfide petrography and S isotope geochemistry in fresh kimberlite rocks provides a further tool to investigate mantle chemical geodynamics through time.Publisher PDFPeer reviewe