Aberrant expression of Jagged1 and Notch1 are associated with poor outcome in breast cancer. However, the reason that Jagged1 and/or Notch overexpression portends a poor prognosis is unknown. We identify Slug, a transcriptional repressor, as a novel Notch target and show that elevated levels of Slug correlate with increased expression of Jagged1 in various human cancers. Slug was essential for Notch-mediated repression of E-cadherin, which resulted in β-catenin activation and resistance to anoikis. Inhibition of ligand-induced Notch signaling in xenografted Slug-positive/E-cadherin–negative breast tumors promoted apoptosis and inhibited tumor growth and metastasis. This response was associated with down-regulated Slug expression, reexpression of E-cadherin, and suppression of active β-catenin. Our findings suggest that ligand-induced Notch activation, through the induction of Slug, promotes tumor growth and metastasis characterized by epithelial-to-mesenchymal transition and inhibition of anoikis.

Abstract-Various studies have identified a critical role for Notch signaling in cardiovascular development. In this and other systems, Notch receptors and ligands are expressed in regions that undergo epithelial-to-mesenchymal transformation. However, there is no direct evidence that Notch activation can induce mesenchymal transdifferentiation.In this study we show that Notch activation in endothelial cells results in morphological, phenotypic, and functional changes consistent with mesenchymal transformation. These changes include downregulation of endothelial markers (vascular endothelial [VE]-cadherin, Tie1, Tie2, platelet-endothelial cell adhesion molecule-1, and endothelial NO synthase), upregulation of mesenchymal markers (␣-smooth muscle actin, fibronectin, and platelet-derived growth factor receptors), and migration toward platelet-derived growth factor-BB. Notch-induced endothelial-to-mesenchymal transformation does not seem to require external regulation and is restricted to cells expressing activated Notch. Jagged1 stimulation of endothelial cells induces a similar mesenchymal transformation, and Jagged1, Notch1, and Notch4 are expressed in the ventricular outflow tract during stages of endocardial cushion formation. This is the first evidence that Jagged1-Notch interactions induce endothelial-to-mesenchymal transformation, and our findings suggest that Notch signaling may be required for proper endocardial cushion differentiation and/or vascular smooth muscle cell development. Key Words: endothelial-to-mesenchymal transformation Ⅲ Notch Ⅲ Jagged1 Ⅲ endocardial cushion T he Notch signaling pathway plays a critical role during development. Four mammalian Notch receptors (Notch1 through 4) and 5 Notch ligands (Delta-like [Dll]-1, Dll3, Dll4, Jagged1, and Jagged2) have been identified. Notch receptorligand interaction results in a series of proteolytic cleavages of the Notch receptor, producing a C-terminal intracellular fragment (NotchIC) that translocates to the nucleus. In the nucleus, NotchIC binds to the transcriptional repressor CBF1/ RBP-J, thereby derepressing or coactivating the expression of various lineage-specific genes. 1 Perturbation of the Notch pathway has been implicated in the pathogenesis of various cardiovascular diseases in humans. 2 Of interest, patients with Jagged1 mutations (Alagille syndrome) display congenital cardiovascular anomalies that seem to be secondary to faulty endocardial cushion formation. [3][4][5][6] In the mouse, Notch1-deficient embryos demonstrate severe vascular developmental defects, which are exacerbated in Notch1/Notch4 double-mutant embryos. 7 Constitutive activation of Notch4 also causes defects in vascular remodeling. 8,9 Mice that are rendered null for Jagged1 die from hemorrhage early during embryogenesis, whereas mice that are doubly heterozygous for a Jagged1-null allele and a Notch2 hypomorphic allele exhibit cardiac anomalies similar to those seen in Alagille syndrome. 10,11 Genes that lie downstream of Notch activation, such as the basic helix-loop...

Shearwaters and petrels (hereafter petrels) are highly adapted seabirds that occur across all the world's oceans. Petrels are a threatened seabird group comprising 124 species. They have bet-hedging life histories typified by extended chick rearing periods, low fecundity, high adult survival, strong philopatry, monogamy and long-term mate fidelity and are thus vulnerable to change. Anthropogenic alterations on land and at sea have led to a poor conservation status of many petrels with 52 (42%) threatened

The widely held assumption that any important scientific information would be available in English underlies the underuse of non-English-language science across disciplines. However, non-English-language science is expected to bring unique and valuable scientific information, especially in disciplines where the evidence is patchy, and for emergent issues where synthesising available evidence is an urgent challenge. Yet such contribution of non-English-language science to scientific communities and the application of science is rarely quantified. Here, we show that non-English-language studies provide crucial evidence for informing global biodiversity conservation. By screening 419,679 peer-reviewed papers in 16 languages, we identified 1,234 non-English-language studies providing evidence on the effectiveness of biodiversity conservation interventions, compared to 4,412 English-language studies identified with the same criteria. Relevant non-English-language studies are being published at an increasing rate in 6 out of the 12 languages where there were a sufficient number of relevant studies. Incorporating non-English-language studies can expand the geographical coverage (i.e., the number of 2° × 2° grid cells with relevant studies) of English-language evidence by 12% to 25%, especially in biodiverse regions, and taxonomic coverage (i.e., the number of species covered by the relevant studies) by 5% to 32%, although they do tend to be based on less robust study designs. Our results show that synthesising non-English-language studies is key to overcoming the widespread lack of local, context-dependent evidence and facilitating evidence-based conservation globally. We urge wider disciplines to rigorously reassess the untapped potential of non-English-language science in informing decisions to address other global challenges. Please see the Supporting information files for Alternative Language Abstracts.

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Knowledge of foraging movements during the breeding season is key to understanding energetic stresses faced by seabirds. Using archival light loggers (geolocators), a Bayesian state–space model, and stable isotope analysis, we compared foraging movements of Leach's storm‐petrels Oceanodroma leucorhoa during their incubation periods in 2012 and 2013. Data were collected from two colonies, Bon Portage Island and Country Island, which are 380 km apart along the coast of Nova Scotia, Canada. Based on allometry for procellariiform mass, predicted foraging ranges for Leach's storm‐petrels are 200 km; however, observed maximum distances from the colony were 3 to 5 times that. Storm‐petrels from Country Island travelled 1015 ± 238 km southeast to the Laurentian fan and south of the Grand Banks whereas storm‐petrels from Bon Portage Island travelled 613 ± 167 km southeast, beyond the continental slope, east of Georges Bank. The average distance travelled in a return trip was 2287 ± 603 km and 1303 ± 351 km for Country Island and Bon Portage Island, respectively. There were no differences between years in cumulative distances travelled within islands, but foraging trips did not last as long in 2013 (4.7 ± 1.5 d) as they did in 2012 (6.2 ± 2.1 d). Stable isotope analyses indicated that, during the incubation period, prey items from Country Island were from higher trophic levels and possibly had higher energy content than those from Bon Portage Island, perhaps explaining the more distant and longer foraging trips for Country Island birds.

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