Can one predict DNA Transcription Start Sites by studying bubbles?

It has been speculated that bubble formation of several base-pairs due to thermal fluctuations is indicatory for biological active sites. Recent evidence, based on experiments and molecular dynamics (MD) simulations using the Peyrard-Bishop-Dauxois model, seems to point in this direction. However, sufficiently large bubbles appear only seldom which makes an accurate calculation difficult even for minimal models. In this letter, we introduce a new method that is orders of magnitude faster than MD. Using this method we show that the present evidence is unsubstantiated.Comment: 4 pages, 3 figures, accepted for publication in physical review letter

P5_3 Pigs on the Wing

This article explores the possibility of a pig flying over Battersea Power Station, as shown on the Pink Floyd album ’Animals,’ and the time it would take for the pig’s height to exceed the height of the chimneys. Using the lift force equation, we graphically show the minimum wind velocity required to lift a 70 kg pig 101 m, the height of the Battersea Power Station. We find that for a pig of this mass, a wind velocity of 20.4 ms-1 was required. Furthermore, in order to measure the time for the pig to reach the height of Battersea Power Station, an acceleration of 3.8 ms-2 was calculated; this assumes a severe gale wind velocity of 24 ms-1 as defined by The Met Office. We find that it would take 7.3 s to travel the required height, assuming only vertical movement.

P5_1 ”Everybody knows the Moon is made of cheese...”: Return of the Cheddar

This Letter explores the repercussions of the Moon turning into cheddar, and finds that with the same volume and lighter mass of m = 2.49 × 1022kg, it would escape the Earth’s sphere of influence. We looked at two possible escape trajectories, prograde and retrograde, and found the new orbital distances to be between 0.73AU and 1.00AU, and between 1.00AU and 1.51AU, respectively. Thus potentially carrying the Moon very near to the orbits of Venus or Mars.

P5_2 Spaghettification: Surviving a Black Hole Event Horizon

We found that it is possible to stay conscious falling through the event horizon of aBlack Hole if the mass exceeds 19,000M_sol. This assumes the average person is ofgood health and can stay conscious with a relative force less than 5 g acting upon them

Superhelical Duplex Destabilization and the Recombination Position Effect

The susceptibility to recombination of a plasmid inserted into a chromosome varies with its genomic position. This recombination position effect is known to correlate with the average G+C content of the flanking sequences. Here we propose that this effect could be mediated by changes in the susceptibility to superhelical duplex destabilization that would occur. We use standard nonparametric statistical tests, regression analysis and principal component analysis to identify statistically significant differences in the destabilization profiles calculated for the plasmid in different contexts, and correlate the results with their measured recombination rates. We show that the flanking sequences significantly affect the free energy of denaturation at specific sites interior to the plasmid. These changes correlate well with experimentally measured variations of the recombination rates within the plasmid. This correlation of recombination rate with superhelical destabilization properties of the inserted plasmid DNA is stronger than that with average G+C content of the flanking sequences. This model suggests a possible mechanism by which flanking sequence base composition, which is not itself a context-dependent attribute, can affect recombination rates at positions within the plasmid

A stitch in time: Efficient computation of genomic DNA melting bubbles

Background: It is of biological interest to make genome-wide predictions of the locations of DNA melting bubbles using statistical mechanics models. Computationally, this poses the challenge that a generic search through all combinations of bubble starts and ends is quadratic. Results: An efficient algorithm is described, which shows that the time complexity of the task is O(NlogN) rather than quadratic. The algorithm exploits that bubble lengths may be limited, but without a prior assumption of a maximal bubble length. No approximations, such as windowing, have been introduced to reduce the time complexity. More than just finding the bubbles, the algorithm produces a stitch profile, which is a probabilistic graphical model of bubbles and helical regions. The algorithm applies a probability peak finding method based on a hierarchical analysis of the energy barriers in the Poland-Scheraga model. Conclusions: Exact and fast computation of genomic stitch profiles is thus feasible. Sequences of several megabases have been computed, only limited by computer memory. Possible applications are the genome-wide comparisons of bubbles with promotors, TSS, viral integration sites, and other melting-related regions.Comment: 16 pages, 10 figure

Ronin Governs Early Heart Development by Controlling Core Gene Expression Programs.

Ronin (THAP11), a DNA-binding protein that evolved from a primordial DNA transposon by molecular domestication, recognizes a hyperconserved promoter sequence to control developmentally and metabolically essential genes in pluripotent stem cells. However, it remains unclear whether Ronin or related THAP proteins perform similar functions in development. Here, we present evidence that Ronin functions within the nascent heart as it arises from the mesoderm and forms a four-chambered organ. We show that Ronin is vital for cardiogenesis during midgestation by controlling a set of critical genes. The activity of Ronin coincided with the recruitment of its cofactor, Hcf-1, and the elevation of H3K4me3 levels at specific target genes, suggesting the involvement of an epigenetic mechanism. On the strength of these findings, we propose that Ronin activity during cardiogenesis offers a template to understand how important gene programs are sustained across different cell types within a developing organ such as the heart

Theoretical Analysis of Competing Conformational Transitions in Superhelical DNA

We develop a statistical mechanical model to analyze the competitive behavior of transitions to multiple alternate conformations in a negatively supercoiled DNA molecule of kilobase length and specified base sequence. Since DNA superhelicity topologically couples together the transition behaviors of all base pairs, a unified model is required to analyze all the transitions to which the DNA sequence is susceptible. Here we present a first model of this type. Our numerical approach generalizes the strategy of previously developed algorithms, which studied superhelical transitions to a single alternate conformation. We apply our multi-state model to study the competition between strand separation and B-Z transitions in superhelical DNA. We show this competition to be highly sensitive to temperature and to the imposed level of supercoiling. Comparison of our results with experimental data shows that, when the energetics appropriate to the experimental conditions are used, the competition between these two transitions is accurately captured by our algorithm. We analyze the superhelical competition between B-Z transitions and denaturation around the c-myc oncogene, where both transitions are known to occur when this gene is transcribing. We apply our model to explore the correlation between stress-induced transitions and transcriptional activity in various organisms. In higher eukaryotes we find a strong enhancement of Z-forming regions immediately 5′ to their transcription start sites (TSS), and a depletion of strand separating sites in a broad region around the TSS. The opposite patterns occur around transcript end locations. We also show that susceptibility to each type of transition is different in eukaryotes and prokaryotes. By analyzing a set of untranscribed pseudogenes we show that the Z-susceptibility just downstream of the TSS is not preserved, suggesting it may be under selection pressure

UK Environmental Change Network stakeholder consultation

During the Environmental Change Network (ECN) site mangers meeting feedback on the role of UK-SCAPE funding was sought. Representatives from collaborating institutions did not restrict their comments to only the period of UK-SCAPE, as this program is a continuation of previous national capability funding. The stakeholders present appreciated the role of UKCEH through the processes of co-design, co-delivery and co-development in shaping the ECN. They further commented on the co-dependency conferred by the network for their institutions and sites. While several stakeholders noted that they could not benefit directly from UK-SCAPE funding they recognised that funding was required for coordination of the network in addition to collecting monitoring data. They highlighted the risk of failure of the network and the lost opportunities in terms of collaborative working and data delivery to the research community if funding is not maintained in the network

Mesoscopic models for DNA stretching under force: new results and comparison to experiments

Single molecule experiments on B-DNA stretching have revealed one or two structural transitions, when increasing the external force. They are characterized by a sudden increase of DNA contour length and a decrease of the bending rigidity. It has been proposed that the first transition, at forces of 60--80 pN, is a transition from B to S-DNA, viewed as a stretched duplex DNA, while the second one, at stronger forces, is a strand peeling resulting in single stranded DNAs (ssDNA), similar to thermal denaturation. But due to experimental conditions these two transitions can overlap, for instance for poly(dA-dT). We derive analytical formula using a coupled discrete worm like chain-Ising model. Our model takes into account bending rigidity, discreteness of the chain, linear and non-linear (for ssDNA) bond stretching. In the limit of zero force, this model simplifies into a coupled model already developed by us for studying thermal DNA melting, establishing a connexion with previous fitting parameter values for denaturation profiles. We find that: (i) ssDNA is fitted, using an analytical formula, over a nanoNewton range with only three free parameters, the contour length, the bending modulus and the monomer size; (ii) a surprisingly good fit on this force range is possible only by choosing a monomer size of 0.2 nm, almost 4 times smaller than the ssDNA nucleobase length; (iii) mesoscopic models are not able to fit B to ssDNA (or S to ss) transitions; (iv) an analytical formula for fitting B to S transitions is derived in the strong force approximation and for long DNAs, which is in excellent agreement with exact transfer matrix calculations; (v) this formula fits perfectly well poly(dG-dC) and $\lambda$-DNA force-extension curves with consistent parameter values; (vi) a coherent picture, where S to ssDNA transitions are much more sensitive to base-pair sequence than the B to S one, emerges.Comment: 14 pages, 9 figure