Robust isogeometric preconditioners for the Stokes system based on the Fast Diagonalization method

In this paper we propose a new class of preconditioners for the isogeometric discretization of the Stokes system. Their application involves the solution of a Sylvester-like equation, which can be done efficiently thanks to the Fast Diagonalization method. These preconditioners are robust with respect to both the spline degree and mesh size. By incorporating information on the geometry parametrization and equation coefficients, we maintain efficiency on non-trivial computational domains and for variable kinematic viscosity. In our numerical tests we compare to a standard approach, showing that the overall iterative solver based on our preconditioners is significantly faster.Comment: 31 pages, 4 figure

RunDec: a Mathematica package for running and decoupling of the strong coupling and quark masses

In this paper the formulae are collected which are needed for the computation of the strong coupling constant and quark masses at different energy scales and for different number of active flavours. All equations contain the state-of-the-art QCD corrections up to three- and sometimes even four-loop order. For the practical implementation {\tt Mathematica} is used and a package containing useful procedures is provided.Comment: 32 pages, ps figures included, accepted for publication in Computer Physics Communication

Measurement procedures affect the interpretation of metatarsophalangeal joint function during accelerated sprinting

This is an Accepted Manuscript of an article published by Taylor & Francis in Journal of Sports Sciences on 7/8/2012, available online: http://wwww.tandfonline.com/10.1080/02640414.2012.713501The metatarsophalangeal joint (MPJ) is a significant absorber of energy in sprinting. This study examined the influence of MPJ axis choice and filter cut-off frequency on kinetic variables describing MPJ function during accelerated sprinting. Eight trained sprinters performed maximal sprints along a runway. Three dimensional high-speed (1000 Hz) kinematic and kinetic data were collected at the 20 m point. Three axis definitions for the five MPJs were compared. MPJ moments, powers and energies were calculated using different filter cut-off frequencies. The more anatomically appropriate dual axis resulted in less energy absorbed at the MPJ compared to the oblique axis which also absorbed less energy compared to the perpendicular axis. Furthermore, a low cut-off frequency (8 Hz) substantially underestimated MPJ kinematics, kinetics and the energy absorbed at the joint and lowered the estimate of energy production during push-off. It is concluded that a better understanding of MPJ function during sprinting would be obtained by using an oblique or anatomically appropriate representation of the joint together with appropriate kinematic data sampling and filtering so that high frequency movement characteristics are retained.This article was submitted to the RAE2014 for the University of Chester - Sport and Exercise Sciences, Leisure and Tourism

A heritable switch in carbon source utilization driven by an unusual yeast prion

Several well-characterized fungal proteins act as prions, proteins capable of multiple conformations, each with different activities, at least one of which is self-propagating. Through such self-propagating changes in function, yeast prions act as protein-based elements of phenotypic inheritance. We report a prion that makes cells resistant to the glucose-associated repression of alternative carbon sources, [GAR[superscript +]] (for “resistant to glucose-associated repression,” with capital letters indicating dominance and brackets indicating its non-Mendelian character). [GAR[superscript +]] appears spontaneously at a high rate and is transmissible by non-Mendelian, cytoplasmic inheritance. Several lines of evidence suggest that the prion state involves a complex between a small fraction of the cellular complement of Pma1, the major plasma membrane proton pump, and Std1, a much lower-abundance protein that participates in glucose signaling. The Pma1 proteins from closely related Saccharomyces species are also associated with the appearance of [GAR[superscript +]]. This allowed us to confirm the relationship between Pma1, Std1, and [GAR[superscript +]] by establishing that these proteins can create a transmission barrier for prion propagation and induction in Saccharomyces cerevisiae. The fact that yeast cells employ a prion-based mechanism for heritably switching between distinct carbon source utilization strategies, and employ the plasma membrane proton pump to do so, expands the biological framework in which self-propagating protein-based elements of inheritance operate.United States. National Institutes of Health (grant GM25874

Targeting DNA repair pathways for cancer therapy

Accumulation of genomic mutations is the consequence of failure in DNA repair as well as increased exposure to endogenous/environmental mutagens. DNA repair pathways safeguard the human genome from such mutagens, and thereby suppress the multi-step process of carcinogenesis. DNA repair pathways that protect the genome from ROS (reactive oxygen species)-induced lesions are attractive anti-cancer targets, as their inhibition may render combinatorial sensitization of tumor cells to both DNA damage and oxidative stresses, known as non-oncogenic addictions of cancer. The aim of this thesis was to validate such DNA repair factors as anti-cancer targets and to develop their inhibitors for potential therapeutic applications. In paper I, we assessed the addiction of cancer cells to MTH1, a nudix hydrolase eliminating oxidized purine nucleotides from the dNTP pool. MTH1 depletion resulted in exclusive accumulation of 8-oxo-dG lesions and cellular toxicity in transformed cells. MTH1 suppression, impaired tumor growth in the xenografts of SW480 cells. We developed potent MTH1 inhibitors (TH278 and TH588), which exhibited target engagement and selective toxicity in transformed cells. Treatment with MTH1 inhibitors caused increased 8-oxo-dG levels in cancer cells, and inhibited the growth of xenografts in vivo. Taken together, our findings revealed the dependency of tumors to MTH1 that can be targeted for cancer therapy. The study in paper II aimed to explore functional cooperation between MTH1 and MUTYH, a DNA glycosylase that removes deoxyadenines paired with 8-oxo-dG. Using stable cell lines expressing inducible shRNA constructs, we showed that combined depletion of MTH1 and MUTYH was more toxic to cells compared to individual knock-downs. In addition, overexpression of nuclear MUTYH could attenuate cell death induced by loss of MTH1. Collectively, this study provided supportive evidence for a protective role of MUTYH. In paper III, we described TH5487 as a novel selective inhibitor of OGG1, a DNA glycosylase that excises 8-oxo-dG opposite deoxycytidine. TH5487 inhibited binding of OGG1 to its substrate and increased thermal stability of the purified protein through interactions with residues in the active site. Moreover, TH5487 engaged with its intended target, increased 8-oxo-dG level, and impaired recruitment of OGG1 to the damage site in cells. Treatment with TH5487 resulted in prolonged S phase, which was similar to the effect of OGG1 depletion using shRNAs. In addition, non-transformed cells could tolerate TH5487 treatment while cancer cells were more sensitive. In sum, this study highlighted the phenotypic lethality of OGG1 inhibition with tumors, by introducing TH5487 as a cell-active OGG1 inhibitor. Overall, our results increased the knowledge about dependency of cancer cells to DNA repair pathways of ROS-induced lesions that can be employed for the development of promising anti-tumor therapies

N_eff in low-scale seesaw models versus the lightest neutrino mass

We evaluate the contribution to N_eff of the extra sterile states in low-scale type I seesaw models (with three extra sterile states). We explore the full parameter space and find that at least two of the heavy states always reach thermalization in the early Universe, while the third one might not thermalize provided the lightest neutrino mass is below O(10(-3) eV). Constraints from cosmology therefore severely restrict the spectra of heavy states in the range 1 eV-100 MeV. The implications for neutrinoless double beta decay are also discussed

Structure and stereochemistry of the base excision repair glycosylase MutY reveal a mechanism similar to retaining glycosidases.

MutY adenine glycosylases prevent DNA mutations by excising adenine from promutagenic 8-oxo-7,8-dihydroguanine (OG):A mismatches. Here, we describe structural features of the MutY active site bound to an azaribose transition state analog which indicate a catalytic role for Tyr126 and approach of the water nucleophile on the same side as the departing adenine base. The idea that Tyr126 participates in catalysis, recently predicted by modeling calculations, is strongly supported by mutagenesis and by seeing close contact between the hydroxyl group of this residue and the azaribose moiety of the transition state analog. NMR analysis of MutY methanolysis products corroborates a mechanism for adenine removal with retention of stereochemistry. Based on these results, we propose a revised mechanism for MutY that involves two nucleophilic displacement steps akin to the mechanisms accepted for 'retaining' O-glycosidases. This new-for-MutY yet familiar mechanism may also be operative in related base excision repair glycosylases and provides a critical framework for analysis of human MutY (MUTYH) variants associated with inherited colorectal cancer