Estimating telomere length from whole genome sequence data.

Telomeres play a key role in replicative ageing and undergo age-dependent attrition in vivo. Here, we report a novel method, TelSeq, to measure average telomere length from whole genome or exome shotgun sequence data. In 260 leukocyte samples, we show that TelSeq results correlate with Southern blot measurements of the mean length of terminal restriction fragments (mTRFs) and display age-dependent attrition comparably well as mTRFs

New Renormalization Group Results for Scaling of Self-Avoiding Tethered Membranes

The scaling properties of self-avoiding polymerized 2-dimensional membranes are studied via renormalization group methods based on a multilocal operator product expansion. The renormalization group functions are calculated to second order. This yields the scaling exponent nu to order epsilon^2. Our extrapolations for nu agree with the Gaussian variational estimate for large space dimension d and are close to the Flory estimate for d=3. The interplay between self-avoidance and rigidity at small d is briefly discussed.Comment: 97 pages, 120 .eps-file

Scaling of Selfavoiding Tethered Membranes: 2-Loop Renormalization Group Results

The scaling properties of selfavoiding polymerized membranes are studied using renormalization group methods. The scaling exponent \nu is calculated for the first time at two loop order. \nu is found to agree with the Gaussian variational estimate for large space dimension d and to be close to the Flory estimate for d=3.Comment: 4 pages, RevTeX + 20 .eps file

The Statistical Mechanics of Membranes

The fluctuations of two-dimensional extended objects membranes is a rich and exciting field with many solid results and a wide range of open issues. We review the distinct universality classes of membranes, determined by the local order, and the associated phase diagrams. After a discussion of several physical examples of membranes we turn to the physics of crystalline (or polymerized) membranes in which the individual monomers are rigidly bound. We discuss the phase diagram with particular attention to the dependence on the degree of self-avoidance and anisotropy. In each case we review and discuss analytic, numerical and experimental predictions of critical exponents and other key observables. Particular emphasis is given to the results obtained from the renormalization group epsilon-expansion. The resulting renormalization group flows and fixed points are illustrated graphically. The full technical details necessary to perform actual calculations are presented in the Appendices. We then turn to a discussion of the role of topological defects whose liberation leads to the hexatic and fluid universality classes. We finish with conclusions and a discussion of promising open directions for the future.Comment: 75 LaTeX pages, 36 figures. To appear in Physics Reports in the Proceedings of RG2000, Taxco, 199

Generalizing the O(N)-field theory to N-colored manifolds of arbitrary internal dimension D

We introduce a geometric generalization of the O(N)-field theory that describes N-colored membranes with arbitrary dimension D. As the O(N)-model reduces in the limit N->0 to self-avoiding polymers, the N-colored manifold model leads to self-avoiding tethered membranes. In the other limit, for inner dimension D->1, the manifold model reduces to the O(N)-field theory. We analyze the scaling properties of the model at criticality by a one-loop perturbative renormalization group analysis around an upper critical line. The freedom to optimize with respect to the expansion point on this line allows us to obtain the exponent \nu of standard field theory to much better precision that the usual 1-loop calculations. Some other field theoretical techniques, such as the large N limit and Hartree approximation, can also be applied to this model. By comparison of low and high temperature expansions, we arrive at a conjecture for the nature of droplets dominating the 3d-Ising model at criticality, which is satisfied by our numerical results. We can also construct an appropriate generalization that describes cubic anisotropy, by adding an interaction between manifolds of the same color. The two parameter space includes a variety of new phases and fixed points, some with Ising criticality, enabling us to extract a remarkably precise value of 0.6315 for the exponent \nu in d=3. A particular limit of the model with cubic anisotropy corresponds to the random bond Ising problem; unlike the field theory formulation, we find a fixed point describing this system at 1-loop order.Comment: 57 pages latex, 26 figures included in the tex

Universal Negative Poisson Ratio of Self Avoiding Fixed Connectivity Membranes

We determine the Poisson ratio of self-avoiding fixed-connectivity membranes, modeled as impenetrable plaquettes, to be sigma=-0.37(6), in statistical agreement with the Poisson ratio of phantom fixed-connectivity membranes sigma=-0.32(4). Together with the equality of critical exponents, this result implies a unique universality class for fixed-connectivity membranes. Our findings thus establish that physical fixed-connectivity membranes provide a wide class of auxetic (negative Poisson ratio) materials with significant potential applications in materials science.Comment: 4 pages, 3 figures, LaTeX (revtex) Published version - title changed, one figure improved and one reference change

Pharmacokinetics, pharmacodynamics and adverse event profile of GSK2256294, a novel soluble epoxide hydrolase inhibitor.

AIMS: Endothelial-derived epoxyeicosatrienoic acids may regulate vascular tone and are metabolized by soluble epoxide hydrolase enzymes (sEH). GSK2256294 is a potent and selective sEH inhibitor that was tested in two phase I studies. METHODS: Single escalating doses of GSK2256294 2-20 mg or placebo were administered in a randomized crossover design to healthy male subjects or obese smokers. Once daily doses of 6 or 18 mg or placebo were administered for 14 days to obese smokers. Data were collected on safety, pharmacokinetics, sEH enzyme inhibition and blood biomarkers. Single doses of GSK2256294 10 mg were also administered to healthy younger males or healthy elderly males and females with and without food. Data on safety, pharmacokinetics and biliary metabolites were collected. RESULTS: GSK2256294 was well-tolerated with no serious adverse events (AEs) attributable to the drug. The most frequent AEs were headache and contact dermatitis. Plasma concentrations of GSK2256294 increased with single doses, with a half-life averaging 25-43 h. There was no significant effect of age, food or gender on pharmacokinetic parameters. Inhibition of sEH enzyme activity was dose-dependent, from an average of 41.9% on 2 mg (95% confidence interval [CI] -51.8, 77.7) to 99.8% on 20 mg (95% CI 99.3, 100.0) and sustained for up to 24 h. There were no significant changes in serum VEGF or plasma fibrinogen. CONCLUSIONS: GSK2256294 was well-tolerated and demonstrated sustained inhibition of sEH enzyme activity. These data support further investigation in patients with endothelial dysfunction or abnormal tissue repair, such as diabetes, wound healing or COPD.LY is funded by a Wellcome Trust-GSK Translational Medicine and Therapeutics (TMAT) Studentship and a Raymond and Beverley Sackler Fellowship. IW is a British Heart Foundation Senior Clinical Fellow and both JC and IW are supported by the Cambridge NIHR Biomedical Research Centre. Funding for the two studies (NCT01762774 and NCT02006537) was provided by GSK. Partial funding for study 1 was provided by the Innovate UK Stratified Medicines programme (ERICA Consortium).This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1111/bcp.1285