µ-Calpain Conversion of Antiapoptotic Bfl-1 (BCL2A1) into a Prodeath Factor Reveals Two Distinct alpha-Helices Inducing Mitochondria-Mediated Apoptosis

Anti-apoptotic Bfl-1 and pro-apoptotic Bax, two members of the Bcl-2 family sharing a similar structural fold, are classically viewed as antagonist regulators of apoptosis. However, both proteins were reported to be death inducers following cleavage by the cysteine protease µ-calpain. Here we demonstrate that calpain-mediated cleavage of full-length Bfl-1 induces the release of C-terminal membrane active α-helices that are responsible for its conversion into a pro-apoptotic factor. A careful comparison of the different membrane-active regions present in the Bfl-1 truncated fragments with homologous domains of Bax show that helix α5, but not α6, of Bfl-1 induces cell death and cytochrome c release from purified mitochondria through a Bax/Bak-dependent mechanism. In contrast, both helices α5 and α6 of Bax permeabilize mitochondria regardless of the presence of Bax or Bak. Moreover, we provide evidence that the α9 helix of Bfl-1 promotes cytochrome c release and apoptosis through a unique membrane-destabilizing action whereas Bax-α9 does not display such activities. Hence, despite a common 3D-structure, C-terminal toxic domains present on Bfl-1 and Bax function in a dissimilar manner to permeabilize mitochondria and induce apoptosis. These findings provide insights for designing therapeutic approaches that could exploit the cleavage of endogenous Bcl-2 family proteins or the use of Bfl-1/Bax-derived peptides to promote tumor cell clearance

The financialization of mass wealth, banking crises and politics over the long run

The co-evolution of democratic politics and mass, financialized wealth has destabilized highly integrated financial systems and the socio-political underpinnings of neoliberal policy norms at domestic and global levels. Over the long run, it has increased the political pressure on governments to undertake bailouts during major banking crises and, by raising voters’ attentiveness to wealth losses and distributional inequities, has sharply raised the bar for government performance. The result has been more costly bailouts, greater political instability and the sustained politicization of wealth cleavages in crisis aftermaths. We underline the crucial importance and modernity of this phenomenon by showing how the high concentration of wealth in pre-1914 Britain and America among elites was associated with limited crisis interventions and surprisingly tranquil political aftermaths. By contrast, the 2007–2009 crises in both countries epitomise the political dilemmas facing elected governments in a new world of mass financialized wealth and the impact on political polarization and democratic politics. We show that these dilemmas were embryonic in the interwar period and highlight how the evolutionary forces shaping policy and political outcomes reveal the importance of time, context and the effects of long cycles in the world economy and global politics

Influence of soil phosphorus and manure on phosphorus leaching in Swedish topsoils

In Sweden, subsurface transport of phosphorus (P) from agricultural soils represents the primary pathway of concern for surface water quality. However, there are mixed findings linking P in leachate with soil P and limited understanding of the interactive effects of applied P sources and soil test P on P leaching potential. Identifying soils that are susceptible to P leaching when manure is applied is critical to management strategies that reduce P loadings to water bodies. Intact soil columns (20 cm deep) from five long-term fertilization trials across Sweden were used in leaching experiments with simulated rainfall to explore the interactive effects of dairy cow (Bos taurus L.) manure application, soil test P and cropping system. Strong relationships were observed between ammonium-lactate extractable P in soil and dissolved reactive P (DRP) concentrations in leachate, although regression slopes varied across soils. For three soils, application of manure (equal to 21-30 kg P ha-1) to the soil columns significantly increased DRP leaching losses. The increase in DRP concentration was correlated to soil test P, but with wide variations between the three soils. For two soils leachate P concentrations after manure addition were independent of soil P status. Despite variable trends in P leaching across the different soils, P concentrations in leachate were always moderate from soils at fertilization rates equivalent to P removal with harvest. Results clearly stress the importance of long-term P balance to limit P leaching losses from Swedish agricultural soils