Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis

Eph receptor tyrosine kinases and their cell-surface-bound ligands, the ephrins, regulate axon guidance and bundling in the developing brain, control cell migration and adhesion, and help patterning the embryo. Here we report that two ephrinB ligands and three EphB receptors are expressed in and regulate the formation of the vascular network. Mice lacking ephrinB2 and a proportion of double mutants deficient in EphB2 and EphB3 receptor signaling die in utero before embryonic day 11.5 (E11.5) because of defects in the remodeling of the embryonic vascular system. Our phenotypic analysis suggests complex interactions and multiple functions of Eph receptors and ephrins in the embryonic vasculature. Interaction between ephrinB2 on arteries and its EphB receptors on veins suggests a role in defining boundaries between arterial and venous domains. Expression of ephrinB1 by arterial and venous endothelial cells and EphB3 by veins and some arteries indicates that endothelial cell-to-cell interactions between ephrins and Eph receptors are not restricted to the border between arteries and veins. Furthermore, expression of ephrinB2 and EphB2 in mesenchyme adjacent to vessels and vascular defects in ephB2/ephB3 double mutants indicate a requirement for ephrin-Eph signaling between endothelial cells and surrounding mesenchymal cells. Finally, ephrinB ligands induce capillary sprouting in vitro with a similar efficiency as angiopoietin-1 (Ang1) and vascular endothelial growth factor (VEGF), demonstrating a stimulatory role of ephrins in the remodeling of the developing vascular system.

Unaltered oncological outcomes of radical cystectomy with extended lymphadenectomy over three decades

OBJECTIVE To evaluate oncological outcome trends over the last three decades in patients after radical cystectomy (RC) and extended pelvic lymph node (LN) dissection. PATIENTS AND METHODS Retrospective analysis of the University of Southern California (USC) RC cohort of patients (1488 patients) operated with intent to cure from 1980 to 2005 for biopsy confirmed muscle-invasive urothelial bladder cancer. To focus on outcomes of unexpected (cN0M0) LN-positive patients, the USC subset was extended with unexpected LN-positive patients from the University of Berne (UB) (combined subgroup 521 patients). Patients were grouped and compared according to decade of surgery (1980-1989/1990-1999/≥2000). Survival probabilities were calculated with Kaplan-Meier plots, log-rank tests compared outcomes according to decade of surgery, followed by multivariable verification. RESULTS The 10-year recurrence-free survival was 78-80% in patients with organ-confined, LN-negative disease, 53-60% in patients with extravesical, yet LN-negative disease and ≈30% in LN-positive patients. Although the number of patients receiving systemic chemotherapy increased, no survival improvement was noted in either the entire USC cohort, or in the combined LN-positive USC-UB cohort. In contrast, patient age at surgery increased progressively, suggesting a relative survival benefit. CONCLUSIONS Radical surgery remains the mainstay of therapy for muscle-invasive bladder cancer. Yet, our study reveals predictable outcomes but no survival improvement in patients undergoing RC over the last three decades. Any future survival improvements are likely to result from more effective systemic treatments and/or earlier detection of the disease.

Atmospheric CO₂ response to volcanic eruptions: The role of ENSO, season, and variability

Tropical explosive volcanism is one of the most important natural factors that significantly impact the climate system and the carbon cycle on annual to multi-decadal time scales. The three largest explosive eruptions in the last 50�years�Agung, El Chichón, and Pinatubo�occurred in spring/summer in conjunction with El Niño events and left distinct negative signals in the observational temperature and CO2 records. However, confounding factors such as seasonal variability and El Niño-Southern Oscillation (ENSO) may obscure the forcing-response relationship. We determine for the first time the extent to which initial conditions, i.e., season and phase of the ENSO, and internal variability influence the coupled climate and carbon cycle response to volcanic forcing and how this affects estimates of the terrestrial and oceanic carbon sinks. Ensemble simulations with the Earth System Model (Climate System Model 1.4-carbon) predict that the atmospheric CO2 response is �60 larger when a volcanic eruption occurs during El Niño and in winter than during La Niña conditions. Our simulations suggest that the Pinatubo eruption contributed 11�±�6 to the 25�Pg terrestrial carbon sink inferred over the decade 1990�1999 and �2�±�1 to the 22�Pg oceanic carbon sink. In contrast to recent claims, trends in the airborne fraction of anthropogenic carbon cannot be detected when accounting for the decadal-scale influence of explosive volcanism and related uncertainties. Our results highlight the importance of considering the role of natural variability in the carbon cycle for interpretation of observations and for data-model intercomparison.

Swiss Air Traffic Policy: Noise Between Berne and Berlin

This article looks at the negotiations between Switzerland and Germany on air traffic regulation with the help of negotiation analysis tools. A number of factors pre-eminent in the literature on negotiation processes and outcomes are presented and critically assessed. In particular arguments of “power”, which are often insufficiently explored in analysing interstate cooperation, are brought back into the picture. The article argues that structural power best explains the negotiation results while domestic politics and information asymmetries both account for non-ratification of the treaty. Institutionalist arguments on the constraining effects of international norms and institutions as well as explanations focusing on negotiation skills are of minor importance. Moreover, the nature of the Swiss intra-governmental setting at the federal level did not encourage the Swiss negotiators to exploit all means during the different stages of the bargaining process. The article concludes by illuminating a number of policy observations in the broader context of Swiss foreign relations and indicating avenues for further research