A monoidal algebraic model for rational SO(2)-spectra

The category of rational SO(2)--equivariant spectra admits an algebraic model. That is, there is an abelian category A(SO(2)) whose derived category is equivalent to the homotopy category of rational$SO(2)--equivariant spectra. An important question is: does this algebraic model capture the smash product of spectra? The category A(SO(2)) is known as Greenlees' standard model, it is an abelian category that has no projective objects and is constructed from modules over a non--Noetherian ring. As a consequence, the standard techniques for constructing a monoidal model structure cannot be applied. In this paper a monoidal model structure on A(SO(2)) is constructed and the derived tensor product on the homotopy category is shown to be compatible with the smash product of spectra. The method used is related to techniques developed by the author in earlier joint work with Roitzheim. That work constructed a monoidal model structure on Franke's exotic model for the K_(p)--local stable homotopy category. A monoidal Quillen equivalence to a simpler monoidal model category that has explicit generating sets is also given. Having monoidal model structures on the two categories removes a serious obstruction to constructing a series of monoidal Quillen equivalences between the algebraic model and rational SO(2)--equivariant spectra.

Relative activity of triclabendazole metabolites against the liver fluke, Fasciola hepatica

A study has been carried Out to determine the relative activity Of triclabendazole (TCBZ) and its sulphoxide (TCBZ(center dot)SO) and sulphone (TCBZ(center dot)SO(2)) metabolites against the adult stage of the liver fluke, Fasciola hepatica. Flukes were incubated for 24 h in vitro in 15 mu g/ml of each of the compounds and prepared for scanning and transmission electron microscopy.

SO and CS observations of molecular clouds - II. Analysis and modelling of the abundance ratios - probing O-2/CO with SO/CS?

We here analyse the observational SO and CS data presented in Nilsson ct al. (2000). The SO/CS integrated intensity ratio maps are presented for 19 molecular clouds, together with tables of relevant ratios at strategic positions, where we have also observed (SO)-S-34 and/or (CS)-S-34. The SO/CS abundance ratio as calculated from an LTE analysis is highly varying within and between the sources. Our isotopomer observations and Monte Carlo simulations verify that this is not an artifact due to optical depth problems. The variation of the maximum SO/CS abundance ratio between the clouds is 0.2-7. The largest variations within a cloud are found for the most nearby objects, possibly indicating resolution effects. We have also performed time dependent chemical simulations. We compare the simulations with our observed SO/CS abundance ratios and suggest a varying oxygen to carbon initial abundance, differing temporal evolution, density differences and X-ray sources associated with young stellar objects as possible explanations to the variations. In particular, the observed variation of the maximum SO/CS abundance ratio between the clouds can be explained by using initial O/C+ abundance ratios in the range 1.3-2.5. We finally derive a relationship between the SO/CS and O-2/CO abundance ratios, which may be used as a guide to find the most promising interstellar O-2 search targets.

Multiproxy evidence for terrestrial and aquatic ecosystem responses during the 8.2 ka cold event as recorded at Hojby So, Denmark

A sediment succession from Hojby So, a lake in eastern Denmark, covering the time period 9400-7400 cal yr BP was studied using high-resolution geochemistry, magnetic susceptibility, pollen, macrofossil, diatom, and algal pigment analysis to investigate responses of the terrestrial and aquatic ecosystems to the 8.2 ka cold event. A reduced pollen production by thermophilous deciduous tree taxa in the period c. 8250-8000 cal yr BP reveal that the forest ecosystem was affected by low temperatures during the summer and winter/early-spring seasons. This finding is consistent with the timing of the 8.2 ka cold event as registered in the Greenland ice cores. At Hojby So, the climate anomaly appears to have started 200-250 yr earlier than the 8.2 ka cold event as the lake proxy data provide strong evidence for a precipitation-induced distinct increase in catchment soil erosion beginning around 8500 cal yr BP. Alteration of the terrestrial environment then resulted in a major aquatic ecosystem change with nutrient enrichment of the lake and enhanced productivity, which lasted until c. 7900 cal yr BP. (C) 2009 University of Washington. Published by Elsevier Inc. All rights reserved.

Unusual voltammetry of the reduction of O-2 in [C(4)dmim][N(Tf)(2)] reveals a strong interaction of O-2(center dot-) with the [C(4)dmim](+) cation

Voltammetric studies of the reduction of oxygen in the room temperature ionic liquid [C(4)dmim][N(Tf)(2)] have revealed a significant positive shift in the back peak potential, relative to that expected for a simple electron transfer. This shift is thought to be due to the strong association of the electrogenerated superoxide anion with the solvent cation. In this work we quantitatively simulate the microdisc electrode voltammetry using a model based upon a one-electron reduction followed by a reversible chemical step, involving the formation of the [C(4)dmim](+)center dot center dot center dot O-2(center dot-) ion-pair, and in doing so we extract a set of parameters completely describing the system. We have simulated the voltammetry in the absence of a following chemical step and have shown that it is impossible to simultaneously fit both the forward and reverse peaks. To further support the parameters extracted from fitting the experimental voltammetry, we have used these parameters to independently simulate the double step chronoamperometric response and found excellent agreement. The parameters used to describe the association of the O-2(center dot-) with the [C(4)dmim](+) were k(f) = 1.4 x 10(3) s(-1) for the first-order rate constant and K-eq = 25 for the equilibrium constant.

Identifying an O-2 supply pathway in CO oxidation on Au/TiO2(110): A density functional theory study on the intrinsic role of water

Au catalysis has been one of the hottest topics in chemistry in the last 10 years or so. How O-2 is supplied and what role water plays in CO oxidation are the two challenging issues in the field at the moment. In this study, using density functional theory we show that these two issues are in fact related to each other. The following observations are revealed: (i) water that can dissociate readily into OH groups can facilitate O-2 adsorption on TiO2; (ii) the effect of OH group on the O-2 adsorption is surprisingly long-ranged; and (iii) O-2 can also diffuse along the channel of Ti (5c) atoms on TiO2(1 10), and this may well be the rate-limiting step for the CO oxidation. We provide direct evidence that O-2 is supplied by O-2 adsorption on TiO2 in the presence of OH and can diffuse to the interface of Au/TiO2 to participate in CO oxidation. Furthermore, the physical origin of the water effects on Au catalysis has been identified by electronic structure analyses: There is a charge transfer from TiO2 in the presence of OH to O-2, and the O-2 adsorption energy depends linearly on the 02 charge. These results are of importance to understand water effects in general in heterogeneous catalysis.

PAR-2 Regulates Dental Pulp Inflammation Associated with Caries

Protease-activated receptors (PARs) are G-protein-coupled receptors that are activated enzymatically by proteolysis of an N-terminal domain. The cleavage and activation of PARs by serine proteases represent a novel mechanism by which such enzymes could influence the host inflammatory response. The aim of this study was to determine whether PAR-2 expression and activation were increased in dental caries. Using immunohistochemistry, we showed PAR-2 to be localized to pulp cells subjacent to caries lesions, but minimally expressed by healthy pulp tissue. Trypsin and the PAR-2 agonist (PAR2-AP) activated PAR-2 in an in vitro functional assay. Endogenous molecules present in pulp cell lysates from carious teeth specifically activated PAR-2, but those from healthy teeth failed to do so. The activation of PAR-2 in vitro was shown to increase the expression of the pro-inflammatory mediator cyclo-oxygenase-2 (COX-2), providing a mechanism whereby PAR-2 could modulate pulpal inflammation.

Partial agonism, neutral antagonism, and inverse agonism at the human wild-type and constitutively active cholecystokinin-2 receptors

Cholecystokinin receptor-2 (CCK2R) is a G protein receptor that regulates a number of physiological functions. Activation of CCK2R and/or expression of a constitutively active CCK2R variant may contribute to human diseases, including digestive cancers. Search for antagonists of the CCK2R has been an important challenge during the last few years, leading to discovery of a set of chemically distinct compounds. However, several early-discovered antagonists turned out to be partial agonists. In this context, we carried out pharmacological characterization of six CCK2R antagonists using COS-7 cells expressing the human CCK2R or a CCK2R mutant having a robust constitutive activity on inositol phosphates production, and we investigated the molecular mechanisms which, at a CCK2R binding site, account for these features. Results indicated that three compounds, 3R(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3- yl)-N'-(3-methylphenyl)urea (L365,260), 4-{[2-[[3-(lH-indol-3-yl)-2- methyl-1-oxo-2-[[[1.7.7-trimethyl-bicyclo[2.2.1]hept-2-yl)-oxy]carbonyl]amino] propyl]amino]-1-phenylethyl]amino-4-oxo-[lS-la.2[S*(S*)]4a]} -butanoate N-methyl-D-glucamine (PD135, 158), and (R)-1-naphthalenepropanoic acid, b-[2-[[2-(8-azaspiro-[4.5]dec-8-ylcarbonyl)-4,6-dimethylphenyl]amino]-2- oxoethyl] (CR2945), were partial agonists; one molecule, 1-[(R)-2,3-dihydro-1- (2,3-dihydro-1-(2-methylphenacyl)-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl] -3-(3-methylphenyl)urea (YM022), was a neutral antagonist; and two compounds, N-(+)-[1-(adamant-1-ylmethyl)-2,4-dioxo-5-phenyl2,3,4,5-tetrahydro-1H-1, 5-benzodiazepin-3-yl]-N'-phenylurea (GV150,013X) and ([(N-[methoxy-3 phenyl] N-[N-methyl N-phenyl carbamoylmethyl], carbomoylmethyl)-3 ureido]-3-phenyl)2-propionic acid (RPR101,048), were inverse agonists. Furthermore, target- and pharmacophore-based docking of ligands followed by molecular dynamic simulation experiments resulted in consistent motion of aromatic residues belonging to a network presumably important for activation, thus providing the first structural explanations for the different pharmacological profiles of tested compounds. This study confirms that several referenced so-called antagonists are in fact partial agonists, and because of this undesired activity, we suggest that newly generated molecules should be preferred to efficiently block CCK2R-related physiological effects. Furthermore, data on the structural basis for the different pharmacological features of CCK2R ligands will serve to further clarify CCK2R mechanism of activation. Copyright © 2006 The American Society for Pharmacology and Experimental Therapeutics.

Evidence That Interspecies Polymorphism in the Human and Rat Cholecystokinin Receptor-2 Affects Structure of the Binding Site for the Endogenous Agonist Cholecystokinin

The cholecystokinin (CCK) receptor-2 exerts very important central and peripheral functions by binding the neuropeptides cholecystokinin or gastrin. Because this receptor is a potential therapeutic target, great interest has been devoted to the identification of efficient antagonists. However, interspecies genetic polymorphism that does not alter cholecystokinin-induced signaling was shown to markedly affect activity of synthetic ligands. In this context, precise structural study of the agonist binding site on the human cholecystokinin receptor-2 is a prerequisite to elucidating the molecular basis for its activation and to optimizing properties of synthetic ligands. In this study, using site-directed mutagenesis and molecular modeling, we delineated the binding site for CCK on the human cholecystokinin receptor-2 by mutating amino acids corresponding to that of the rat homolog. By doing so, we demonstrated that, although resembling that of rat homolog, the human cholecystokinin receptor-2 binding site also displays important distinct structural features that were demonstrated by susceptibility to several point mutations (F120A, Y189A, H207A). Furthermore, docking of CCK in the human and rat cholecystokinin receptor-2, followed by dynamic simulations, allowed us to propose a plausible structural explanation of the experimentally observed difference between rat and human cholecystokinin-2 receptors.

Observation of K-Shell Soft X Ray Emission of Nitrogen Irradiated by XUV-Free Electron Laser FLASH at Intensities Greater than 10(16) W/cm(2)

In the past few years, the development of light sources of the 4(th) generation, namely XUV/X-ray Free Electron Lasers provides to the scientific community outstanding tools to investigate matter under extreme conditions never obtained in laboratories so far. As theory is at its infancy, the analysis of matter via the self-emission of the target is of central importance. The characterization of such dense matter is possible if photons can escape the medium. As the absorption of K-shell X-ray transitions is minimal, it plays a key role in this study. We report here the first successful observation of K-shell emission of Nitrogen at 430 eV using an XUV-Free Electron Laser to irradiate solid Boron Nitride targets under exceptional conditions: photon energy of 92 eV, pulse duration of similar to 20 fs, micro focusing leading to intensities larger than 10(16) W/cm(2). Using a Bragg crystal of THM coupled to a CCD, we resolved K-shell line emission from different charge states. We demonstrate that the spectroscopic data allow characterization of electron heating processes when X-ray radiation is interacting with solid matter. As energy transport is non-trivial because the light source is monochromatic, these results have an important impact on the theory. (C) 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Activation of GPVI by collagen is regulated by alpha(2)beta(1) and secondary mediators

We have compared the roles of adenosine diphosphate (ADP), thromboxanes and the integrin alpha(2)beta(1) in the activation of washed platelets by collagen in the presence of the alpha(IIb)beta3 antagonist lotrafiban. The stimulation of protein tyrosine phosphorylation by a collagen suspension is markedly delayed in the presence of the above inhibitors but shows substantial recovery with time. In comparison, activation of phospholipase C (PLC), Ca2+ elevation and dense granule secretion are more severely suppressed by the above inhibitors. blockade has a slightly greater inhibitory effect on all of the above responses than a combination of ADP receptor antagonists and cyclooxygenase inhibitor. Platelets exposed to a collagen monolayer show robust elevation of Ca2+ that is delayed in the presence of the above inhibitors and which is accompanied by of-granule secretion. These results demonstrate that secondary mediators and alpha(2)beta(1) modulate collagen-induced intracellular signaling but have negligible effect on GPVI signaling induced by the specific agonist convulxin. This work supports the postulate that the major role of of alpha(2)beta(1) is to increase the avidity of collagen for the platelet surface and by doing so enhance activation of GPVI. Therefore we propose an important role of secondary mediators in collagen-induced signaling is the indirect regulation of GPVI signaling via activation of alpha(2)beta(1).

Detection of a novel porcine boca-like virus in the background of porcine circovirus type 2 induced postweaning multisystemic wasting syndrome

Porcine circovirus type 2 (PCV-2) has been found to be the causative agent of postweaning multisystemic wasting syndrome (PMWS). However, PCV-2 is a ubiquitous virus in the swine population and a majority of pigs infected with PCV-2 do not develop the disease. Different factors such as age, maintenance, the genetics of PCV-2, other pathogens, etc. have been suggested to contribute to the development of PMWS. However, so far no proven connection between any of these factors and the disease development has been found. In this study we explored the possible presence of other so far unknown DNA containing infectious agents in lymph nodes collected from Swedish pigs with confirmed PMWS through random amplification and high-throughput sequencing. Although the vast majority of the amplified genetic sequences belonged to PCV-2, we also found genome sequences of Torque Teno virus (TTV) and of a novel parvovirus. The detection of TTV was expected since like PCV-2, TTV has been found to have high prevalence in pigs around the world. We were able to amplify a longer region of the parvovirus genome, consisting of the entire NP1 and partial VP1/2. By comparative analysis of the nucleotide sequences and phylogenetic studies we propose that this is a novel porcine parvovirus, with genetic relationship to bocaviruses.

Article 260(2) TFEU: An Effective Judicial Procedure for the Enforcement of Judgments?

Article 260(2) TFEU (ex 228(2) EC) enables the European Court of Justice to enforce compliance with its judgements. This article analyses its use in doing so and questions whether it could be applied more effectively. It commences by highlighting the principally economic and environmental context of the case-law, and by examining the initiatives taken to tackle delays in bringing these cases before the Court. The article then critically evaluates the effectiveness of the financial sanctions available to the Court. In doing so, it aims to fill a gap in present research by looking beyond the procedural measures through which the Court and the Commission operate to examine the practical impact of Article 260(2) itself.