A mathematical model for cell cycle-specific cancer virotherapy

Oncolytic viruses preferentially infect and replicate in cancerous cells, leading to elimination of tumour populations, while sparing most healthy cells. Here, we study the cell cycle-specific activity of viruses such as vesicular stomatitis virus (VSV). In spite of its capacity as a robust cytolytic agent,VSVcannot effectively attack certain tumour cell types during the quiescent, or resting, phase of the cell cycle. In an effort to understand the interplay between the time course of the cell cycle and the specificity of VSV, we develop a mathematical model for cycle-specific virus therapeutics. We incorporate the minimum biologically required time spent in the non-quiescent cell cycle phases using systems of differential equations with incorporated time delays. Through analysis and simulation of the model, we describe how varying the minimum cycling time and the parameters that govern viral dynamics affect the stability of the cancer-free equilibrium, which represents therapeutic success

Joint neutron/X-ray crystal structure of a mechanistically relevant complex of perdeuterated urate oxidase and simulations provide insight into the hydration step of catalysis

Cofactor-independent urate oxidase (UOX) is an ~137 kDa tetrameric enzyme essential for uric acid (UA) catabolism in many organisms. UA is first oxidized by O2 to dehydroisourate (DHU) via a peroxo intermediate. DHU then undergoes hydration to 5-hydroxyisourate (5HIU). At different stages of the reaction both catalytic O2 and water occupy the 'peroxo hole' above the organic substrate. Here, high-resolution neutron/X-ray crystallographic analysis at room temperature has been integrated with molecular dynamics simulations to investigate the hydration step of the reaction. The joint neutron/X-ray structure of perdeuterated Aspergillus flavus UOX in complex with its 8-azaxanthine (8AZA) inhibitor shows that the catalytic water molecule (W1) is present in the peroxo hole as neutral H2O, oriented at 45° with respect to the ligand. It is stabilized by Thr57 and Asn254 on different UOX protomers as well as by an O-H∙ ∙ ∙π interaction with 8AZA. The active site Lys10-Thr57 dyad features a charged Lys10-NH3+ side chain engaged in a strong hydrogen bond with Thr57OG1, while the Thr57OG1-HG1 bond is rotationally dynamic and oriented toward the π system of the ligand, on average. Our analysis offers support for a mechanism in which W1 performs a nucleophilic attack on DHUC5 with Thr57HG1 central to a Lys10-assisted proton-relay system. Room-temperature crystallography and simulations also reveal conformational heterogeneity for Asn254 that modulates W1 stability in the peroxo hole. This is proposed to be an active mechanism to facilitate W1/O2 exchange during catalysis

A Counterexample Regarding Labelled Well-Quasi-Ordering

Korpelainen, Lozin, and Razgon conjectured that a hereditary property of graphs which is well-quasi-ordered by the induced subgraph order and defined by only finitely many minimal forbidden induced subgraphs is labelled well-quasi-ordered, a notion stronger than that of n-well-quasi-order introduced by Pouzet in the 1970s. We present a counterexample to this conjecture. In fact, we exhibit a hereditary property of graphs which is well-quasi-ordered by the induced subgraph order and defined by finitely many minimal forbidden induced subgraphs yet is not 2-well-quasi-ordered. This counterexample is based on the widdershins spiral, which has received some study in the area of permutation patterns

Reducing the clique and chromatic number via edge contractions and vertex deletions.

We consider the following problem: can a certain graph parameter of some given graph G be reduced by at least d, for some integer d, via at most k graph operations from some specified set S, for some given integer k? As graph parameters we take the chromatic number and the clique number. We let the set S consist of either an edge contraction or a vertex deletion. As all these problems are NP-complete for general graphs even if d is fixed, we restrict the input graph G to some special graph class. We continue a line of research that considers these problems for subclasses of perfect graphs, but our main results are full classifications, from a computational complexity point of view, for graph classes characterized by forbidding a single induced connected subgraph H

Pre-Excitation Studies for Rubidium-Plasma Generation

The key element in the Proton-Driven-Plasma-Wake-Field-Accelerator (AWAKE) project is the generation of highly uniform plasma from Rubidium vapor. The standard way to achieve full ionization is to use high power laser which can assure the over-barrier-ionization (OBI) along the 10 meters long active region. The Wigner-team in Budapest is investigating an alternative way of uniform plasma generation. The proposed Resonance Enhanced Multi Photon Ionization (REMPI) scheme probably can be realized by much less laser power. In the following the resonant pre-excitations of the Rb atoms are investigated, theoretically and the status report about the preparatory work on the experiment are presented.Comment: 8 pages, 6 figures, submitted to Nucl. Inst. and Meth. in Phys. Res.

Status of short-pulse KrF amplifier research and development at Hill, Szeged

The small saturation energy density of excimers requires amplifiers of large cross-sections for amplification of short pulses of already medium power. Homogeneous excitation of large volumes of Fluorine-based gas mixtures by discharge pumping is a critical interplay of the properties of both pumping and preionization; generally necessitating an intense, spatially and temporally controlled xray preionization. In the present realization at High Intensity Laser Laboratory (HILL) the stringent intensity requirements of preionization are fulfilled by reducing the pulse duration of the x-ray flash to ~16 ns, and by positioning the x-ray source in the near vicinity of the active volume. By proper choice of the positions of two cylindrical x-ray guns the spatial distribution of preionization can be tuned to (and around) the optimum distribution giving a practical method to compensate for eventual inhomogenities of the E-field of excitation and to tune the discharge to the desired geometry. In this way the realization of a KrF excimer amplifier of ~5 x 4 cm2 cross-section is presented

Steiner trees for hereditary graph classes.

We consider the classical problems (Edge) Steiner Tree and Vertex Steiner Tree after restricting the input to some class of graphs characterized by a small set of forbidden induced subgraphs. We show a dichotomy for the former problem restricted to (H1,H2) -free graphs and a dichotomy for the latter problem restricted to H-free graphs. We find that there exists an infinite family of graphs H such that Vertex Steiner Tree is polynomial-time solvable for H-free graphs, whereas there exist only two graphs H for which this holds for Edge Steiner Tree. We also find that Edge Steiner Tree is polynomial-time solvable for (H1,H2) -free graphs if and only if the treewidth of the class of (H1,H2) -free graphs is bounded (subject to P≠NP ). To obtain the latter result, we determine all pairs (H1,H2) for which the class of (H1,H2) -free graphs has bounded treewidth