Encoding folding paths of RNA switches

RNA co-transcriptional folding has long been suspected to play an active role in helping proper native folding of ribozymes and structured regulatory motifs in mRNA untranslated regions. Yet, the underlying mechanisms and coding requirements for efficient co-transcriptional folding remain unclear. Traditional approaches have intrinsic limitations to dissect RNA folding paths, as they rely on sequence mutations or circular permutations that typically perturb both RNA folding paths and equilibrium structures. Here, we show that exploiting sequence symmetries instead of mutations can circumvent this problem by essentially decoupling folding paths from equilibrium structures of designed RNA sequences. Using bistable RNA switches with symmetrical helices conserved under sequence reversal, we demonstrate experimentally that native and transiently formed helices can guide efficient co-transcriptional folding into either long-lived structure of these RNA switches. Their folding path is controlled by the order of helix nucleations and subsequent exchanges during transcription, and may also be redirected by transient antisense interactions. Hence, transient intra- and intermolecular base pair interactions can effectively regulate the folding of nascent RNA molecules into different native structures, provided limited coding requirements, as discussed from an information theory perspective. This constitutive coupling between RNA synthesis and RNA folding regulation may have enabled the early emergence of autonomous RNA-based regulation networks.Comment: 9 pages, 6 figure

Localized Joule heating produced by ion current focusing through micron-size holes

We provide an experimental demonstration that the focusing of ionic currents in a micron size hole connecting two chambers can produce local temperature increases of up to $100^\circ$ C with gradients as large as $1^\circ$ K$\mu m^{-1}$. We find a good agreement between the measured temperature profiles and a finite elements-based numerical calculation. We show how the thermal gradients can be used to measure the full melting profile of DNA duplexes within a region of 40 $\mu$m. The possibility to produce even larger gradients using sub-micron pores is discussed.Comment: 3 pages, accepted to Appl. Phys. Lett

Kinefold web server for RNA/DNA folding path and structure prediction including pseudoknots and knots

The Kinefold web server provides a web interface for stochastic folding simulations of nucleic acids on second to minute molecular time scales. Renaturation or co-transcriptional folding paths are simulated at the level of helix formation and dissociation in agreement with the seminal experimental results. Pseudoknots and topologically ‘entangled’ helices (i.e. knots) are efficiently predicted taking into account simple geometrical and topological constraints. To encourage interactivity, simulations launched as immediate jobs are automatically stopped after a few seconds and return adapted recommendations. Users can then choose to continue incomplete simulations using the batch queuing system or go back and modify suggested options in their initial query. Detailed output provide (i) a series of low free energy structures, (ii) an online animated folding path and (iii) a programmable trajectory plot focusing on a few helices of interest to each user. The service can be accessed at

Durkheim: Eine Moralwissenschaft für eine laizistische Moral

Die hohe Bedeutung, die Durkheim der Moral beimisst, ist aufs Engste mit einer Bewusstwerdung des Niedergangs der Religion als traditioneller Stütze der Moral verbunden. Es ist kein Zufall, dass der erste von Durkheim veröffentlichte Artikel die positive Moralwissenschaft in Deutschland behandelt und der letzte Text, den wir von ihm besitzen, der Moral eine wissenschaftliche Begründung verschaffen will. Durkheim selbst hat zwar kein Buch mit dem expliziten Thema einer laizistischen Moral verö..

L’Élaboration de la notion de sacré dans l’« école » durkheimienne

In Durkheim’s works the notion of the holy progressively acquires an importance it does not have at the beginning. A reading of Robertson Smith and the works of Hubert and Mauss give Durkheim’s reflexion a new basis which finds its full expression in the synthesis of The Elementary Forms of the Religious Life

Durkheim: Eine Moralwissenschaft für eine laizistische Moral

Die hohe Bedeutung, die Durkheim der Moral beimisst, ist aufs Engste mit einer Bewusstwerdung des Niedergangs der Religion als traditioneller Stütze der Moral verbunden. Es ist kein Zufall, dass der erste von Durkheim veröffentlichte Artikel die positive Moralwissenschaft in Deutschland behandelt und der letzte Text, den wir von ihm besitzen, der Moral eine wissenschaftliche Begründung verschaffen will. Durkheim selbst hat zwar kein Buch mit dem expliziten Thema einer laizistischen Moral verö..

Durkheim : une science de la morale pour une morale laïque

On the basis of quotations from his works, the author presents a Durkheim who is not only a sociologist but a moralist. True to his original exigencies, Durkheim’s intention is to deduce, from the facts, a purely scientific method which would provide modern man — over and above any religions considerations or traditionnal moral values — with a means of gaining mastery over moral facts, just as science, for its part, provides man with the ability to gain mastery over other facts of nature

Probing complex RNA structures by mechanical force

RNA secondary structures of increasing complexity are probed combining single molecule stretching experiments and stochastic unfolding/refolding simulations. We find that force-induced unfolding pathways cannot usually be interpretated by solely invoking successive openings of native helices. Indeed, typical force-extension responses of complex RNA molecules are largely shaped by stretching-induced, long-lived intermediates including non-native helices. This is first shown for a set of generic structural motifs found in larger RNA structures, and then for Escherichia coli's 1540-base long 16S ribosomal RNA, which exhibits a surprisingly well-structured and reproducible unfolding pathway under mechanical stretching. Using out-of-equilibrium stochastic simulations, we demonstrate that these experimental results reflect the slow relaxation of RNA structural rearrangements. Hence, micromanipulations of single RNA molecules probe both their native structures and long-lived intermediates, so-called "kinetic traps", thereby capturing -at the single molecular level- the hallmark of RNA folding/unfolding dynamics.Comment: 9 pages, 9 figure

Prediction and statistics of pseudoknots in RNA structures using exactly clustered stochastic simulations

Ab initio RNA secondary structure predictions have long dismissed helices interior to loops, so-called pseudoknots, despite their structural importance. Here, we report that many pseudoknots can be predicted through long time scales RNA folding simulations, which follow the stochastic closing and opening of individual RNA helices. The numerical efficacy of these stochastic simulations relies on an O(n^2) clustering algorithm which computes time averages over a continously updated set of n reference structures. Applying this exact stochastic clustering approach, we typically obtain a 5- to 100-fold simulation speed-up for RNA sequences up to 400 bases, while the effective acceleration can be as high as 100,000-fold for short multistable molecules (<150 bases). We performed extensive folding statistics on random and natural RNA sequences, and found that pseudoknots are unevenly distributed amongst RNAstructures and account for up to 30% of base pairs in G+C rich RNA sequences (Online RNA folding kinetics server including pseudoknots : http://kinefold.u-strasbg.fr/ ).Comment: 6 pages, 5 figure