Sail optimization for upwind sailing: application in a Tornado, the Olympic class catamaran.

A study of a boat’s motion is carried out in order to analyze the aerodynamic properties of the optimal sail for obtaining the maximum velocity when sailing to windward. The mechanics study shows the optimal CL and CD for a given sail and how the shape of the aerodynamic polar of the sail should be. A parametrical analysis of the aerodynamics of a sail is then carried out varying the maximum camber, position of the maximum camber in the chord direction and position of the maximum camber in the mast direction. The parametric analysis is done numerically with a vortex lattice method (VLM) and experimentally in a wind tunnel. The results show that the influence of the relevant parameters studied can be reduced to the variation of two parameters, A and B, defining the polar of the sail, CD = B + A2CL 2; and the influence of parameters A and B on the maximum VMG obtainable are calculated

Vitamin B6 modulates transcriptional activation by multiple members of the steroid hormone receptor superfamily.

Recent studies have shown that vitamin B6 modulates transcriptional activation by the human glucocorticoid receptor in HeLa S3 cells. We have now examined the possibility that vitamin B6 might similarly influence transcriptional activation by the glucocorticoid receptor in other cell types, as well as gene expression mediated by other members of the steroid hormone receptor superfamily. We show that elevated vitamin B6 concentrations suppress by 40-65% the level of transcription mediated through the endogenous murine L cell glucocorticoid receptor, as well as the human receptor transfected into E8.2 and T47D cells. In contrast, glucocorticoid receptor-mediated transcription was enhanced 60-110% in mild vitamin deficiency. The level of hormone-independent constitutive gene expression was not affected by these same alterations in vitamin B6 concentration. These studies indicated that the transcriptional modulatory effects of the vitamin were neither restricted to specific cell types nor limited to the human form of the glucocorticoid receptor. We next determined if hormone-induced transcription by several other steroid receptors (androgen, progesterone, and estrogen receptors) was analogously affected by alterations in vitamin B6 concentration. Analysis of gene expression mediated through the mouse mammary tumor virus promoter revealed that transcriptional activation of both the androgen and progesterone receptors was reduced by 35-40% under conditions of elevated vitamin B6 and enhanced by 60-90% in deficiency, again under conditions where constitutive expression was unaffected. Using a different promoter, the estrogen-regulated vitellogenin promoter, we found that transcriptional activation of the estrogen receptor was similarly affected. Estrogen-induced gene expression was reduced by 30% under conditions of elevated intracellular vitamin B6 and enhanced by 85% in vitamin deficiency. Thus, vitamin B6 modulates transcriptional activation by multiple classes of steroid hormone receptors. The similarities in vitamin B6 effects on transcription mediated through different promoters, the mouse mammary tumor virus and vitellogenin promoters, suggest that this vitamin may modulate the expression of a diverse array of hormonally responsive genes. These observations together support the hypothesis that vitamin B6 represents a physiological modulator of steroid hormone action

Modulation by vitamin B6 of glucocorticoid receptor-mediated gene expression requires transcription factors in addition to the glucocorticoid receptor.

We have investigated the mechanism by which vitamin B6 acts to modulate steroid hormone-mediated gene expression. We show that the level of glucocorticoid-induced gene expression from simple promoters, containing only hormone response elements and a TATA sequence, was not affected by alterations in intracellular vitamin B6 concentration. However, modulation of hormone-induced gene expression was restored with the inclusion of a binding site for the transcription factor nuclear factor 1 (NF1) within the hormone-responsive promoter; glucocorticoid-induced gene expression was reduced by 44% under conditions of elevated intracellular vitamin B6 concentration and enhanced by 98% in mild vitamin deficiency. Under these conditions, neither glucocorticoid receptor sedimentation characteristics, receptor activation, nor DNA binding capacity was affected. Quantitatively analogous effects were detected with estrogen-induced gene expression when an NF1 binding site was removed from or introduced into an estrogen-responsive promoter. NF1-mediated constitutive transcription was not affected by alterations in vitamin concentration. The modulatory effect of vitamin did not require strict positioning of or spacing between the glucocorticoid response element and NF1 binding site. Moreover, a heterologous transcriptional activator, composed of the viral E1a transactivation domain and the GAL4 DNA binding domain, does not substitute for NF1 in restoring vitamin B6 modulation of hormone-induced gene expression. These results suggest that vitamin B6 modulates steroid hormone-mediated gene expression through its influence on a functional or cooperative interaction between steroid hormone receptors and the transcription factor NF1

Plasma heat shock protein 27 is associated with coronary artery disease, abdominal aortic aneurysm and peripheral artery disease

Low protein levels of Hsp27 have been reported in atherosclerotic plaques. In addition, human studies have indicated that circulating Hsp27 levels are lower in coronary artery disease patients compared with controls. It remains, however, unclear whether this applies to other forms of atherosclerotic disease. Plasma Hsp27 from 280 subjects was examined by ELISA. The cohort included 80 coronary artery disease (CAD), 40 peripheral artery disease (PAD) and 80 abdominal aortic aneurysm (AAA) patients. Eighty elderly subjects, without any clinical history of vascular diseases, were used as a control group. Receiver operating curve (ROC) and logistic regression model analysis were performed to evaluate the potential value of Hsp27 as a circulating biomarker. Patients with atherosclerotic vascular diseases had significantly lower levels of Hsp27 than control subjects (p < 0.001). Moreover, Hsp27 was significantly lower in CAD patients than other atherosclerotic vascular disease groups (p < 0.001). There was no difference in Hsp27 levels between the AAA and PAD groups. Using the ROC-generated optimal cut-off values for Hsp27, logistic regression modeling indicated that low plasma Hsp27 was independently associated with the presence of multiple forms of atherosclerotic disease. In conclusion, circulating Hsp27 is significantly lower in patients with multiple forms of atherosclerotic arterial disease

Flavour Physics in the Soft Wall Model

We extend the description of flavour that exists in the Randall-Sundrum (RS) model to the soft wall (SW) model in which the IR brane is removed and the Higgs is free to propagate in the bulk. It is demonstrated that, like the RS model, one can generate the hierarchy of fermion masses by localising the fermions at different locations throughout the space. However, there are two significant differences. Firstly the possible fermion masses scale down, from the electroweak scale, less steeply than in the RS model and secondly there now exists a minimum fermion mass for fermions sitting towards the UV brane. With a quadratic Higgs VEV, this minimum mass is about fifteen orders of magnitude lower than the electroweak scale. We derive the gauge propagator and despite the KK masses scaling as $m_n^2\sim n$, it is demonstrated that the coefficients of four fermion operators are not divergent at tree level. FCNC's amongst kaons and leptons are considered and compared to calculations in the RS model, with a brane localised Higgs and equivalent levels of tuning. It is found that since the gauge fermion couplings are slightly more universal and the SM fermions typically sit slightly further towards the UV brane, the contributions to observables such as $\epsilon_K$ and $\Delta m_K$, from the exchange of KK gauge fields, are significantly reduced.Comment: 33 pages, 15 figures, 5 tables; v2: references added; v3: modifications to figures 4,5 and 6. version to appear in JHE

Activity of the DNA minor groove cross-linking agent SG2000 (SJG-136) against canine tumours

BACKGROUND: Cancer is the leading cause of death in older dogs and its prevalence is increasing. There is clearly a need to develop more effective anti-cancer drugs in dogs. SG2000 (SJG-136) is a sequence selective DNA minor groove cross-linking agent. Based on its in vitro potency, the spectrum of in vivo and clinical activity against human tumours, and its tolerability in human patients, SG2000 has potential as a novel therapeutic against spontaneously occurring canine malignancies. RESULTS: In vitro cytotoxicity was assessed using SRB and MTT assays, and in vivo activity was assessed using canine tumour xenografts. DNA interstrand cross-linking (ICL) was determined using a modification of the single cell gel electrophoresis (comet) assay. Effects on cell cycle distribution were assessed by flow cytometry and measurement of γ-H2AX by immunofluorescence and immunohistochemistry. SG2000 had a multi-log differential cytotoxic profile against a panel of 12 canine tumour cell lines representing a range of common tumour types in dogs. In the CMeC-1 melanoma cell line, DNA ICLs increased linearly with dose following a 1 h treatment. Peak ICL was achieved within 1 h and no removal was observed over 48 h. A relationship between DNA ICL formation and cytotoxicity was observed across cell lines. The formation of γ-H2AX foci was slow, becoming evident after 4 h and reaching a peak at 24 h. SG2000 exhibited significant anti-tumour activity against two canine melanoma tumour models in vivo. Anti-tumour activity was observed at 0.15 and 0.3 mg/kg given i.v. either once, or weekly x 3. Dose-dependent DNA ICL was observed in tumours (and to a lower level in peripheral blood mononuclear cells) at 2 h and persisted at 24 h. ICL increased following the second and third doses in a repeated dose schedule. At 24 h, dose dependent γ-H2AX foci were more numerous than at 2 h, and greater in tumours than in peripheral blood mononuclear cells. SG2000-induced H2AX phosphorylation measured by immunohistochemistry showed good correspondence, but less sensitivity, than measurement of foci. CONCLUSIONS: SG2000 displayed potent activity in vitro against canine cancer cell lines as a result of the formation and persistence of DNA ICLs. SG2000 also had significant in vivo antitumour activity against canine melanoma xenografts, and the comet and γ-H2AX foci methods were relevant pharmacodynamic assays. The clinical testing of SG2000 against spontaneous canine cancer is warranted. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12917-015-0534-2) contains supplementary material, which is available to authorized users

The Effective Lagrangian for Bulk Fermions in Models with Extra Dimensions

We compute the dimension 6 effective Lagrangian arising from the tree level integration of an arbitrary number of bulk fermions in models with warped extra dimensions. The coefficients of the effective operators are written in terms of simple integrals of the metric and are valid for arbitrary warp factors, with or without an infrared brane, and for a general Higgs profile. All relevant tree level fermion effects in electroweak and flavor observables can be computed using this effective Lagrangian.Comment: 22 pages. V2: typos corrected, matches published versio

Assay strategies for the discovery and validation of therapeutics targeting <i>Brugia pahangi</i> Hsp90

The chemotherapy of lymphatic filariasis relies upon drugs such as diethylcarbamazine and ivermectin that largely target the microfilarial stages of the parasite, necessitating continued treatment over the long reproductive life span of the adult worm. The identification of compounds that target adult worms has been a long-term goal of WHO. Here we describe a fluorescence polarization assay for the identification of compounds that target Hsp90 in adult filarial worms. The assay was originally developed to identify inhibitors of Hsp90 in tumor cells, and relies upon the ability of small molecules to inhibit the binding of fluorescently labelled geldanamycin to Hsp90. We demonstrate that the assay works well with soluble extracts of Brugia, while extracts of the free-living nematode C. elegans fail to bind the probe, in agreement with data from other experiments. The assay was validated using known inhibitors of Hsp90 that compete with geldanamycin for binding to Hsp90, including members of the synthetic purine-scaffold series of compounds. The efficacy of some of these compounds against adult worms was confirmed in vitro. Moreover, the assay is sufficiently sensitive to differentiate between binding of purine-scaffold compounds to human and Brugia Hsp90. The assay is suitable for high-throughput screening and provides the first example of a format with the potential to identify novel inhibitors of Hsp90 in filarial worms and in other parasitic species where Hsp90 may be a target

Suppressing Electroweak Precision Observables in 5D Warped Models

We elaborate on a recently proposed mechanism to suppress large contributions to the electroweak precision observables in five dimensional (5D) warped models, without the need for an extended 5D gauge sector. The main ingredient is a modification of the AdS metric in the vicinity of the infrared (IR) brane corresponding to a strong deviation from conformality in the IR of the 4D holographic dual. We compute the general low energy effective theory of the 5D warped Standard Model, emphasizing additional IR contributions to the wave function renormalization of the light Higgs mode. We also derive expressions for the S and T parameters as a function of a generic 5D metric and zero-mode wave functions. We give an approximate formula for the mass of the radion that works even for strong deviation from the AdS background. We proceed to work out the details of an explicit model and derive bounds for the first KK masses of the various bulk fields. The radion is the lightest new particle although its mass is already at about 1/3 of the mass of the lightest resonances, the KK states of the gauge bosons. We examine carefully various issues that can arise for extreme choices of parameters such as the possible reintroduction of the hierarchy problem, the onset of nonperturbative physics due to strong IR curvature or the creation of new hierarchies near the Planck scale. We conclude that a KK scale of 1 TeV is compatible with all these constraints.Comment: 44 pages, 11 figures, references adde