MicroRNA control of Nodal signalling

MicroRNAs are crucial modulators of gene expression, yet their involvement as effectors of growth factor signalling is largely unknown. Ligands of the transforming growth factor-beta superfamily are essential for development and adult tissue homeostasis. In early Xenopus embryos, signalling by the transforming growth factor-beta ligand Nodal is crucial for the dorsal induction of the Spemann's organizer. Here we report that Xenopus laevis microRNAs miR-15 and miR-16 restrict the size of the organizer by targeting the Nodal type II receptor Acvr2a. Endogenous miR-15 and miR-16 are ventrally enriched as they are negatively regulated by the dorsal Wnt/beta-catenin pathway. These findings exemplify the relevance of microRNAs as regulators of early embryonic patterning acting at the crossroads of fundamental signalling cascades.     

Asymptotic normal and bootstrap inference in structural VAR analysis

The aim of the paper is to examine the performance of bootstrap and asymptotic parametric inference methods in structural VAR analysis. The results obtained through a Monte Carlo experiment suggest that the two approaches are largely equivalent in most, but not all, cases. While the asymptotic method turns out to be surprisingly robust with respect to the distribution of the errors, the bootstrap does deliver results superior in terms of both length of the confidence interval and coverage when highly non-linear statistics (such as the components of the variance of the forecast error) are considered.     

The insulin-degrading enzyme is an allosteric modulator of the 20S proteasome and a potential competitor of the 19S

The interaction of insulin-degrading enzyme (IDE) with the main intracellular proteasome assemblies (i.e, 30S, 26S and 20S) was analyzed by enzymatic activity, mass spectrometry and native gel electrophoresis. IDE was mainly detected in association with assemblies with at least one free 20S end and biochemical investigations suggest that IDE competes with the 19S in vitro. IDE directly binds the 20S and affects its proteolytic activities in a bimodal fashion, very similar in human and yeast 20S, inhibiting at (IDE)?≤?30 nM and activating at (IDE)?≥?30 nM. Only an activating effect is observed in a yeast mutant locked in the “open” conformation (i.e., the α-3ΔN 20S), envisaging a possible role of IDE as modulator of the 20S “open”–”closed” allosteric equilibrium. Protein–protein docking in silico proposes that the interaction between IDE and the 20S could involve the C-term helix of the 20S α-3 subunit which regulates the gate opening of the 20S.     

Stability criteria for complex ecosystems

Forty years ago, May proved that sufficiently large or complex ecological networks have a probability of persisting that is close to zero, contrary to previous expectations. May analysed large networks in which species interact at random. However, in natural systems pairs of species have well-defined interactions (for example predator-prey, mutualistic or competitive). Here we extend May's results to these relationships and find remarkable differences between predator-prey interactions, which are stabilizing, and mutualistic and competitive interactions, which are destabilizing. We provide analytic stability criteria for all cases. We use the criteria to prove that, counterintuitively, the probability of stability for predator-prey networks decreases when a realistic food web structure is imposed or if there is a large preponderance of weak interactions. Similarly, stability is negatively affected by nestedness in bipartite mutualistic networks. These results are found by separating the contribution of network structure and interaction strengths to stability. Stable predator-prey networks can be arbitrarily large and complex, provided that predator-prey pairs are tightly coupled. The stability criteria are widely applicable, because they hold for any system of differential equations.     

FRET studies of various conformational states adopted by transthyretin

Transthyretin (TTR) is an extracellular protein able to deposit into well-defined protein aggregates called amyloid, in pathological conditions known as senile systemic amyloidosis, familial amyloid polyneuropathy, familial amyloid cardiomyopathy and leptomeningeal amyloidosis. At least three distinct partially folded states have been described for TTR, including the widely studied amyloidogenic state at mildly acidic pH. Here, we have used fluorescence resonance energy transfer (FRET) experiments in a monomeric variant of TTR (M-TTR) and in its W41F and W79F mutants, taking advantage of the presence of a unique, solvent-exposed, cysteine residue at position 10, that we have labelled with a coumarin derivative (DACM, acceptor), and of the two natural tryptophan residues at positions 41 and 79 (donors). Trp41 is located in an ideal position as it is one of the residues of β-strand C, whose degree of unfolding is debated. We found that the amyloidogenic state at low pH has the same FRET efficiency as the folded state at neutral pH in both M-TTR and W79F-M-TTR, indicating an unmodified Cys10–Trp41 distance. The partially folded state populated at low denaturant concentrations also has a similar FRET efficiency, but other spectroscopic probes indicate that it is distinct from the amyloidogenic state at acidic pH. By contrast, the off-pathway state accumulating transiently during refolding has a higher FRET efficiency, indicating non-native interactions that reduce the Cys10–Trp41 spatial distance, revealing a third distinct conformational state. Overall, our results clarify a negligible degree of unfolding of β-strand C in the formation of the amyloidogenic state and establish the concept that TTR is a highly plastic protein able to populate at least three distinct conformational states.