Experimental and theoretical studies of sequence effects on the fluctuation and melting of short DNA molecules

Understanding the melting of short DNA sequences probes DNA at the scale of the genetic code and raises questions which are very different from those posed by very long sequences, which have been extensively studied. We investigate this problem by combining experiments and theory. A new experimental method allows us to make a mapping of the opening of the guanines along the sequence as a function of temperature. The results indicate that non-local effects may be important in DNA because an AT-rich region is able to influence the opening of a base pair which is about 10 base pairs away. An earlier mesoscopic model of DNA is modified to correctly describe the time scales associated to the opening of individual base pairs well below melting, and to properly take into account the sequence. Using this model to analyze some characteristic sequences for which detailed experimental data on the melting is available [Montrichok et al. 2003 Europhys. Lett. {\bf 62} 452], we show that we have to introduce non-local effects of AT-rich regions to get acceptable results. This brings a second indication that the influence of these highly fluctuating regions of DNA on their neighborhood can extend to some distance.Comment: To be published in J. Phys. Condensed Matte

Effect of β-cyclodextrin on trans fats, CLA, PUFA, and phospholipids of milk fat: Method update

Peer Reviewe

On the dynamic adaptation of language models based on dialogue information

We present an approach to adapt dynamically the language models (LMs) used by a speech recognizer that is part of a spoken dialogue system. We have developed a grammar generation strategy that automatically adapts the LMs using the semantic information that the user provides (represented as dialogue concepts), together with the information regarding the intentions of the speaker (inferred by the dialogue manager, and represented as dialogue goals). We carry out the adaptation as a linear interpolation between a background LM, and one or more of the LMs associated to the dialogue elements (concepts or goals) addressed by the user. The interpolation weights between those models are automatically estimated on each dialogue turn, using measures such as the posterior probabilities of concepts and goals, estimated as part of the inference procedure to determine the actions to be carried out. We propose two approaches to handle the LMs related to concepts and goals. Whereas in the first one we estimate a LM for each one of them, in the second one we apply several clustering strategies to group together those elements that share some common properties, and estimate a LM for each cluster. Our evaluation shows how the system can estimate a dynamic model adapted to each dialogue turn, which helps to improve the performance of the speech recognition (up to a 14.82% of relative improvement), which leads to an improvement in both the language understanding and the dialogue management tasks

Improving the mesoscopic modeling of DNA denaturation dynamics

Although previously developed mesoscopic DNA models have successfully reproduced thermodynamic denaturation data, recent studies show that these overestimate the rate of denaturation by orders of magnitude. Using adapted Peyrard–Bishop–Dauxois (PBD) models, we have calculated the denaturation rates of several DNA hairpins and made comparison with experimental data. We show that the addition of a barrier at the onsite potential of the PBD model gives a more accurate description of the unzipping dynamics of short DNA sequences. The new models provide a refined theoretical insight on the dynamical mechanisms of unzipping which can have implications for the understanding of transcription and replication processes. Still, this class of adapted PBD models seems to have a fundamental limitation which implies that it is not possible to get agreement with available experimental results on the dynamics of long DNA sequences and at the same time maintain the good agreement regarding its thermodynamics. The reason for this is that the denaturation rate of long DNA chains is not dramatically lowered by the additional barrier—as the base-pairs that open are more likely to remain open, facilitating the opening of the full DNA molecule. Some care has to be taken, since experimental techniques suitable to the study of denaturation rates of long sequences seem not to agree with other experimental data on short DNA sequences. Further research, both theoretical and experimental, is therefore needed to resolve these inconsistencies—which will be a starting point for new minimalistic models that are able to describe both thermodynamics and dynamics at a predictive level.Spanish Ministry of Economy, Industry and Competitiveness (BES-2013-065453, FIS2012-38827) and the University of Burgos and the Anders Jahre fund (Project 40105000

Modelling DNA at the mesoscale: a challenge for nonlinear science?

Invited paper, in the series "Open Problems" of NonlinearityInternational audienceWhen it is viewed at the scale of a base pair, DNA appears as a nonlinear lattice. Modelling its properties is a fascinating goal. The detailed experiments that can be performed on this system impose constraints on the models and can be used as a guide to improve them. There are nevertheless many open problems, particularly to describe DNA at the scale of a few tens of base pairs, which is relevant for many biological phenomena

THE EUROPEAN PHYSICAL JOURNAL E Model for DNA hairpin denaturation

Abstract. We investigate the thermal denaturation of DNA hairpins using molecular dynamics simulations of a simple model describing the molecule at a scale of a nucleotide. The model allows us to analyze the different interacting features that determine how an hairpin opens, such as the role of the loop and the properties intrinsic to the stem. PAC

Thermal denaturation of A-DNA

The DNA molecule can take various conformational forms. Investigations focus mainly on the so-called ‘B-form’, schematically drawn in the famous paper by Watson and Crick [1]. This is the usual form of DNA in a biological environment and is the only form that is stable in an aqueous environment. Other forms, however, can teach us much about DNA. They have the same nucleotide base pairs for ‘building blocks’ as B-DNA, but with different relative positions, and studying these forms gives insight into the interactions between elements under conditions far from equilibrium in the B-form. Studying the thermal denaturation is particularly interesting because it provides a direct probe of those interactions which control the growth of the fluctuations when the ‘melting’ temperature is approached. Here we report such a study on the ‘A-form’ using calorimetry and neutron scattering. We show that it can be carried further than a similar study on B-DNA, requiring the improvement of thermodynamic models for DNA

Bubbles and denaturation in DNA

The local opening of DNA is an intriguing phenomenon from a statistical physics point of view, but is also essential for its biological function. For instance, the transcription and replication of our genetic code can not take place without the unwinding of the DNA double helix. Although these biological processes are driven by proteins, there might well be a relation between these biological openings and the spontaneous bubble formation due to thermal fluctuations. Mesoscopic models, like the Peyrard-Bishop-Dauxois model, have fairly accurately reproduced some experimental denaturation curves and the sharp phase transition in the thermodynamic limit. It is, hence, tempting to see whether these models could be used to predict the biological activity of DNA. In a previous study, we introduced a method that allows to obtain very accurate results on this subject, which showed that some previous claims in this direction, based on molecular dynamics studies, were premature. This could either imply that the present PBD should be improved or that biological activity can only be predicted in a more complex frame work that involves interactions with proteins and super helical stresses. In this article, we give detailed description of the statistical method introduced before. Moreover, for several DNA sequences, we give a thorough analysis of the bubble-statistics as function of position and bubble size and the so-called $l$-denaturation curves that can be measured experimentally. These show that some important experimental observations are missing in the present model. We discuss how the present model could be improved.Comment: 15 pages, 5 figures, published as Eur. Phys. J. E 20 : 421-434 AUG 200

Programmed cell senescence during mammalian embryonic development

Cellular senescence disables proliferation in damaged cells, and it is relevant for cancer and aging. Here, we show that senescence occurs during mammalian embryonic development at multiple locations, including the mesonephros and the endolymphatic sac of the inner ear, which we have analyzed in detail. Mechanistically, senescence in both structures is strictly dependent on p21, but independent of DNA damage, p53, or other cell-cycle inhibitors, and it is regulated by the TGF-beta/SMAD and PI3K/FOXO pathways. Developmentally programmed senescence is followed by macrophage infiltration, clearance of senescent cells, and tissue remodeling. Loss of senescence due to the absence of p21 is partially compensated by apoptosis but still results in detectable developmental abnormalities. Importantly, the mesonephros and endolymphatic sac of human embryos also show evidence of senescence. We conclude that the role of developmentally programmed senescence is to promote tissue remodeling and propose that this is the evolutionary origin of damage-induced senescence

Alteración termoxidativa en un aceite de girasol utilizado en 75 frituras de patatas

The alteration of a sunflower oil used in 75 repeated deep fat frying of potatoes performed with addition of unused oil every 4-5 fryings with the aim to keep constant the proportion food/oil in 500 g / 3 liters, was evaluated by column and high performance size exclusion chromatographies. The polar components increased from 5.09 ± 0.21 (unused oil) to 19.11 ± 0,40 mg/100 mg oil mainly due to the formation of polymers and dimers of triacylglycerides, and to oxidized triacylglycerides. Oils, unused and from the 75 frying, were included at a rate of 15% on rat-diets. Dietary food intakes were similar, however body weight gain was a 22.3% lower in rat fed with the used oil-diet. Apparent digestibility ratios of fat and protein were similar in both groups of rats, however both. Alimentary and Protein Efficiency ratios decreased on the 75 frying oil fed rats.Se evalúa la alteración de un aceite de girasol utilizado en 75 frituras repetidas de patatas, efectuadas con adición de aceite sin usar cada 4-5 frituras con la finalidad de mantener constante la proporción alimento/aceite en 500 g / 3 litros, mediante cromatografías en columna y de alta eficacia por exclusión de tamaño de partícula. El contenido de los compuestos polares se incrementó de 5.09 ± 0.21 (aceite sin usar) a 19.11 ± 0.40 mg/100 mg de aceite, predominando los polímeros y dímeros de triacilglicéridos y los triacilglicéridos oxidados. Dichos aceites, sin usar y utilizado en 75 frituras, se incluyeron en la proporción del 15% en las dietas del lote basal y del lote fritura 75, respectivamente. La ingesta de ambas dietas fue similar, pero la ganancia de peso resultó ser un 22,3% menor en el lote fritura 75. Los coeficientes de digestibilidad aparente de grasa y proteína fueron similares en ambos lotes, pero la utilización nutritiva en términos de coeficientes de Eficacia Alimentaria y Proteica fue menor en el lote fritura 75