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Coauthored Publications

Below are a number publications where the involvement of ICHEC staff members has lead to their inclusion as coauthors.

Title:Gene Expression and epigenetic discovery screen reveal methylation of SFRP2 in prostate cancer
Authors:Perry A., O'Hurley G., Raheem O.A., Brennan K., Wong S., O'Grady A., Kennedy A.-M., Marignol L., Murphy T.M., Sullivan L., Barrett C., Loftus B., Thornhill J., Hewitt S.M., Lawler M., Kay E., Lynch T. and Hollywood D., 2013
Abstract: Aberrant activation of Wnts is common in human cancers, including prostate. Hypermethylation associated transcriptional silencing of Wnt antagonist genes SFRPs (Secreted Frizzled-Related Proteins) is a frequent oncogenic event. The significance of this is not known in prostate cancer. The objectives of this study were to (1) profile Wnt signaling related gene expression and (2) investigate methylation of Wnt antagonist genes in prostate cancer. Using TaqMan Low Density Arrays, we identified 15 Wnt signaling related genes with significantly altered expression in prostate cancer; the majority of which were upregulated in tumors. Notably, histologically benign tissue from men with prostate cancer appeared more similar to tumor (r=0.76) than to benign prostatic hyperplasia (BPH) (r=0.57) (P<0.001). Overall, the expression profile was highly similar between tumors of high (≥7) and low (≤6) Gleason scores. Pharmacological demethylation of PC-3 cells with 5-Aza-CdR reactivated 39 genes (≥2-fold); 40% of which inhibit Wnt signaling. Methylation frequencies in prostate cancer were 10% (2/20) (SFRP1), 64.86% (48/74) (SFRP2), 0% (0/20) (SFRP4) and 60% (12/20) (SFRP5). SFRP2 methylation was detected at significantly lower frequencies in high-grade prostatic intraepithelial neoplasia (HGPIN) (30%, 6/20), P=0.0096), tumor adjacent benign areas (8.82%, 7/69 P<0.0001) and BPH (11.43% (4/35), P<0.0001). The quantitative level of SFRP2 methylation (normalised index of methylation, NIM) was also significantly higher in tumors (116) than in the other samples (HGPIN=7.45, HB=0.47 and BPH=0.12). We show that SFRP2 hypermethylation is a common event in prostate cancer. SFRP2 methylation in combination with other epigenetic markers may be a useful biomarker of prostate cancer.
ICHEC Project:
Publication:International Journal of Cancer (2013) 132:1771-1780.
URL: http://dx.doi.org/10.1002/ijc.27798
Keywords: SFRP2; Prostate cancer; Hypermethylation; Wnt signaling
Status: Published

Title:Integrated Virtual Screening for the Identification of Novel and Selective Peroxisome Proliferator-Activated Receptor (PPAR) Scaffolds
Authors:Daniel K. Nevin, Martin B. Peters, Giorgio Carta, Darren Fayne, and David G. Lloyd, 2012
Abstract: We describe a fully customizable and integrated target-specific “tiered” virtual screening approach tailored to identifying and characterizing novel peroxisome proliferator activated receptor γ (PPARγ) scaffolds. Built on structure- and ligand-based computational techniques, a consensus protocol was developed for use in the virtual screening of chemical databases, focused toward retrieval of novel bioactive chemical scaffolds for PPARγ. Consequent from application, three novel PPAR scaffolds displaying distinct chemotypes have been identified, namely, 5-(4-(benzyloxy)-3-chlorobenzylidene)dihydro-2-thioxopyrimidine-4,6(1H,5H)-dione (MDG 548), 3-((4-bromophenoxy)methyl)-N-(4-nitro-1H-pyrazol-1-yl)benzamide (MDG 559), and ethyl 2-[3-hydroxy-5-(5-methyl-2-furyl)-2-oxo-4-(2-thienylcarbonyl)-2,5-dihydro-1H-pyrrol-1-yl]-4-methyl-1,3-thiazole-5-carboxylate (MDG 582). Fluorescence polarization(FP) and time resolved fluorescence resonance energy transfer (TR-FRET) show that these compounds display high affinity competitive binding to the PPARγ-LBD (EC50 of 215 nM to 5.45 μM). Consequent characterization by a TR-FRET activation reporter assay demonstrated agonism of PPARγ by all three compounds (EC50 of 467–594nM). Additionally, differential PPAR isotype specificity was demonstrated through assay against PPARα and PPARδ subtypes. This work showcases the ability of target specific “tiered screen” protocols to successfully identify novel scaffolds of individual receptor subtypes with greater efficacy than isolated screening methods.
ICHEC Project:PPARgamma Tiered Virtual Screening- Development of an Improved Post-Hit Scoring Process
Publication:J. Med. Chem., Article ASAP, May 14, 2012
URL: http://pubs.acs.org/doi/abs/10.1021/jm300068n
Keywords: Virtual Screening;drug discovery;workflows
Status: Published

Title:A molecular analysis of desiccation tolerance mechanisms in the anhydrobiotic nematode Panagrolaimus superbus using expressed sequenced tags
Authors:Tyson T., O'Mahony Zamora G., Wong S., Skelton M., Daly B., Jones J.T., Mulvihill E.D., Elsworth B., Phillips M., Blaxter M. and Burnell A.M., 2012
Abstract:

Background:
Some organisms can survive extreme desiccation by entering into a state of suspended animation known as anhydrobiosis. Panagrolaimus superbus is a free-living anhydrobiotic nematode that can survive rapid environmental desiccation. The mechanisms that P. superbus uses to combat the potentially lethal effects of cellular dehydration may include the constitutive and inducible expression of protective molecules, along with behavioural and/or morphological adaptations that slow the rate of cellular water loss. In addition, inducible repair and revival programmes may also be required for successful rehydration and recovery from anhydrobiosis.

Results
To identify constitutively expressed candidate anhydrobiotic genes we obtained 9,216 ESTs from an unstressed mixed stage population of P. superbus. We derived 4,009 unigenes from these ESTs. These unigene annotations and sequences can be accessed at http://www.nematodes.org/nembase4/species_info.php?species=PSC. We manually annotated a set of 187 constitutively expressed candidate anhydrobiotic genes from P. superbus. Notable among those is a putative lineage expansion of the lea (late embryogenesis abundant) gene family. The most abundantly expressed sequence was a member of the nematode specific sxp/ral-2 family that is highly expressed in parasitic nematodes and secreted onto the surface of the nematodes' cuticles. There were 2,059 novel unigenes (51.7% of the total), 149 of which are predicted to encode intrinsically disordered proteins lacking a fixed tertiary structure. One unigene may encode an exo-beta-1,3-glucanase (GHF5 family), most similar to a sequence from Phytophthora infestans. GHF5 enzymes have been reported from several species of plant parasitic nematodes, with horizontal gene transfer (HGT) from bacteria proposed to explain their evolutionary origin. This P. superbus sequence represents another possible HGT event within the Nematoda. The expression of five of the 19 putative stress response genes tested was upregulated in response to desiccation. These were the antioxidants glutathione peroxidase, dj-1 and 1-Cys peroxiredoxin, an shsp sequence and an lea gene.

Conclusions
P. superbus appears to utilise a strategy of combined constitutive and inducible gene expression in preparation for entry into anhydrobiosis. The apparent lineage expansion of lea genes, together with their constitutive and inducible expression, suggests that LEA3 proteins are important components of the anhydrobiotic protection repertoire of P. superbus.

ICHEC Project:Transcriptomic and Genomic Analyses of the Nematode Panagrolaimus superbus
Publication:BMC Research Notes (2012) 5:68
URL: http://dx.doi.org/10.1186/1756-0500-5-68
Status: Published

Title:Transitioning a message passing interface wavefront sensor model to a graphics processor environment
Authors:Michael T. Browne, Renato Miceli, 2011
Abstract: Previous work produced a parallel and moderately scalable wavefront sensor model as part of a larger integrated telescope model. This relied on traditional high performance computing (HPC) techniques using optimised C and MPI based parallelism to marry maximum performance with the productive high-level modelling environment of MATLAB. In the intervening period the computational power and flexibility offered by graphics processors (GPUs) has increased dramatically. This presents both new options in terms of the level of hardware required to perform simulations and also new capabilities in terms of the scope of such simulations. We present a discussion of the currently available approaches and test case performance results based on a port to a GPU platform.
ICHEC Project:
Publication:Integrated Modeling of Complex Optomechanical Systems, Proceedings Vol. 8336, DOI: 10.1117/12.915921
URL: http://dx.doi.org/10.1117/12.915921
Keywords: GPU MATLAB Wavefront sensor
Status: Published

Title:The Eyjafjallajökull ash plume – Part 2: Simulating ash cloud dispersion with REMOTE
Authors:C. O'Dowd, S. Varghese, D. Martin, R. Flanagan, A. McKinstry, D. Ceburnis, J. Ovadnevaite, G. Martucci, J. Bialek, C. Monahan, H. Berresheim, A. Vaishya, T. Grigas, Z. McGraw, S.G. Jennings, B. Langmann, T. Semmler, R. McGrath, 2011
Abstract: The recent eruption of Iceland's Eyjafjallajökull volcano caused extensive disruption across Europe. In this paper, we describe the volcanic ash parameterisation incorporated in the regional climate model (REMOTE) for forecasting volcanic ash dispersion. We investigate model sensitivity to emission parameters including eruption column height and vertical release distribution. Model results over a number of key ash incursion events are assessed in terms of agreement with both ground based measurements and retrieved LIDAR data at a number of European sites.
ICHEC Project:
Publication:DOI:10.1016/j.atmosenv.2011.10.037
URL: http://www.sciencedirect.com/science/article/pii/S1352231011011113
Keywords: Volcano, Ash, REMOTE, Eyjafjallajokull; Volcanic ash; Dispersion; Modelling
Status: Published

Title:The impact of Arctic sea ice on the Arctic energy budget and on the climate of the Northern mid- latitudes
Authors:Tido Semmler, Raymond McGrath, Shiyu Wang, 2012
Abstract: The atmospheric general circulation model EC-EARTH-IFS has been applied to investigate the influence of both a reduced and a removed Arctic sea ice cover and therefore a reduced meridional temperature gradient on the climate of the Northern mid-latitudes. Three 40-year simulations driven by original and modified ERA-40 sea surface temperatures and sea ice distributions have been performed at T255L62 resolution, corresponding to about 50 km horizontal resolution. Simulated changes between sensitivity and reference experiments are most pronounced over the Arctic itself where the reduced or removed sea ice leads to strongly increased upward heat and longwave radiation fluxes and precipitation in winter. In summer, the most pronounced change is the stronger absorption of shortwave radiation which is enhanced by optically thinner clouds. Averaged over the year and over the area north of 70° N, the negative energy imbalance at the top of the atmosphere decreases by about 10 W/m2 in both sensitivity experiments. The energy transport across 70° N is reduced as a result of the decreased temperature gradient. Changes are not restricted to the Arctic. A weaker pressure gradient, less extreme cold events and less precipitation are simulated in sub-Arctic and Northern mid- latitude regions in winter
ICHEC Project:Simulating the Global Climate with the EC-EARTH Coupled Atmosphere-Ocean-Ice Model
URL: http://ecearth.knmi.nl/Semmleretal.pdf
Keywords: climate, EC-EARTH
Status: Submitted

Title:EC-EARTH: A seamless earth system prediction approach in action
Authors:Hazeleger, W., Severijns, C., Semmler, T., Stefanescu, S., Yang, S., Wang, X., Wyser, K., Baldasano, J. M., Bintanja, R., Bougeault, P., Caballero, R., Dutra, E., Ekman, A. M. L., Christensen, J. H., van den Hurk, B., Jimenez, P., Jones, C., Kallberg, P., Koenigk, T., McGrath, R., Miranda, P., van Noije, T., Parodi, J. A., Schmith, T., Selten, F., Storelvmo, T., Sterl, A., Tapamo, H., Vancoppenolle, M., Viterbo, P., and Willen, U., 2010
ICHEC Project:Simulating the Global Climate with the EC-EARTH Coupled Atmosphere-Ocean-Ice Model
Publication:Bulletin of the American Meteorological Society,
URL: http://www.ametsoc.org/PUBS/bams/
Status: Published

Title:A prediction of cell differentiation and proliferation within a collagen-glycosaminoglycan scaffold subjected to mechanical strain and perfusive fluid flow
Authors:AJF Stops, KB Heraty, M Browne, FJ O’Brien, PE McHugh, 2010
Abstract: scaffold strain magnitudes and inlet fluid velocities to specific cell responses are thus far underdeveloped. This investigation attempted to simulate cell responses in a collagen–glycosaminoglycan (CG) scaffold within a bioreactor. CG scaffold deformation was simulated using μ-computed tomography (CT) and an in-house finite element solver (FEEBE/linear). Similarly, the internal fluid velocities were simulated using the afore-mentioned μCT dataset with a computational fluid dynamics solver (ANSYS/CFX). From the ensuing cell-level mechanics, albeit octahedral shear strain or fluid velocity, the proliferation and differentiation of the representative cells were predicted from deterministic functions. Cell proliferation patterns concurred with previous experiments. MSC differentiation was dependent on the level of CG scaffold strain and the inlet fluid velocity. Furthermore, MSC differentiation patterns indicated that specific combinations of scaffold strains and inlet fluid flows cause phenotype assemblies dominated by single cell types. Further to typical laboratory procedures, this predictive methodology demonstrated loading-specific differentiation lineages and proliferation patterns. It is hoped these results will enhance in-vitro tissue engineering procedures by providing a platform from which the scaffold loading applications can be tailored to suit the desired tissue.
ICHEC Project:A FINITE ELEMENT ANALYSIS OF THE MICROSCALE FORCES THAT DRIVE CELL-DERIVED TISSUE FORMATION: A TISSUE ENGINEERING SOLUTION
Publication:Journal of Biomechanics, vol. 43, pp. 618-626, DOI: 10.1016/j.jbiomech.2009.10.037
URL: http://www.jbiomech.com/
Keywords: Collagen–glycosaminoglycan scaffold, Perfusion bioreactor, Tissue engineering
Status: Published

Title:Dispersion analysis and computational efficiency of elastic lattice methods for seismic wave propagation
Authors:O'Brien G.S., Bean C.J. and Tapamo H., 2009
Abstract: Discrete particle methods or elastic lattice methods represent a 3D elastic solid by a series of interconnected springs arranged on a regular lattice. Generally, these methods only consider nearest neighbour interactions, i.e. they are first-order in space. These interconnected springs interacted through a force term (Hooke's Law for an elastic body), which when viewed on a macroscopic scale provide a numerical solution for the elastodynamic wave equations. Along with solving the elastodynamic wave equations these schemes are capable of simulating elastic static deformation. However, as these methods rely on nearest neighbour interactions they suffer from more pronounced numerical dispersion than traditional continuum methods. By including a new force term, the numerical dispersion can be reduced while keeping the flexibility of the nearest neighbour interaction rule. We present results of simulations where the additional force term reduces the numerical dispersion and increases the accuracy of the elastic lattice method solution. The computational efficiency and parallel scaling of this method on multiple processors is compared with a finite-difference solution to assess the computational cost of using this approach for simulating seismic wave propagation. We also show the applicability of this method to modelling seismic propagation in a complex Earth model.
ICHEC Project:Seismic source modelling and wave propagation in volcanoes
Publication:Computers & Geosciences (2009) 35:1768-1775
URL: http://dx.doi.org/10.1016/j.cageo.2008.12.004
Keywords: Computational seismic wave propagation; Discrete particle method; Elastic lattice method; Numerical seismic dispersion
Status: Published

Title:Spectrum of the non-abelian phase in Kitaev’s honeycomb lattice model
Authors:Lahtinen V., Kells G., Carollo A., Stitt T., Vala J. and Pachos J.K., 2008
Abstract: The spectral properties of Kitaev's honeycomb lattice model are investigated both analytically and numerically with the focus on the non-abelian phase of the model. After summarizing the fermionization technique which maps spins into free Majorana fermions, we evaluate the spectrum of sparse vortex configurations and derive the interaction between two vortices as a function of their separation. We consider the effect vortices can have on the fermionic spectrum as well as on the phase transition between the abelian and non-abelian phases. We explicitly demonstrate the 2n-fold ground state degeneracy in the presence of 2n well separated vortices and the lifting of the degeneracy due to their short-range interactions. The calculations are performed on an infinite lattice. In addition to the analytic treatment, a numerical study of finite size systems is performed which is in exact agreement with the theoretical considerations. The general spectral properties of the non-abelian phase are considered for various finite toroidal systems.
ICHEC Project:Topological phases in quantum lattice systems
Publication:Annals of Physics (2008) 323:2286-2310
URL: http://dx.doi.org/10.1016/j.aop.2007.12.009
Keywords: Topological models; Non-abelian vortices; Kitaev's model
Status: Published

Title:Shoreline approximation for unstructured mesh generation
Authors:G.J. Gorman, D. Piggott, and C.C. Pain, 2007
Abstract: A new method for approximating shorelines (polygons and polylines) is presented. The algorithm differs from commonly used Douglas-Peucker type algorithms as the method can approximate to some feature error given the constraint that edge lengths must satisfy some minimum edge length criteria. This constraint is necessary for the shoreline approximation to be useful for unstructured mesh generation for ocean modelling. In addition the method applies local optimisations to iteratively improve the shoreline approximation. Applications of the method are presented.
ICHEC Project:Parallel unstructured adaptive mesh method for three-dimensional range-of-scale ocean modelling
Publication:Computers & Geosciences, to appear
Keywords: simplification; shoreline; mesh generation; ocean modelling
Status: Accepted