Redefining British policy at the beginning of the Cold War: South-East Europe in London's foreign policy strategies

Great Britain played a significant part in the endeavours directed at organizing the peace process in the aftermath of the Second World War. A series of myths were consequently associated to its actions and foreign policies-related decisions, myths that still surface to the present day in some areas, especially with regard to London's attitude towards Eastern-European countries. Our study proposes a more nuanced approach of the events of the first post-war years, focusing primarily on the impact the domestic situation of the Empire had upon its foreign policy decisions. Our research is based on the recent contributions of several British and Eastern-European researchers who shed new light on Great Britain's attitude towards South-Eastern Europe. Our study discusses the factors that influenced the foreign policy decisions taken by London with regard to that region, by attempting to analyse the general framework from less explored perspectives

Worm-like ising model for protein mechanical unfolding under the effect of osmolytes.

We show via single-molecule mechanical unfolding experiments that the osmolyte glycerol stabilizes the native state of the human cardiac I27 titin module against unfolding without shifting its unfolding transition state on the mechanical reaction coordinate. Taken together with similar findings on the immunoglobulin-binding domain of streptococcal protein G (GB1), these experimental results suggest that osmolytes act on proteins through a common mechanism that does not entail a shift of their unfolding transition state. We investigate the above common mechanism via an Ising-like model for protein mechanical unfolding that adds worm-like-chain behavior to a recent generalization of the Wako-Sait\uf4-Mu\uf1oz-Eaton model with support for group-transfer free energies. The thermodynamics of the model are exactly solvable, while protein kinetics under mechanical tension can be simulated via Monte Carlo algorithms. Notably, our force-clamp and velocity-clamp simulations exhibit no shift in the position of the unfolding transition state of GB1 and I27 under the effect of various osmolytes. The excellent agreement between experiment and simulation strongly suggests that osmolytes do not assume a structural role at the mechanical unfolding transition state of proteins, acting instead by adjusting the solvent quality for the protein chain analyte

Observing the osmophobic effect in action at the single molecule level

Protecting osmolytes are widespread small organic molecules able to stabilize the folded state of most proteins against various denaturing stresses in vivo. The osmophobic model explains thermodynamically their action through a preferential exclusion of the osmolyte molecules from the protein surface, thus favoring the formation of intrapeptide hydrogen bonds. Few works addressed the influence of protecting osmolytes on the protein unfolding transition state and kinetics. Among those, previous single molecule force spectroscopy experiments evidenced a complexation of the protecting osmolyte molecules at the unfolding transition state of the protein, in apparent contradiction with the osmophobic nature of the protein backbone. We present single-molecule evidence that glycerol, which is a ubiquitous protecting osmolyte, stabilizes a globular protein against mechanical unfolding without binding into its unfolding transition state structure. We show experimentally that glycerol does not change the position of the unfolding transition state as projected onto the mechanical reaction coordinate. Moreover, we compute theoretically the projection of the unfolding transition state onto two other common reaction coordinates, that is, the number of native peptide bonds and the weighted number of native contacts. To that end, we augment an analytic Ising-like protein model with support for group-transfer free energies. Using this model, we find again that the position of the unfolding transition state does not change in the presence of glycerol, giving further support to the conclusions based on the single-molecule experiments

Single-molecule-level evidence for the osmophobic effect.

Protecting osmolytes play a crucial role in preventing protein denaturation in harsh environmental conditions of living organisms. Experimental evidence is provided for a mechanism of protein-fold stabilization by these molecules that is in accord with the hypothesis of a backbone-based osmophobic effect. (In picture: \u394G=free energy, [O]=osmolyte concentration, \u3c7=unfolding reaction coordinate.

The chaperone-like protein 14-3-3\u3b7 interacts with human \u3b1-synuclein aggregation intermediates rerouting the amyloidogenic pathway and reducing \u3b1-synuclein cellular toxicity.

Familial and idiopathic Parkinson's disease (PD) is associated with the abnormal neuronal accumulation of \u3b1-synuclein (aS) leading to \u3b2-sheet-rich aggregates called Lewy Bodies (LBs). Moreover, single point mutation in aS gene and gene multiplication lead to autosomal dominant forms of PD. A connection between PD and the 14-3-3 chaperone-like proteins was recently proposed, based on the fact that some of the 14-3-3 isoforms can interact with genetic PD-associated proteins such as parkin, LRRK2 and aS and were found as components of LBs in human PD. In particular, a direct interaction between 14-3-3\u3b7 and aS was reported when probed by co-immunoprecipitation from cell models, from parkinsonian brains and by surface plasmon resonance in vitro. However, the mechanisms through which 14-3-3\u3b7 and aS interact in PD brains remain unclear. Herein, we show that while 14-3-3\u3b7 is unable to bind monomeric aS, it interacts with aS oligomers which occur during the early stages of aS aggregation. This interaction diverts the aggregation process even when 14-3-3\u3b7 is present in sub stoichiometric amounts relative to aS. When aS level is overwhelmingly higher than that of 14-3-3\u3b7, the fibrillation process becomes a sequestration mechanism for 14-3-3\u3b7, undermining all processes governed by this protein. Using a panel of complementary techniques, we single out the stage of aggregation at which the aS/14-3-3\u3b7 interaction occurs, characterize the products of the resulting processes, and show how the processes elucidated in vitro are relevant in cell models. Our findings constitute a first step in elucidating the molecular mechanism of aS/14-3-3\u3b7 interaction and in understanding the critical aggregation step at which 14-3-3\u3b7 has the potential to rescue aS-induced cellular toxicity