Mechanism of strand displacement synthesis by DNA replicative polymerases

Replicative holoenzymes exhibit rapid and processive primer extension DNA synthesis, but inefficient strand displacement DNA synthesis. We investigated the bacteriophage T4 and T7 holoenzymes primer extension activity and strand displacement activity on a DNA hairpin substrate manipulated by a magnetic trap. Holoenzyme primer extension activity is moderately hindered by the applied force. In contrast, the strand displacement activity is strongly stimulated by the applied force; DNA polymerization is favoured at high force, while a processive exonuclease activity is triggered at low force. We propose that the DNA fork upstream of the holoenzyme generates a regression pressure which inhibits the polymerization-driven forward motion of the holoenzyme. The inhibition is generated by the distortion of the template strand within the polymerization active site thereby shifting the equilibrium to a DNA-protein exonuclease conformation. We conclude that stalling of the holoenzyme induced by the fork regression pressure is the basis for the inefficient strand displacement synthesis characteristic of replicative polymerases. The resulting processive exonuclease activity may be relevant in replisome disassembly to reset a stalled replication fork to a symmetrical situation. Our findings offer interesting applications for single-molecule DNA sequencing

Microscopic Selection of Fluid Fingering Pattern

We study the issue of the selection of viscous fingering patterns in the limit of small surface tension. Through detailed simulations of anisotropic fingering, we demonstrate conclusively that no selection independent of the small-scale cutoff (macroscopic selection) occurs in this system. Rather, the small-scale cutoff completely controls the pattern, even on short time scales, in accord with the theory of microscopic solvability. We demonstrate that ordered patterns are dynamically selected only for not too small surface tensions. For extremely small surface tensions, the system exhibits chaotic behavior and no regular pattern is realized.Comment: 6 pages, 5 figure

Normal random matrix ensemble as a growth problem

In general or normal random matrix ensembles, the support of eigenvalues of large size matrices is a planar domain (or several domains) with a sharp boundary. This domain evolves under a change of parameters of the potential and of the size of matrices. The boundary of the support of eigenvalues is a real section of a complex curve. Algebro-geometrical properties of this curve encode physical properties of random matrix ensembles. This curve can be treated as a limit of a spectral curve which is canonically defined for models of finite matrices. We interpret the evolution of the eigenvalue distribution as a growth problem, and describe the growth in terms of evolution of the spectral curve. We discuss algebro-geometrical properties of the spectral curve and describe the wave functions (normalized characteristic polynomials) in terms of differentials on the curve. General formulae and emergence of the spectral curve are illustrated by three meaningful examples.Comment: 44 pages, 14 figures; contains the first part of the original file. The second part will be submitted separatel

Bending Moduli of Charged Membranes Immersed in Polyelectrolyte Solutions

We study the contribution of polyelectrolytes in solution to the bending moduli of charged membranes. Using the Helfrich free energy, and within the mean-field theory, we calculate the dependence of the bending moduli on the electrostatics and short-range interactions between the membrane and the polyelectrolyte chains. The most significant effect is seen for strong short-range interactions and low amounts of added salt where a substantial increase in the bending moduli of order $1 k_BT$ is obtained. From short-range repulsive membranes, the polyelectrolyte contribution to the bending moduli is small, of order $0.1 k_BT$ up to at most $1 k_BT$. For weak short-range attraction, the increase in membrane rigidity is smaller and of less significance. It may even become negative for large enough amounts of added salt. Our numerical results are obtained by solving the adsorption problem in spherical and cylindrical geometries. In some cases the bending moduli are shown to follow simple scaling laws.Comment: 16 pages, 6 figure

Domain Structures in Fourth-Order Phase and Ginzburg-Landau Equations

In pattern-forming systems, competition between patterns with different wave numbers can lead to domain structures, which consist of regions with differing wave numbers separated by domain walls. For domain structures well above threshold we employ the appropriate phase equation and obtain detailed qualitative agreement with recent experiments. Close to threshold a fourth-order Ginzburg-Landau equation is used which describes a steady bifurcation in systems with two competing critical wave numbers. The existence and stability regime of domain structures is found to be very intricate due to interactions with other modes. In contrast to the phase equation the Ginzburg-Landau equation allows a spatially oscillatory interaction of the domain walls. Thus, close to threshold domain structures need not undergo the coarsening dynamics found in the phase equation far above threshold, and can be stable even without phase conservation. We study their regime of stability as a function of their (quantized) length. Domain structures are related to zig-zags in two-dimensional systems. The latter are therefore expected to be stable only when quenched far enough beyond the zig-zag instability.Comment: Submitted to Physica D, 11 pages (RevTeX 3), 12 postscript figure

Treatment patterns of patients diagnosed with major headache disorders: A retrospective claims analysis

Objective: To describe patient characteristics, treatment patterns, and health care costs among patients diagnosed with major headache disorders overall and by type (tension-type headache [TTH], migraine, cluster headache [CH], or \u3e1 primary headache type), and secondarily to evaluate drug treatment patterns among triptan initiators with a major headache diagnosis. Methods: Using US claims data from January 2012 through December 2017, we identified adults with evidence of a major headache disorder: TTH, migraine, or CH; the first diagnosis date was deemed the index date. To evaluate triptan use specifically, patients who initiated triptans were identified; the first triptan claim date was deemed the index date. Patient characteristics, treatment patterns (concomitant treatments, adherence, number of fills), and annual health care costs data were obtained. Results: Of the 418,779 patients diagnosed with major headache disorders, the following 4 cohorts were created: TTH (8%), migraine (87%), CH (1%), and \u3e1 primary headache type (4%). The majority used analgesic (54–73%) and psychotropic (57–81%) drugs, primarily opioids (36–53%). Headache-related costs accounted for one-fifth of all-cause costs. Of the 229,946 patients who initiated triptans, the following 7 study cohorts were analyzed: sumatriptan (68%), rizatriptan (21%), eletriptan (5%), zolmitriptan (3%), naratriptan (2%), frovatriptan (1%), and almotriptan ( Conclusion: The primary headache disorder treatment paradigm is complex, with significant variability. Predominant concomitant use of opioids and switching to opioids is of concern, necessitating solutions to minimize opioid use. Switching to non-oral/fast-acting or targeted preventive therapies should be considered

Folding of the Triangular Lattice with Quenched Random Bending Rigidity

We study the problem of folding of the regular triangular lattice in the presence of a quenched random bending rigidity + or - K and a magnetic field h (conjugate to the local normal vectors to the triangles). The randomness in the bending energy can be understood as arising from a prior marking of the lattice with quenched creases on which folds are favored. We consider three types of quenched randomness: (1) a ``physical'' randomness where the creases arise from some prior random folding; (2) a Mattis-like randomness where creases are domain walls of some quenched spin system; (3) an Edwards-Anderson-like randomness where the bending energy is + or - K at random independently on each bond. The corresponding (K,h) phase diagrams are determined in the hexagon approximation of the cluster variation method. Depending on the type of randomness, the system shows essentially different behaviors.Comment: uses harvmac (l), epsf, 17 figs included, uuencoded, tar compresse

A history of the French in London: liberty, equality, opportunity

This book examines, for the first time, the history of the social, cultural, political and economic presence of the French in London, and explores the multiple ways in which this presence has contributed to the life of the city. The capital has often provided a place of refuge, from the Huguenots in the 17th century, through the period of the French Revolution, to various exile communities during the 19th century, and on to the Free French in the Second World War. It also considers the generation of French citizens who settled in post-war London, and goes on to provide insights into the contemporary French presence by assessing the motives and lives of French people seeking new opportunities in the late 20th and early 21st centuries. It analyses the impact that the French have had historically, and continue to have, on London life in the arts, gastronomy, business, industry and education, manifest in diverse places and institutions from the religious to the political via the educational, to the commercial and creative industries