Metallicity Gradients in the Intracluster Gas of Abell 496

Analysis of spatially resolved ASCA spectra of the intracluster gas in Abell 496 confirms there are mild metal abundance enhancements near the center, as previously found by White et al. (1994) in a joint analysis of Ginga LAC and Einstein SSS spectra. Simultaneous analysis of spectra from all ASCA instruments (SIS + GIS) shows that the iron abundance is 0.36 +- 0.03 solar 3-12' from the center of the cluster and rises ~50% to 0.53 +- 0.04 solar within the central 2'. The F-test shows that this abundance gradient is significant at the >99.99% level. Nickel and sulfur abundances are also centrally enhanced. We use a variety of elemental abundance ratios to assess the relative contribution of SN Ia and SN II to the metal enrichment of the intracluster gas. We find spatial gradients in several abundance ratios, indicating that the fraction of iron from SN Ia increases toward the cluster center, with SN Ia accounting for ~50% of the iron mass 3-12' from the center and ~70% within 2'. The increased proportion of SN Ia ejecta at the center is such that the central iron abundance enhancement can be attributed wholly to SN Ia; we find no significant gradient in SN II ejecta. These spatial gradients in the proportion of SN Ia/II ejecta imply that the dominant metal enrichment mechanism near the center is different than in the outer parts of the cluster. We show that the central abundance enhancement is unlikely to be due to ram pressure stripping of gas from cluster galaxies, or to secularly accumulated stellar mass loss within the central cD. We suggest that the additional SN Ia ejecta near the center is the vestige of a secondary SN Ia-driven wind from the cD (following a more energetic protogalactic SN II-driven wind phase), which was partially smothered in the cD due to its location at the cluster center.Comment: 25 pages AASTeX; 6 encapsulated PostScript figures; accepted for publication in ApJ. Replaced with revised versio

In Vitro and In Vivo Behaviour of 111In Complexes of TTHA, TTHA-Bis(Butylamide) and TTHA-Bis(Glucamide): Stability, Biodistribution and Excretion Studied by Gamma Imaging

Aiming at radiopharmaceutical application, 111In3+ complexes of the polyaminocarboxylates TTHA, TTHA-bis(butylamide) and TTHA-bis(glucamide) were investigated. The in vitro stability of 111In(TTHA)3− and 111In(TTHA-bis(butylamide)- was evaluated by measuring the exchange of 111In3+ from the complexes to transferrin and the results were compared with those for 111In(DTPA)2−. We also performed biodistribution studies of the three 111In3+ complexes by gamma-imaging in Wistar rats and by measuring the radioactivity in their organs. TTHA and its derivatives seem to have similar in vivo biodistribution with prevailing renal excretion

Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence.

Activation of NOTCH signalling is associated with advanced prostate cancer and treatment resistance in prostate cancer patients. However, the mechanism that drives NOTCH activation in prostate cancer remains still elusive. Moreover, preclinical evidence of the therapeutic efficacy of NOTCH inhibitors in prostate cancer is lacking. Here, we provide evidence that PTEN loss in prostate tumours upregulates the expression of ADAM17, thereby activating NOTCH signalling. Using prostate conditional inactivation of both Pten and Notch1 along with preclinical trials carried out in Pten-null prostate conditional mouse models, we demonstrate that Pten-deficient prostate tumours are addicted to the NOTCH signalling. Importantly, we find that pharmacological inhibition of γ-secretase promotes growth arrest in both Pten-null and Pten/Trp53-null prostate tumours by triggering cellular senescence. Altogether, our findings describe a novel pro-tumorigenic network that links PTEN loss to ADAM17 and NOTCH signalling, thus providing the rational for the use of γ-secretase inhibitors in advanced prostate cancer patients

Issues concerning the implementation of the CCS Directive in the Netherlands

In June 2009, the EU Directive on the Geological Storage of Carbon Dioxide entered into force. The European Member states are obliged to transpose the directive in their national legislations no later than 25 June 2011. The EU legislator has applied a regime of minimum harmonisation when drafting the CCS Directive, amongst others to achieve that an agreement could be reached on the CCS Directive by a majority of Member States. In other words; Member States have considerable discretionary powers while implementing the Directive. The CO2 Storage Directive is mainly transposed into Dutch legislation by means of adaptation of the Dutch Mining Act. There are, however, still some issues in the implementation of this directive that need further clarification. The way these issues are addressed may impact the deployment of large-scale CO2 capture and storage (CCS) in the Netherlands and Europ

The Transcription Factor Cux1 Regulates Dendritic Morphology of Cortical Pyramidal Neurons

In the murine cerebral cortex, mammalian homologues of the Cux family transcription factors, Cux1 and Cux2, have been identified as restricted molecular markers for the upper layer (II-IV) pyramidal neurons. However, their functions in cortical development are largely unknown. Here we report that increasing the intracellular level of Cux1, but not Cux2, reduced the dendritic complexity of cultured cortical pyramidal neurons. Consistently, reducing the expression of Cux1 promoted the dendritic arborization in these pyramidal neurons. This effect required the existence of the DNA-binding domains, hence the transcriptional passive repression activity of Cux1. Analysis of downstream signals suggested that Cux1 regulates dendrite development primarily through suppressing the expression of the cyclin-dependent kinase inhibitor p27Kip1, and RhoA may mediate the regulation of dendritic complexity by Cux1 and p27. Thus, Cux1 functions as a negative regulator of dendritic complexity for cortical pyramidal neurons

p53 Target Gene SMAR1 Is Dysregulated in Breast Cancer: Its Role in Cancer Cell Migration and Invasion

Tumor suppressor SMAR1 interacts and stabilizes p53 through phosphorylation at its serine-15 residue. We show that SMAR1 transcription is regulated by p53 through its response element present in the SMAR1 promoter. Upon Doxorubicin induced DNA damage, acetylated p53 is recruited on SMAR1 promoter that allows activation of its transcription. Once SMAR1 is induced, cell cycle arrest is observed that is correlated to increased phospho-ser-15-p53 and decreased p53 acetylation. Further we demonstrate that SMAR1 expression is drastically reduced during advancement of human breast cancer. This was correlated with defective p53 expression in breast cancer where acetylated p53 is sequestered into the heterochromatin region and become inaccessible to activate SMAR1 promoter. In a recent report we have shown that SMAR1 represses Cyclin D1 transcription through recruitment of HDAC1 dependent repressor complex at the MAR site of Cyclin D1 promoter. Here we show that downmodulation of SMAR1 in high grade breast carcinoma is correlated with upregulated Cyclin D1 expression. We also established that SMAR1 inhibits tumor cell migration and metastases through inhibition of TGFβ signaling and its downstream target genes including cutl1 and various focal adhesion molecules. Thus, we report that SMAR1 plays a central role in coordinating p53 and TGFβ pathways in human breast cancer

Antagonistic Regulation of Apoptosis and Differentiation by the Cut Transcription Factor Represents a Tumor-Suppressing Mechanism in Drosophila

Apoptosis is essential to prevent oncogenic transformation by triggering self-destruction of harmful cells, including those unable to differentiate. However, the mechanisms linking impaired cell differentiation and apoptosis during development and disease are not well understood. Here we report that the Drosophila transcription factor Cut coordinately controls differentiation and repression of apoptosis via direct regulation of the pro-apoptotic gene reaper. We also demonstrate that this regulatory circuit acts in diverse cell lineages to remove uncommitted precursor cells in status nascendi and thereby interferes with their potential to develop into cancer cells. Consistent with the role of Cut homologues in controlling cell death in vertebrates, we find repression of apoptosis regulators by Cux1 in human cancer cells. Finally, we present evidence that suggests that other lineage-restricted specification factors employ a similar mechanism to put the brakes on the oncogenic process

Comparative Developmental Expression Profiling of Two C. elegans Isolates

Gene expression is known to change during development and to vary among genetically diverse strains. Previous studies of temporal patterns of gene expression during C. elegans development were incomplete, and little is known about how these patterns change as a function of genetic background. We used microarrays that comprehensively cover known and predicted worm genes to compare the landscape of genetic variation over developmental time between two isolates of C. elegans. We show that most genes vary in expression during development from egg to young adult, many genes vary in expression between the two isolates, and a subset of these genes exhibit isolate-specific changes during some developmental stages. This subset is strongly enriched for genes with roles in innate immunity. We identify several novel motifs that appear to play a role in regulating gene expression during development, and we propose functional annotations for many previously unannotated genes. These results improve our understanding of gene expression and function during worm development and lay the foundation for linkage studies of the genetic basis of developmental variation in gene expression in this important model organism

Cell-specific microarray profiling experiments reveal a comprehensive picture of gene expression in the C. elegans nervous system

A novel strategy for profiling Caenorhabditis elegans cells identifies transcripts highly enriched in either the embryonic or larval C. elegans nervous system, including 19 conserved transcripts of unknown function that are also expressed in the mammalian brain