First Order Phase Transition in a Two Higgs-doublet Model with Mh>MWM_{h}>M_{W}

We study the 3d effective field theory of a weakly coupled two Higgs-doublet scalar model at high temperature. Our model has three scalar quartic couplings and an $O(4)$ symmetry which is spontaneously broken by a nonzero scalar field $vev$ at zero temperature. Using high temperature perturbation theory, renormalization group arguments in $4-\epsilon$ dimensions, as well as $1/N$ expansion techniques in 3 dimensions, we argue that the transition from the high temperature symmetry restoring phase to the low temperature phase is first order for a range of scalar couplings. This result is not due to gauge couplings. We discuss the implications of our results for baryogenesis in the two Higgs-doublet electroweak model, especially when the lightest neutral Higgs is heavier than the W--bosons.Comment: 15 page

A telephone survey of cancer awareness among frontline staff: informing training needs

Background: Studies have shown limited awareness about cancer risk factors among hospital-based staff. Less is known about general cancer awareness among community frontline National Health Service and social care staff. Methods: A cross-sectional computer-assisted telephone survey of 4664 frontline community-based health and social care staff in North West England. Results: A total of 671 out of 4664 (14.4%) potentially eligible subjects agreed to take part. Over 92% of staff recognised most warning signs, except an unexplained pain (88.8%, n=596), cough or hoarseness (86.9%, n=583) and a sore that does not heal (77.3%, n=519). The bowel cancer-screening programme was recognised by 61.8% (n=415) of staff. Most staff agreed that smoking and passive smoking ‘increased the chance of getting cancer.’ Fewer agreed about getting sunburnt more than once as a child (78.0%, n=523), being overweight (73.5%, n=493), drinking more than one unit of alcohol per day (50.2%, n=337) or doing less than 30 min of moderate physical exercise five times a week (41.1%, n=276). Conclusion: Cancer awareness is generally good among frontline staff, but important gaps exist, which might be improved by targeted education and training and through developing clearer messages about cancer risk factors

Critical Exponents, Hyperscaling and Universal Amplitude Ratios for Two- and Three-Dimensional Self-Avoiding Walks

We make a high-precision Monte Carlo study of two- and three-dimensional self-avoiding walks (SAWs) of length up to 80000 steps, using the pivot algorithm and the Karp-Luby algorithm. We study the critical exponents $\nu$ and $2\Delta_4 -\gamma$ as well as several universal amplitude ratios; in particular, we make an extremely sensitive test of the hyperscaling relation $d\nu = 2\Delta_4 -\gamma$. In two dimensions, we confirm the predicted exponent $\nu = 3/4$ and the hyperscaling relation; we estimate the universal ratios $\ / \ = 0.14026 \pm 0.00007$, $\ / \ = 0.43961 \pm 0.00034$ and $\Psi^* = 0.66296 \pm 0.00043$ (68\% confidence limits). In three dimensions, we estimate $\nu = 0.5877 \pm 0.0006$ with a correction-to-scaling exponent $\Delta_1 = 0.56 \pm 0.03$ (subjective 68\% confidence limits). This value for $\nu$ agrees excellently with the field-theoretic renormalization-group prediction, but there is some discrepancy for $\Delta_1$. Earlier Monte Carlo estimates of $\nu$, which were $\approx\! 0.592$, are now seen to be biased by corrections to scaling. We estimate the universal ratios $\ / \ = 0.1599 \pm 0.0002$ and $\Psi^* = 0.2471 \pm 0.0003$; since $\Psi^* > 0$, hyperscaling holds. The approach to $\Psi^*$ is from above, contrary to the prediction of the two-parameter renormalization-group theory. We critically reexamine this theory, and explain where the error lies.Comment: 87 pages including 12 figures, 1029558 bytes Postscript (NYU-TH-94/09/01

The effect of polymer/plasticiser ratio in film forming solutions on the properties of chitosan films

In this work physical-chemical properties of chitosan/ glycerol film forming solutions (FFS) and the resulting films were analysed. Solutions were prepared using different concentrations of plasticising agent (glycerol) and chitosan. Films were produced by solvent casting and equilibrated in a controlled atmosphere. FFS water activity and rheological behaviour were determined. Films water content, solubility, water vapour and oxygen permeabilities, thickness, and mechanical and thermal properties were determined. Fourier transform infrared (FTIR) spectroscopy was also used to study the chitosan/glycerol interactions. Results demonstrate that FFS chitosan concentration influenced solutions consistency coefficient and this was related with differences in films water retention and structure. Plasticiser addition led to an increase in films moisture content, solubility and water vapour permeability, water affinity and structural changes. Films thermo-mechanical properties are significantly affected by both chitosan and glycerol addition. FTIR experiments confirm these results. This work highlights the importance of glycerol and water plasticisation in films properties.This work was supported by National Funds from FCT - Fundacao para a Ciencia e a Tecnologia, through project PEst-OE/EQB/LA0016/2011.Authors Joana F. Fundo, Andrea C. Galvis-Sanchez and Mafalda A. C. Quintas acknowledge FCT for research grants SFRH/ BD / 62176 / 2009, SFRH/BPD/37890/2007 and SFRH / BPD / 41715 / 2007, respectively

Conformational changes during pore formation by the perforin-related protein pleurotolysin

Membrane attack complex/perforin-like (MACPF) proteins comprise the largest superfamily of pore-forming proteins, playing crucial roles in immunity and pathogenesis. Soluble monomers assemble into large transmembrane pores via conformational transitions that remain to be structurally and mechanistically characterised. Here we present an 11 Å resolution cryo-electron microscopy (cryo-EM) structure of the two-part, fungal toxin Pleurotolysin (Ply), together with crystal structures of both components (the lipid binding PlyA protein and the pore-forming MACPF component PlyB). These data reveal a 13-fold pore 80 Å in diameter and 100 Å in height, with each subunit comprised of a PlyB molecule atop a membrane bound dimer of PlyA. The resolution of the EM map, together with biophysical and computational experiments, allowed confident assignment of subdomains in a MACPF pore assembly. The major conformational changes in PlyB are a ~70° opening of the bent and distorted central β-sheet of the MACPF domain, accompanied by extrusion and refolding of two α-helical regions into transmembrane β-hairpins (TMH1 and TMH2). We determined the structures of three different disulphide bond-trapped prepore intermediates. Analysis of these data by molecular modelling and flexible fitting allows us to generate a potential trajectory of β-sheet unbending. The results suggest that MACPF conformational change is triggered through disruption of the interface between a conserved helix-turn-helix motif and the top of TMH2. Following their release we propose that the transmembrane regions assemble into β-hairpins via top down zippering of backbone hydrogen bonds to form the membrane-inserted β-barrel. The intermediate structures of the MACPF domain during refolding into the β-barrel pore establish a structural paradigm for the transition from soluble monomer to pore, which may be conserved across the whole superfamily. The TMH2 region is critical for the release of both TMH clusters, suggesting why this region is targeted by endogenous inhibitors of MACPF function

Exome sequencing of pleuropulmonary blastoma reveals frequent biallelic loss of TP53 and two hits in DICER1 resulting in retention of 5p-derived miRNA hairpin loop sequences

Pleuropulmonary blastoma is a rare childhood malignancy of lung mesenchymal cells that can remain dormant as epithelial cysts or progress to high-grade sarcoma. Predisposing germline loss-of-function DICER1 variants have been described. We sought to uncover additional contributors through whole exome sequencing of 15 tumor/normal pairs, followed by targeted resequencing, miRNA analysis and immunohistochemical analysis of additional tumors. In addition to frequent biallelic loss of TP53 and mutations of NRAS or BRAF in some cases, each case had compound disruption of DICER1: a germline (12 cases) or somatic (3 cases) loss-of-function variant plus a somatic missense mutation in the RNase IIIb domain. 5p-Derived microRNA (miRNA) transcripts retained abnormal precursor miRNA loop sequences normally removed by DICER1. This work both defines a genetic interaction landscape with DICER1 mutation and provides evidence for alteration in miRNA transcripts as a consequence of DICER1 disruption in cancer

A highly mutagenised barley (cv. Golden Promise) TILLING population coupled with strategies for screening-by-sequencing

Background:We developed and characterised a highly mutagenised TILLING population of the barley (Hordeum vulgare) cultivar Golden Promise. Golden Promise is the 'reference' genotype for barley transformation and a primary objective of using this cultivar was to be able to genetically complement observed mutations directly in order to prove gene function. Importantly, a reference genome assembly of Golden Promise has also recently been developed. As our primary interest was to identify mutations in genes involved in meiosis and recombination, to characterise the population we focused on a set of 46 genes from the literature that are possible meiosis gene candidates. Results:Sequencing 20 plants from the population using whole exome capture revealed that the mutation density in this population is high (one mutation every 154 kb), and consequently even in this small number of plants we identified several interesting mutations. We also recorded some issues with seed availability and germination. We subsequently designed and applied a simple two-dimensional pooling strategy to identify mutations in varying numbers of specific target genes by Illumina short read pooled-amplicon sequencing and subsequent deconvolution. In parallel we assembled a collection of semi-sterile mutants from the population and used a custom exome capture array targeting the 46 candidate meiotic genes to identify potentially causal mutations. Conclusions:We developed a highly mutagenised barley TILLING population in the transformation competent cultivar Golden Promise. We used novel and cost-efficient screening approaches to successfully identify a broad range of potentially deleterious variants that were subsequently validated by Sanger sequencing. These resources combined with a high-quality genome reference sequence opens new possibilities for efficient functional gene validation.Miriam Schreiber, Abdellah Barakate, Nicola Uzrek, Malcolm Macaulay, Adeline Sourdille, Jenny Morris, Pete E. Hedley, Luke Ramsay and Robbie Waug

Temporal and spatial instability in neutral and adaptive (MHC) genetic variation in marginal salmon populations

The role of marginal populations for the long-term maintenance of species’ genetic diversity and evolutionary potential is particularly timely in view of the range shifts caused by climate change. The Centre-Periphery hypothesis predicts that marginal populations should bear reduced genetic diversity and have low evolutionary potential. We analysed temporal stability at neutral microsatellite and adaptive MHC genetic variation over five decades in four marginal Atlantic salmon populations located at the southern limit of the species’ distribution with a complicated demographic history, which includes stocking with foreign and native salmon for at least 2 decades. We found a temporal increase in neutral genetic variation, as well as temporal instability in population structuring, highlighting the importance of temporal analyses in studies that examine the genetic diversity of peripheral populations at the margins of the species’ range, particularly in face of climate change

Identification of ABC Transporter Interaction of a Novel Cyanoquinoline Radiotracer and Implications for Tumour Imaging by Positron Emission Tomography

BACKGROUND: The epidermal growth factor receptor (EGFR) is overexpressed in many cancers including lung, ovarian, breast, head and neck and brain. Mutation of this receptor has been shown to play a crucial role in the response of non-small cell lung carcinoma (NSCLC) to EGFR-targeted therapies. It is envisaged that imaging of EGFR using positron emission tomography (PET) could aid in selection of patients for treatment with novel inhibitors. We recognised multi-drug resistant phenotype as a threat to development of successful imaging agents. In this report, we describe discovery of a novel cyanoquinoline radiotracer that lacks ABC transporter activity. METHODS: Cellular retention of the prototype cyanoquinoline [18F](2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxyquinolin-6-yl}-4-({[1-(2-fluoroethyl)-1H-1,2,3-triazol-4-yl]methyl}amino)-but-2-enamide ([18F]FED6) and [18F](2E)-N-{4-[(3-chloro-4-fluorophenyl)amino]-3-cyano-7-ethoxyquinolin-6-yl}-4-[({1-[(2R,5S)-3-fluoro-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]-1H-1,2,3-triazol-4-yl}methyl)amino]but-2-enamide ([18F]FED20) were evaluated to establish potential for imaging specificity. The substrate specificity of a number of cyanoquinolines towards ABC transporters was investigated in cell lines proficient or deficient in ABCB1 or ABCG2. RESULTS: FED6 demonstrated substrate specificity for both ABCG2 and ABCB1, a property that was not observed for all cyanoquinolines tested, suggesting scope for designing novel probes. ABC transporter activity was confirmed by attenuating the activity of transporters with drug inhibitors or siRNA. We synthesized a more hydrophilic compound [18F]FED20 to overcome ABC transporter activity. FED20 lacked substrate specificity for both ABCB1 and ABCG2, and maintained a strong affinity for EGFR. Furthermore, FED20 showed higher inhibitory affinity for active mutant EGFR versus wild-type or resistant mutant EGFR; this property resulted in higher [18F]FED20 cellular retention in active mutant EGFR expressing NSCLC. CONCLUSION: [18F]FED20 binds EGFR but is devoid of ABC transporter activity, thus, has potential for EGFR imaging

A novel TOPSIS–CBR goal programming approach to sustainable healthcare treatment

Cancer is one of the most common diseases worldwide and its treatment is a complex and time-consuming process. Specifically, prostate cancer as the most common cancer among male population has received the attentions of many researchers. Oncologists and medical physicists usually rely on their past experience and expertise to prescribe the dose plan for cancer treatment. The main objective of dose planning process is to deliver high dose to the cancerous cells and simultaneously minimize the side effects of the treatment. In this article, a novel TOPSIS case based reasoning goal-programming approach has been proposed to optimize the dose plan for prostate cancer treatment. Firstly, a hybrid retrieval process TOPSIS–CBR [technique for order preference by similarity to ideal solution (TOPSIS) and case based reasoning (CBR)] is used to capture the expertise and experience of oncologists. Thereafter, the dose plans of retrieved cases are adjusted using goal-programming mathematical model. This approach will not only help oncologists to make a better trade-off between different conflicting decision making criteria but will also deliver a high dose to the cancerous cells with minimal and necessary effect on surrounding organs at risk. The efficacy of proposed method is tested on a real data set collected from Nottingham City Hospital using leave-one-out strategy. In most of the cases treatment plans generated by the proposed method is coherent with the dose plan prescribed by an experienced oncologist or even better. Developed decision support system can assist both new and experienced oncologists in the treatment planning process