Stability of string defects in models of non-Abelian symmetry breaking

In this paper we describe a new type of topological defect, called a homilia string, which is stabilized via interactions with the string network. Using analytical and numerical techniques, we investigate the stability and dynamics of homilia strings, and show that they can form stable electroweak strings. In SU(2)xU(1) models of symmetry breaking the intersection of two homilia strings is identified with a sphaleron. Due to repulsive forces, the homilia strings seperate, resulting in sphaleron annihilation. It is shown that electroweak homilia string loops cannot stabilize as vortons, which circumvents the adverse cosmological problems associated with stable loops. The consequences for GUT scale homilia strings are also discussed.Comment: 15 pages, revtex, with 8 figures. Submitted to PR

A novel aspirin prodrug inhibits NFκB activity and breast cancer stem cell properties

INTRODUCTION: Activation of cyclooxygenase (COX)/prostaglandin and nuclear factor κB (NFκB) pathways can promote breast tumor initiation, growth, and progression to drug resistance and metastasis. Thus, anti-inflammatory drugs have been widely explored as chemopreventive and antineoplastic agents. Aspirin (ASA), in particular, is associated with reduced breast cancer incidence but gastrointestinal toxicity has limited its usefulness. To improve potency and minimize toxicity, ASA ester prodrugs have been developed, in which the carboxylic acid of ASA is masked and ancillary pharmacophores can be incorporated. To date, the effects of ASA and ASA prodrugs have been largely attributed to COX inhibition and reduced prostaglandin production. However, ASA has also been reported to inhibit the NFκB pathway at very high doses. Whether ASA prodrugs can inhibit NFκB signaling remains relatively unexplored. METHODS: A library of ASA prodrugs was synthesized and screened for inhibition of NFκB activity and cancer stem-like cell (CSC) properties, an important PGE2-and NFκB-dependent phenotype of aggressive breast cancers. Inhibition of NFκB activity was determined by dual luciferase assay, RT-QPCR, p65 DNA binding activity and Western blots. Inhibition of CSC properties was determined by mammosphere growth, CD44(+)CD24(−)immunophenotype and tumorigenicity at limiting dilution. RESULTS: While we identified multiple ASA prodrugs that are capable of inhibiting the NFκB pathway, several were associated with cytotoxicity. Of particular interest was GTCpFE, an ASA prodrug with fumarate as the ancillary pharmacophore. This prodrug potently inhibits NFκB activity without innate cytotoxicity. In addition, GTCpFE exhibited selective anti-CSC activity by reducing mammosphere growth and the CD44(+)CD24(−)immunophenotype. Moreover, GTCpFE pre-treated cells were less tumorigenic and, when tumors did form, latency was increased and growth rate was reduced. Structure-activity relationships for GTCpFE indicate that fumarate, within the context of an ASA prodrug, is essential for anti-NFκB activity, whereas both the ASA and fumarate moieties contributed to attenuated mammosphere growth. CONCLUSIONS: These results establish GTCpFE as a prototype for novel ASA-and fumarate-based anti-inflammatory drugs that: (i) are capable of targeting CSCs, and (ii) may be developed as chemopreventive or therapeutic agents in breast cancer. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-015-1868-7) contains supplementary material, which is available to authorized users

Fragment-based discovery of a regulatory site in thioredoxin glutathione reductase acting as "doorstop" for NADPH entry

Members of the FAD/NAD-linked reductase family are recognized as crucial targets in drug development for cancers, inflammatory disorders, and infectious diseases. However, individual FAD/NAD reductases are difficult to inhibit in a selective manner with off target inhibition reducing usefulness of identified compounds. Thioredoxin glutathione reductase (TGR), a high molecular weight thioredoxin reductase-like enzyme, has emerged as a promising drug target for the treatment of schistosomiasis, a parasitosis afflicting more than 200 million people. Taking advantage of small molecules selected from a high-throughput screen and using X-ray crystallography, functional assays, and docking studies, we identify a critical secondary site of the enzyme. Compounds binding at this site interfere with well-known and conserved conformational changes associated with NADPH reduction, acting as a doorstop for cofactor entry. They selectivity inhibit TGR from Schistosoma mansoni and are active against parasites in culture. Since many members of the FAD/NAD-linked reductase family have similar catalytic mechanisms the unique mechanism of inhibition identified in this study for TGR broadly opens new routes to selectively inhibit homologous enzymes of central importance in numerous diseases

On the binary nature of 1RXS J162848.1-415241

We present spectroscopy of the optical counterpart to 1RXS J162848.1-41524, also known as the microquasar candidate MCQC J162847-4152. All the data indicate that this X-ray source is not a microquasar, and that it is a single-lined chromospherically active binary system with a likely orbital period of 4.9 days. Our analysis supports a K3IV spectral classification for the star, which is dominant at optical wavelengths. The unseen binary component is most likely a late-type (K7-M) dwarf or a white dwarf. Using the high resolution spectra we have measured the K3 star's rotational broadening to be vsini = 43 +/- 3 km/s and determined a lower limit to the binary mass ratio of q(=M2/M1)>2.0. The high rotational broadening together with the strong CaII H & K / Halpha emission and high-amplitude photometric variations indicate that the evolved star is very chromospherically active and responsible for the X-ray/radio emission.Comment: 15 pages, 5 figures, accepted for publication in Ap

The transformative potential of reflective diaries for elite English cricketers

The sport of cricket has a history of its players suffering from mental health issues. The psychological study of cricket and, in particular, the attendant demands of participating at an elite level has not previously received rigorous academic attention. This study explored ten elite male cricketers’ experiences of keeping a daily reflective diary for one month during the competitive season. The aim was to assess how valuable qualitative diaries are in this field. Participants were interviewed regarding their appraisal of the methodology as a self‐help tool that could assist coping with performance pressures and wider life challenges. Three outcomes were revealed: first, that diary keeping was an effective opportunity to reflect upon the past and enhance one’s self (both as an individual and a performer); second, that diary keeping acted as a form of release that allowed participants to progress; and third, that diary keeping allowed participants to discover personal patterns of success that increased the likeliness of optimum performance

Adaptive walks on time-dependent fitness landscapes

The idea of adaptive walks on fitness landscapes as a means of studying evolutionary processes on large time scales is extended to fitness landscapes that are slowly changing over time. The influence of ruggedness and of the amount of static fitness contributions are investigated for model landscapes derived from Kauffman's $NK$ landscapes. Depending on the amount of static fitness contributions in the landscape, the evolutionary dynamics can be divided into a percolating and a non-percolating phase. In the percolating phase, the walker performs a random walk over the regions of the landscape with high fitness.Comment: 7 pages, 6 eps-figures, RevTeX, submitted to Phys. Rev.

Effects of treadmill versus overground soccer match simulations on biomechanical markers of anterior cruciate ligament injury risk in side cutting.

Abstract This study aimed to investigate whether treadmill versus overground soccer match simulations have similar effects on knee joint mechanics during side cutting. Nineteen male recreational soccer players completed a 45-min treadmill and overground match simulation. Heart rate (HR) and rating of perceived exertion (RPE) were recorded every 5 min. Prior to exercise (time 0 min), at "half-time" (time 45 min) and 15 min post-exercise (time 60 min), participants performed five trials of 45° side-cutting manoeuvres. Knee abduction moments and knee extension angles were analysed using two-way repeated measures analysis of variance (α = 0.05). Physiological responses were significantly greater during the overground (HR 160 ± 7 beats ∙ min(-1); RPE 15 ± 2) than the treadmill simulation (HR 142 ± 5 beats ∙ min(-1); RPE 12 ± 2). Knee extension angles significantly increased over time and were more extended at time 60 min compared with time 0 min and time 45 min. No significant differences in knee abduction moments were observed. Although knee abduction moments were not altered over time during both simulations, passive rest during half-time induced changes in knee angles that may have implications for anterior cruciate ligament injury risk

Thermal Conductivity across the Phase Diagram of Cuprates: Low-Energy Quasiparticles and Doping Dependence of the Superconducting Gap

Heat transport in the cuprate superconductors YBa$_2$Cu$_3$O$_{y}$ and La$_{2-x}$Sr$_x$CuO$_4$ was measured at low temperatures as a function of doping. A residual linear term kappa_{0}/T is observed throughout the superconducting region and it decreases steadily as the Mott insulator is approached from the overdoped regime. The low-energy quasiparticle gap extracted from kappa_{0}/T is seen to scale closely with the pseudogap. The ubiquitous presence of nodes and the tracking of the pseudogap shows that the overall gap remains of the pure d-wave form throughout the phase diagram, which excludes the possibility of a complex component (ix) appearing at a putative quantum phase transition and argues against a non-superconducting origin to the pseudogap. A comparison with superfluid density measurements reveals that the quasiparticle effective charge is weakly dependent on doping and close to unity.Comment: 12 pages, 9 figure