Mode of action of claudin peptidomimetics in the transient opening of cellular tight junction barriers

In epithelial/endothelial barriers, claudins form tight junctions, seal the paracellular cleft, and limit the uptake of solutes and drugs. The peptidomimetic C1C2 from the C-terminal half of claudin-1's first extracellular loop increases drug delivery through epithelial claudin-1 barriers. However, its molecular and structural mode of action remains unknown. In the present study, >100 μM C1C2 caused paracellular opening of various barriers with different claudin compositions, ranging from epithelial to endothelial cells, preferentially modulating claudin-1 and claudin-5. After 6 h incubation, C1C2 reversibly increased the permeability to molecules of different sizes; this was accompanied by redistribution of claudins and occludin from junctions to cytosol. Internalization of C1C2 in epithelial cells depended on claudin-1 expression and clathrin pathway, whereby most C1C2 was retained in recyclosomes >2 h. In freeze-fracture electron microscopy, C1C2 changed claudin-1 tight junction strands to a more parallel arrangement and claudin-5 strands from E-face to P-face association - drastic and novel effects. In conclusion, C1C2 is largely recycled in the presence of a claudin, which explains the delayed onset of barrier and junction loss, the high peptide concentration required and the long-lasting effect. Epithelial/endothelial barriers are specifically modulated via claudin-1/claudin-5, which can be targeted to improve drug delivery.

Diagnosing institutional barriers and opportunities for adaptation to climate change

Institutions are one of the decisive factors which enable, constrain and shape adaptation to the impacts of climate change, variability and extreme events. However, current understanding of institutions in adaptation situations is fragmented across the scientific community, evidence diverges, and cumulative learning beyond single studies is limited. This study adopts a diagnostic approach to elaborate a nuanced understanding of institutional barriers and opportunities in climate adaptation by means of a model-centred meta-analysis of 52 case studies of public climate adaptation in Europe. The first result is a novel taxonomy of institutional attributes in adaptation situations. It conceptually organises and decomposes the many details of institutions that empirical research has shown to shape climate adaptation. In the second step, the paper identifies archetypical patterns of institutional traps and trade-offs which hamper adaptation. Thirdly, corresponding opportunities are identified that enable actors to alleviate, prevent or overcome specific institutional traps or trade-offs. These results cast doubt on the validity of general institutional design principles for successful adaptation. In contrast to generic principles, the identified opportunities provide leverage to match institutions to specific governance problems that are encountered in specific contexts. Taken together, the results may contribute to more coherence and integration of adaptation research that we need if we are to foster learning about the role of institutions in adaptation situations in a cumulative fashion.

Non-tariff barriers, integration and the transatlantic economy

We examine the potential impact of TTIP through trade-cost reductions, applying a mix of econometric and computational methods to develop estimates of the benefits (and costs) for the EU, United States, and third countries. Econometric results point to an approximate 80% growth in bilateral trade with an ambitious trade agreement. However, at the same time, computable general equilibrium (CGE) estimates highlight distributional impacts across countries and factors not evident from econometrics alone. Translated through our CGE framework, while bilateral trade increases roughly 80%, there is a fall of about 2.5% in trade with the rest of the world in our central case. The estimated gains in annual consumption range between 1% and 2.25% for the United States and EU, respectively. A purely discriminatory agreement would harm most countries outside the agreement, while the direction of third-country effects hinges critically on whether NTB reductions end up being discriminatory or not. Within the United States and EU, while labour gains across skill categories, the impact on farmers is mixed.