Alterations of beta-adrenoceptor-density and cAMP-synthesis in rat-erythrocytes after stress erythropoiesis.

During the maturation of red blood cells from rats after stress erythropoiesis, adenyl cyclase activity and beta-adrenoceptor density (pmoles/mg protein) decrease at distinctly different rates suggesting a different turnover of these membrane units.     

Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase

Notch signalling is a key intercellular communication mechanism that is essential for cell specification and tissue patterning, and which coordinates critical steps of blood vessel growth. Although subtle alterations in Notch activity suffice to elicit profound differences in endothelial behaviour and blood vessel formation, little is known about the regulation and adaptation of endothelial Notch responses. Here we report that the NAD(+)-dependent deacetylase SIRT1 acts as an intrinsic negative modulator of Notch signalling in endothelial cells. We show that acetylation of the Notch1 intracellular domain (NICD) on conserved lysines controls the amplitude and duration of Notch responses by altering NICD protein turnover. SIRT1 associates with NICD and functions as a NICD deacetylase, which opposes the acetylation-induced NICD stabilization. Consequently, endothelial cells lacking SIRT1 activity are sensitized to Notch signalling, resulting in impaired growth, sprout elongation and enhanced Notch target gene expression in response to DLL4 stimulation, thereby promoting a non-sprouting, stalk-cell-like phenotype. In vivo, inactivation of Sirt1 in zebrafish and mice causes reduced vascular branching and density as a consequence of enhanced Notch signalling. Our findings identify reversible acetylation of the NICD as a molecular mechanism to adapt the dynamics of Notch signalling, and indicate that SIRT1 acts as rheostat to fine-tune endothelial Notch responses.     

CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis

Macrophages, which are abundant in the tumour microenvironment, enhance malignancy. At metastatic sites, a distinct population of metastasis-associated macrophages promotes the extravasation, seeding and persistent growth of tumour cells. Here we define the origin of these macrophages by showing that Gr1-positive inflammatory monocytes are preferentially recruited to pulmonary metastases but not to primary mammary tumours in mice. This process also occurs for human inflammatory monocytes in pulmonary metastases of human breast cancer cells. The recruitment of these inflammatory monocytes, which express CCR2 (the receptor for chemokine CCL2), as well as the subsequent recruitment of metastasis-associated macrophages and their interaction with metastasizing tumour cells, is dependent on CCL2 synthesized by both the tumour and the stroma. Inhibition of CCL2-CCR2 signalling blocks the recruitment of inflammatory monocytes, inhibits metastasis in vivo and prolongs the survival of tumour-bearing mice. Depletion of tumour-cell-derived CCL2 also inhibits metastatic seeding. Inflammatory monocytes promote the extravasation of tumour cells in a process that requires monocyte-derived vascular endothelial growth factor. CCL2 expression and macrophage infiltration are correlated with poor prognosis and metastatic disease in human breast cancer. Our data provide the mechanistic link between these two clinical associations and indicate new therapeutic targets for treating metastatic breast cancer.     

Glucodigifucosid,Neo-Glucodigifucosid und Digitoxigenin-allomethylosid aus den Blättern vonDigitalis lanata Ehrh

Summary The primary glycosides, glucodigifucoside and neo-glucodigifucoside, were isolated from the extract ofDigitalis lanata leaves. They are isomeric glucosides of digiproside and differ in the position of attachment of thed-glucose residue. Digitoxigenin-allomethylosid was isolated from the leaves after enzymatic decomposition.

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23. Mitteilung über Herzglykoside; unter der ausgezeichneten experimentellen Mitarbeit vonH. Gerlach.     

Fish-Farming and the Precautionary Principle: Context and Values in Environmental Science for Policy

The paper starts with the assumption that the Precautionary Principle (PP) is one of the most important elements of the concept of sustainability. It is noted that PP has entered international treaties and national law. PP is widely referred to as a central principle of environmental policy. However, the precise content of PP remains largely unclear. In particular it seems unclear how PP relates to science. In section 2 of the paper a general overview of some historical and systematic features of PP are presented. In section 3 a specific case is discussed in greater detail. It is claimed that the escape of farmed salmon from fish cages in the Sea, and its eventual invasion of the breeding places of the wild salmon up the rivers, must be regarded a proper case for applying PP. Yet there is no single PP-strategy. Instead, four different strategies are presented, and all of them can be regarded precautionary strategies in the light of PP. The choice between these strategies is based upon personal values. In section 4 of the paper a general analysis is given which relates these different value perspectives to basic differences in risk aversion, which in turn are related to differing conceptions of nature and/or society. In the concluding section 5 some general consequences of the foregoing analysis are outlined.