UK tourists, the great recession and Irish tourism policy

Inbound tourism to Ireland fell sharply in 2009 and 2010. Visits to Ireland from the UK, the dominant country of origin of visitors to Ireland, did not fall faster than UK visits elsewhere. We use micro-data for UK travellers to estimate price elasticities of tourism demand for various market segments. The proposed reduction in the travel tax, and the reduction in the VAT rate for "tourism goods and services" would lead to a modest increase in visitor numbers and expenditure. However, the increase in expenditure is small compared to the foregone tax revenue

Examining Prehistoric Migration Patterns in the Palauan Archipelago: A Computer Simulated Analysis of Drift Voyaging

A number of recent genetic, linguistic, and archaeological studies have attempted to ascertain the origin of settlers to the Palauan archipelago, but it remains a complex and debated issue. To provide additional insight into colonization strategies and settlement patterns, we conducted computer simulations of drift voyages to the Palauan archipelago based on historically recorded winds and currents. Drift voyages were considered here as drifting before the wind when lost, a strategy documented for Pacific Islanders. The simulations suggest that peoples drifting before the wind from the southern Philippines would have had the most success in landfall. This finding supports the current hypothesis of human colonization to the islands of Palau. KEYWORDS: Computer simulation, drift voyaging, seafaring, colonization, Palau, Micronesia

UK Tourists, The Great Recession and Irish Tourism Policy. ESRI WP412. October 2011

Inbound tourism to Ireland fell sharply in 2009 and 2010. Visits to Ireland from the UK, the dominant country of origin of visitors to Ireland, did not fall faster than UK visits elsewhere. We use micro-data for UK travellers to estimate price elasticities of tourism demand for various market segments. The proposed reduction in the travel tax, and the reduction in the VAT rate for “tourism goods and services” would lead to a modest increase in visitor numbers and expenditure. However, the increase in expenditure is small compared to the foregone tax revenue

Fractional boundary value problems: Analysis and numerical methods

This is the author's PDF of an article published in Fractional calculus and applied analysis 2011. The original publication is available at www.springerlink.comThis journal article discusses nonlinear boundary value problems.Fundacao para a Ciencia e Tecnologi

SEDLIN forms homodimers: characterisation of SEDLIN mutations and their interactions with transcription factors MBP1, PITX1 and SF1

BACKGROUND SEDLIN, a 140 amino acid subunit of the Transport Protein Particle (TRAPP) complex, is ubiquitously expressed and interacts with the transcription factors c-myc promoter-binding protein 1 (MBP1), pituitary homeobox 1 (PITX1) and steroidogenic factor 1 (SF1). SEDLIN mutations cause X-linked spondyloepiphyseal dysplasia tarda (SEDT). METHODOLOGY/PRINCIPAL FINDINGS We investigated the effects of 4 missense (Asp47Tyr, Ser73Leu, Phe83Ser and Val130Asp) and the most C-terminal nonsense (Gln131Stop) SEDT-associated mutations on interactions with MBP1, PITX1 and SF1 by expression in COS7 cells. Wild-type SEDLIN was present in the cytoplasm and nucleus and interacted with MBP1, PITX1 and SF1; the SEDLIN mutations did not alter these subcellular localizations or the interactions. However, SEDLIN was found to homodimerize, and the formation of dimers between wild-type and mutant SEDLIN would mask a loss in these interactions. A mammalian SEDLIN null cell-line is not available, and the interactions between SEDLIN and the transcription factors were therefore investigated in yeast, which does not endogenously express SEDLIN. This revealed that all the SEDT mutations, except Asp47Tyr, lead to a loss of interaction with MBP1, PITX1 and SF1. Three-dimensional modelling studies of SEDLIN revealed that Asp47 resides on the surface whereas all the other mutant residues lie within the hydrophobic core of the protein, and hence are likely to affect the correct folding of SEDLIN and thereby disrupt protein-protein interactions. CONCLUSIONS/SIGNIFICANCE Our studies demonstrate that SEDLIN is present in the nucleus, forms homodimers and that SEDT-associated mutations cause a loss of interaction with the transcription factors MBP1, PITX1 and SF1.This work was supported by the Oliver Bird Fund (Studentship No. RHE/00029/G), The Nuffield Foundation (J.J.), Arthritis Research Campaign (Grant ID 16438) (M.A.N. and R.V.T.), European Community Framework 7 programme grant TREAT-OA (HEALTH-F2-2008-00) (M.A.N. and R.V.T.) and the Medical Research Council (J.J., M.A.N. and R.V.T.). J.J. was an Oliver Bird funded PhD student

Sensitivity of an ecosystem model to hydrology and temperature

We tested the sensitivity of a dynamic ecosystem model (LPJ-GUESS) to the representation of soil moisture and soil temperature and to uncertainties in the prediction of precipitation and air temperature. We linked the ecosystem model with an advanced hydrological model (JULES) and used its soil moisture and soil temperature as input into the ecosystem model. We analysed these sensitivities along a latitudinal gradient in northern Russia. Differences in soil temperature and soil moisture had only little influence on the vegetation carbon fluxes, whereas the soil carbon fluxes were very sensitive to the JULES soil estimations. The sensitivity changed with latitude, showing stronger influence in the more northern grid cell. The sensitivity of modelled responses of both soil carbon fluxes and vegetation carbon fluxes to uncertainties in soil temperature were high, as both soil and vegetation carbon fluxes were strongly impacted. In contrast, uncertainties in the estimation of the amount of precipitation had little influence on the soil or vegetation carbon fluxes. The high sensitivity of soil respiration to soil temperature and moisture suggests that we should strive for a better understanding and representation of soil processes in ecosystem models to improve the reliability of predictions of future ecosystem change

Analgesic alpha-Conotoxins Vc1.1 and Rg1A inhibit N-type calcium channels in rat sensory neurons via GABA-B receptor activation

alpha-Conotoxins Vc1.1 and Rg1A are peptides from the venom of marine Conus snails that are currently in development as a treatment for neuropathic pain. Here we report that the alpha 9 alpha 10 nicotinic acetylcholine receptor-selective conotoxins Vc1.1 and Rg1A potently and selectively inhibit high-voltage-activated (HVA) calcium channel currents in dissociated DRG neurons in a concentration-dependent manner. The post-translationally modified peptides vc1a and [P60] Vc1.1 were inactive, as were all other alpha-conotoxins tested. Vc1.1 inhibited the alpha-conotoxin-sensitive HVA currents in DRG neurons but not those recorded from Xenopus oocytes expressing Ca(V)2.2, Ca(V)2.1, Ca(V)2.3, or Ca(V)1.2 channels. Inhibition of HVA currents by Vc1.1 was not reversed by depolarizing prepulses but was abolished by pertussis toxin (PTX), intracellular GDP beta S, or a selective inhibitor of pp60c-src tyrosine kinase. These data indicate that Vc1.1 does not interact with N-type calcium channels directly but inhibits them via a voltage-independent mechanism involving a PTX-sensitive, G-protein-coupled receptor. Preincubation with a variety of selective receptor antagonists demonstrated that only the GABAB receptor antagonists, [S-(R*, R*)][-3-[[1-(3,4-dichlorophenyl)ethyl]amino]-2-hydroxy propyl]([3,4]-cyclohexylmethyl) phosphinic acid hydrochloride (2S)-3[[(1S)-1-(3,4-dichlorophenyl)-ethyl]amino-2-hydroxypropyl](phenylmethyl) phosphinic acid and phaclofen, blocked the effect of Vc1.1 and Rg1A on Ca2+ channel currents. Together, the results identify CaV2.2 as a target of Vc1.1 and Rg1A, potentially mediating their analgesic actions. We propose a novel mechanism by which alpha-conotoxins Vc1.1 and Rg1A modulate native N-type (Ca(V)2.2) Ca2+ channel currents, namely acting as agonists via G-protein-coupled GABAB receptors

Dual effects of the PI3K inhibitor ZSTK474 on multidrug efflux pumps in resistant cancer cells

ZSTK474 is a potent phosphoinositide 3-kinase (PI3K) inhibitor that reduces cell proliferation via G1-arrest. However, there is little information on the susceptibility of this anticancer drug to resistance conferred by the multidrug pumps P-glycoprotein (ABCB1) and ABCG2. We have demonstrated that ZSTK474 generated cytotoxicity in cells over-expressing either pump with potency similar to that in drug sensitive cells. In addition, the co-administration of ZSTK474 with the cytotoxic anti-cancer drugs vinblastine and mitoxantrone caused a potentiated cytotoxic effect in both drug sensitive and efflux pump expressing cells. These observations suggest that ZSTK474 is unaffected by the presence of multidrug efflux pumps and may circumvent their activities. Indeed, ZSTK474 increased the cellular accumulation of calcein-AM and mitoxantrone in cells expressing ABCB1 and ABCG2, respectively. ZSTK474 treatment also resulted in reduced expression of both efflux pumps in multidrug resistant cancer cells. Measurement of ABCB1 or ABCG2 mRNA levels demonstrated that the reduction was not due to altered transcription. Similarly, inhibitor studies showed that the proteasomal degradation pathway for ABCB1 and the lysosomal route for ABCG2 degradation were unaffected by ZSTK474. Thus the mechanism underlying reduced ABCB1 and ABCG2 levels caused by ZSTK474 was due to a reduction in overall protein synthesis; a process influenced by the PI3K pathway. In summary, ZSTK474 is not susceptible to efflux by the resistance mediators ABCB1 and ABCG2. Moreover, it inhibits the drug transport function of the pumps and leads to a reduction in their cellular expression levels. Our observations demonstrate that ZSTK474 is a powerful anticancer drug.The work in this manuscript was generously supported by a project grant (#12-0008) from Worldwide Cancer Research