NOTCH1 mediates a switch between two distinct secretomes during senescence

Senescence, a persistent form of cell-cycle arrest, is often associated with a diverse secretome, which provides complex functionality for senescent cells within the tissue microenvironment. We show that oncogene-induced senescence is accompanied by a dynamic fluctuation of NOTCH1 activity, which drives a TGF-β-rich secretome, while suppressing the senescence-associated pro-inflammatory secretome through inhibition of C/EBPβ. NOTCH1 and NOTCH1-driven TGF-β contribute to 'lateral induction of senescence' through a juxtacrine NOTCH-JAG1 pathway. In addition, NOTCH1 inhibition during senescence facilitates upregulation of pro-inflammatory cytokines, promoting lymphocyte recruitment and senescence surveillance in vivo. As enforced activation of NOTCH1 signalling confers a near mutually exclusive secretory profile compared with typical senescence, our data collectively indicate that the dynamic alteration of NOTCH1 activity during senescence dictates a functional balance between these two distinct secretomes: one representing TGF-β and the other pro-inflammatory cytokines, highlighting that NOTCH1 is a temporospatial controller of secretome composition.This work was supported by the University of Cambridge, Cancer Research UK and Hutchison Whampoa. The M.N. laboratory is supported by Cancer Research UK Cambridge Institute Core Grant (C14303/A17197). M.H. was supported by CRUK Translational Medicine Research Fellowship and CRUK Clinician Scientist Fellowship (C52489/A19924). This work was also supported by a Wellcome Trust PRF (WT101835) to P.J.L., a Wellcome Trust Senior Fellowship to M.P.W. (108070/Z/15/Z), a Wellcome Trust Training Fellowship to N.J.M. (093964/Z/10/Z), and a Wellcome Trust Intermediate Fellowship (097162/Z/11/Z) to S.S. L.Z. was funded by the German Research Foundation (DFG; grants FOR2314 and SFB685), the Gottfried Wilhelm Leibniz Program, the European Research Council (projects ‘CholangioConcept’), the German Ministry for Education and Research (BMBF) (eMed-Multiscale HCC), the German Universities Excellence Initiative (third funding line: ‘future concept’), the German Center for Translational Cancer Research (DKTK) and the German–Israeli Cooperation in Cancer Research (DKFZ–MOST).This is the author accepted manuscript. The final version is available from Nature Publishing Group at http://dx.doi.org/10.1038/ncb3397

Landscape patterns and water-quality relationships in New Jersey Pinelands streams

We evaluated how landscape patterns might influence land-use-proximity and water-quality relationships in New Jersey Pinelands streams by relating pH and specific conductance to the percentage of altered land (developed land and upland agriculture) in a series of cumulative stream buffers (ranging in width from 0-100 m to 0-700 m) and associated watersheds. Specific conductance and pH were positively correlated. The percentage of altered land in all seven buffers and associated watersheds provided a proportional measure of watershed disturbance. R-square values produced by the pH regression models increased upgradient (near stream to basin divide), ranging from 0.69 to 0.77. In contrast, the R-square values for the specific conductance models decreased upgradient, ranging from 0.81 to 0.71. These contrasting patterns are most likely attributable to subtle variations in the distribution of the water-quality variables in relation to altered land in each of the cumulative buffers rather than to a proximity effect. Although we cannot conclude that proximity has a direct effect on water quality, our results strongly support a conclusion that variations in land use are associated with changes in water quality and that both near and far land uses provide a relatively good measure of water quality in the Pinelands watersheds that we studied

Occurrence of Perfluorinated Compounds in Raw Water from New Jersey Public Drinking Water Systems

Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS) were previously detected (≥4 ng/L) in 65% and 30%, respectively, of 23 New Jersey (NJ) public drinking water systems (PWS) sampled in 2006. We now report on a 2009 study of the occurrence of PFOA, PFOS, and eight other perfluorinated compounds (PFCs) in raw water samples from 30 intakes (18 groundwater and 12 surface water) from 29 additional NJ PWS. Between 1 and 8 PFCs were detected (≥5 ng/L) in 21 (70%) of 30 PWS samples at total PFC concentrations of 5–174 ng/L. Although PFOA was the most commonly detected PFC (57% of samples) and was found at the highest maximum concentration (100 ng/L), some of the higher levels of other PFCs were at sites with little or no PFOA. Perfluorononanoic acid was detected more frequently (30%) and at higher concentrations (up to 96 ng/L) than in raw or finished drinking water elsewhere, and it was found at several sites as the sole or predominant PFC, a pattern not reported in other drinking water studies. PFOS, perfluoropentanoic acid, and perfluorohexanoic acid were each detected in more than 20% of samples, while perfluoroheptanoic acid, perfluorobutane sulfonic acid, and perfluorohexane sulfonic acid were detected less frequently. Perfluorobutanoic acid was found only once (6 ng/L), and perfluorodecanoic acid was not detected. Total PFCs were highest in two reservoirs near an airfield; these were also the only sites with total perfluorosulfonic acids higher than total perfluorocarboxylic acids (PFCAs). PFC levels in raw and finished water from the same source were similar at those sites where both were tested. Five wells of two additional NJ PWS known to be contaminated with PFOA were also each sampled 4–9 times in 2010–13 for nine of the same PFCs. Total PFCs (almost completely PFCAs) at one of these PWS located near an industrial source of PFCs were higher than in any other PWS tested (up to 330 ng/L). These results show that multiple PFCs are commonly found in raw water from NJ PWS. Future work is needed to develop approaches for assessing the potential human health risks of exposure to mixtures of PFCs found in drinking water and other environmental media

Effects of angiopoietins-1 and -2 on the receptor tyrosine kinase Tie2 are differentially regulated at the endothelial cell surface

Angiopoietin-1 (Ang1) and Ang2 are ligands for the receptor tyrosine kinase Tie2. Structural data suggest that the two ligands bind Tie2 similarly. However, in endothelial cells Ang1 activates Tie2 whereas Ang2 can act as an apparent antagonist. In addition, each ligand exhibits distinct kinetics of release following binding. These observations suggest that additional factors influence function and binding of angiopoietins with receptors in the cellular context. Previous work has shown that Ang1 binding and activation of Tie2 are inhibited by Tiel, a related receptor that complexes with Tie2 in cells. In this study we have investigated binding of Ang1 and Ang2 to Tie2 in endothelial cells. In contrast to Ang1, binding of Ang2 to Tie2 was found to be not affected by Tiel. Neither PMA-induced Tiel ectodomain cleavage nor suppression of Tiel expression by siRNA affected the ability of Ang2 to bind Tie2. Analysis of the level of Tiel co-immunoprecipitating with angiopoietin-bound Tie2 demonstrated that Ang2 can bind Tie2 in Tie2:Tie1 complexes whereas Ang1 preferentially binds non-complexed Tie2. Stimulation of Tiel ectodomain cleavage did not increase the agonist activity of Ang2 for Tie2. Similarly, the Tie2-agonist activity of Ang2 was not affected by siRNA suppression of Tiel expression. Consistent with previous reports, loss of Tiel ectodomain enhanced the agonist activity of Ang1 for Tie2. Importantly, Ang2 was still able to antagonize the elevated Ang1-activation of Tie2 that occurs on Tiel ectodomain loss. Together these data demonstrate that Ang1 and Ang2 bind differently to Tie2 at the cell surface and this is controlled by Tiel. This differential regulation of angiopoietin binding allows control of Tie2 activation response to Ang1 without affecting Ang2 agonist activity and maintains the ability of Ang2 to antagonize even the enhanced Ang1 activation of Tie2 that occurs on loss of Tiel ectodomain. This provides a mechanism by which signalling through Tie2 can be modified by stimuli in the cellular microrenviromment. (C) 2009 Elsevier Inc. All rights reserved

Advances in bone preservation: Identifying possible collagen preservation using sulfur speciation mapping

International audienc