139 research outputs found
Force-induced misfolding in RNA
RNA folding is a kinetic process governed by the competition of a large
number of structures stabilized by the transient formation of base pairs that
may induce complex folding pathways and the formation of misfolded structures.
Despite of its importance in modern biophysics, the current understanding of
RNA folding kinetics is limited by the complex interplay between the weak
base-pair interactions that stabilize the native structure and the disordering
effect of thermal forces. The possibility of mechanically pulling individual
molecules offers a new perspective to understand the folding of nucleic acids.
Here we investigate the folding and misfolding mechanism in RNA secondary
structures pulled by mechanical forces. We introduce a model based on the
identification of the minimal set of structures that reproduce the patterns of
force-extension curves obtained in single molecule experiments. The model
requires only two fitting parameters: the attempt frequency at the level of
individual base pairs and a parameter associated to a free energy correction
that accounts for the configurational entropy of an exponentially large number
of neglected secondary structures. We apply the model to interpret results
recently obtained in pulling experiments in the three-helix junction S15 RNA
molecule (RNAS15). We show that RNAS15 undergoes force-induced misfolding where
force favors the formation of a stable non-native hairpin. The model reproduces
the pattern of unfolding and refolding force-extension curves, the distribution
of breakage forces and the misfolding probability obtained in the experiments.Comment: 28 pages, 11 figure
Trap models with slowly decorrelating observables
We study the correlation and response dynamics of trap models of glassy
dynamics, considering observables that only partially decorrelate with every
jump. This is inspired by recent work on a microscopic realization of such
models, which found strikingly simple linear out-of-equilibrium
fluctuation-dissipation relations in the limit of slow decorrelation. For the
Barrat-Mezard model with its entropic barriers we obtain exact results at zero
temperature for arbitrary decorrelation factor . These are then
extended to nonzero , where the qualitative scaling behaviour and all
scaling exponents can still be found analytically. Unexpectedly, the choice of
transition rates (Glauber versus Metropolis) affects not just prefactors but
also some exponents. In the limit of slow decorrelation even complete scaling
functions are accessible in closed form. The results show that slowly
decorrelating observables detect persistently slow out-of-equilibrium dynamics,
as opposed to intermittent behaviour punctuated by excursions into fast,
effectively equilibrated states.Comment: 29 pages, IOP styl
Tailoring symmetry groups using external alternate fields
Macroscopic systems with continuous symmetries subjected to oscillatory
fields have phases and transitions that are qualitatively different from their
equilibrium ones. Depending on the amplitude and frequency of the fields
applied, Heisenberg ferromagnets can become XY or Ising-like -or, conversely,
anisotropies can be compensated -thus changing the nature of the ordered phase
and the topology of defects. The phenomena can be viewed as a dynamic form of
"order by disorder".Comment: 4 pages, 2 figures finite dimension and selection mechanism clarifie
Dynamical transition for a particle in a squared Gaussian potential
We study the problem of a Brownian particle diffusing in finite dimensions in
a potential given by where is Gaussian random field.
Exact results for the diffusion constant in the high temperature phase are
given in one and two dimensions and it is shown to vanish in a power-law
fashion at the dynamical transition temperature. Our results are confronted
with numerical simulations where the Gaussian field is constructed, in a
standard way, as a sum over random Fourier modes. We show that when the number
of Fourier modes is finite the low temperature diffusion constant becomes
non-zero and has an Arrhenius form. Thus we have a simple model with a fully
understood finite size scaling theory for the dynamical transition. In addition
we analyse the nature of the anomalous diffusion in the low temperature regime
and show that the anomalous exponent agrees with that predicted by a trap
model.Comment: 18 pages, 4 figures .eps, JPA styl
Virosaurus A Reference to Explore and Capture Virus Genetic Diversity.
The huge genetic diversity of circulating viruses is a challenge for diagnostic assays for emerging or rare viral diseases. High-throughput technology offers a new opportunity to explore the global virome of patients without preconception about the culpable pathogens. It requires a solid reference dataset to be accurate. Virosaurus has been designed to offer a non-biased, automatized and annotated database for clinical metagenomics studies and diagnosis. Raw viral sequences have been extracted from GenBank, and cleaned up to remove potentially erroneous sequences. Complete sequences have been identified for all genera infecting vertebrates, plants and other eukaryotes (insect, fungus, etc.). To facilitate the analysis of clinically relevant viruses, we have annotated all sequences with official and common virus names, acronym, genotypes, and genomic features (linear, circular, DNA, RNA, etc.). Sequences have been clustered to remove redundancy at 90% or 98% identity. The analysis of clustering results reveals the state of the virus genetic landscape knowledge. Because herpes and poxviruses were under-represented in complete genomes considering their potential diversity in nature, we used genes instead of complete genomes for those in Virosaurus
Number partitioning as random energy model
Number partitioning is a classical problem from combinatorial optimisation.
In physical terms it corresponds to a long range anti-ferromagnetic Ising spin
glass. It has been rigorously proven that the low lying energies of number
partitioning behave like uncorrelated random variables. We claim that
neighbouring energy levels are uncorrelated almost everywhere on the energy
axis, and that energetically adjacent configurations are uncorrelated, too.
Apparently there is no relation between geometry (configuration) and energy
that could be exploited by an optimization algorithm. This ``local random
energy'' picture of number partitioning is corroborated by numerical
simulations and heuristic arguments.Comment: 8+2 pages, 9 figures, PDF onl
MAR-Mediated transgene integration into permissive chromatin and increased expression by recombination pathway engineering.
Untargeted plasmid integration into mammalian cell genomes remains a poorly understood and inefficient process. The formation of plasmid concatemers and their genomic integration has been ascribed either to non-homologous end-joining (NHEJ) or homologous recombination (HR) DNA repair pathways. However, a direct involvement of these pathways has remained unclear. Here, we show that the silencing of many HR factors enhanced plasmid concatemer formation and stable expression of the gene of interest in Chinese hamster ovary (CHO) cells, while the inhibition of NHEJ had no effect. However, genomic integration was decreased by the silencing of specific HR components, such as Rad51, and DNA synthesis-dependent microhomology-mediated end-joining (SD-MMEJ) activities. Genome-wide analysis of the integration loci and junction sequences validated the prevalent use of the SD-MMEJ pathway for transgene integration close to cellular genes, an effect shared with matrix attachment region (MAR) DNA elements that stimulate plasmid integration and expression. Overall, we conclude that SD-MMEJ is the main mechanism driving the illegitimate genomic integration of foreign DNA in CHO cells, and we provide a recombination engineering approach that increases transgene integration and recombinant protein expression in these cells. Biotechnol. Bioeng. 2017;114: 384-396. © 2016 The Authors. Biotechnology and Bioengineering published by Wiley Periodicals, Inc
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