Continuity and Change in the European Union’s Approach to Enlargement::Turkey and Central and Eastern Europe compared

Existing studies of European Union (EU) enlargement provide few answers to questions concerning continuity and change in the dynamics of the process. This article identifies a number of conditioning factors that have shaped the EU’s approach to eastern enlargement and traces elements of continuity and change in the EU’s handling of Turkey’s membership aspirations. The article focuses on three established factors – member state preferences, supranational activism and EU capacity – and two less prominent factors – public opinion and narrative frame

First record of minimum Irish hare (Lepus timidus hibernicus Bell 1837) longevity in the wild.

Average longevity of the mountain hare (Lepus timidus L., 1758) has been estimated at nine years in the wild (Macdonald D. and Barrett, P. 1993 Mammals of Britain and Europe. Harper Collins Publishers, London) with a maximum recorded age of 18 years for one marked animal (Angerbjörn, A. and Flux, J. E. C. 1995 Lepus timidus. Mammalian Species 495: 1–11). However, the longevity of the Irish hare (L. t. hibernicus Bell 1837) is entirely unknown. A total of 14 Irish hares was trapped and tagged at Belfast International Airport, Co. Antrim from February to April 2005. The sex, age (juvenile or adult) and weight of each animal were recorded. Adults were taken as those individuals >8-10 months old defined by the fusing of the notch between the apophysis and diaphysis of the tibia and humerus (Flux, J. E. C. 1970 Journal of Zoology 161: 75-123). Individual identification was made by a system of colourcoded ear tags (Roxan iD Ltd. Selkirk, Scotland) being inserted in the centre of the pinna of each ear. Each ear tag (6 × 34 mm) and puncture site was disinfected with 70 per cent ethanol prior to insertion. An adult male, #001/002 ‘Blue/Blue’, was tagged on 3 March 2005 weighing 3.8 kg and was sighted during a return site visit on 4 April 2007. An adult female, #026/003 ‘Green/Yellow’, was tagged on 15 April 2005 weighing 4.0 kg and was sighted during return visits on 25 March 2010 and 19 October 2010. The latest possible date of birth for both individuals was spring/summer 2004. Consequently, they were at least 3 years and 6.5 years old, respectively. This is the first record of minimum Irish hare longevity in the wild. These observations suggest that ear tagging does not compromise animal welfare and is an effective means of long-term monitoring. Future research may utilize capture-mark-recapture methods.

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.

Comparison of mechanical and electrical activity and interstitial cells of Cajal in urinary bladders from wild-type and W/W-v mice

Background and purpose: W/Wv and wild-type murine bladders were studied to determine whether the W/Wv phenotype, which causes a reduction in, but not abolition of, tyrosine kinase activity, is a useful tool to study the function of bladder interstitial cells of Cajal (ICC).

Experimental approach: Immunohistochemistry, tension recordings and microelectrode recordings of membrane potential were performed on wild-type and mutant bladders.

Key results: Wild-type and W/Wv detrusors contained c-Kit- and vimentin-immunopositive cells in comparable quantities, distribution and morphology. Electrical field stimulation evoked tetrodotoxin-sensitive contractions in wild-type and W/Wv detrusor strips. Atropine reduced wild-type responses by 50% whereas a 25% reduction occurred in W/Wv strips. The atropine-insensitive component was blocked by pyridoxal-5-phosphate-6-azophenyl-2',4'-disulphonic acid in both tissue types. Wild-type and W/Wv detrusors had similar resting membrane potentials of -48 mV. Spontaneous electrical activity in both tissue types comprised action potentials and unitary potentials. Action potentials were nifedipine-sensitive whereas unitary potentials were not. Excitatory junction potentials were evoked by single pulses in both tissues. These were reduced by atropine in wild-type tissues but not in W/Wv preparations. The atropine-insensitive component was abolished by pyridoxal-5-phosphate-6-azophenyl-2',4'-disulphonic acid in both preparations.

Conclusions and implications: Bladders from W/Wv mice contain c-Kit- and vimentin-immunopositive ICC. There are similarities in the electrical and contractile properties of W/Wv and wild-type detrusors. However, significant differences were found in the pharmacology of the responses to neurogenic stimulation with an apparent up-regulation of the purinergic component. These findings indicate that the W/Wv strain may not be the best model to study ICC function in the bladder.

Early crime writing and the state: Jonathan Wild, Daniel Defoe and Bernard Mandeville in 1720s London

This article argues that the early development of crime writing needs to be understood in relation to the consolidation of the modern state. It demonstrates that London in the 1720s constitutes a significant moment in this early development for three main reasons. First, the period witnessed a crime epidemic which reached its climax in the 1720s and which precipitated a set of particularly aggressive counter-measures by the state; second, it saw the rise and eventual fall of the infamous Jonathan Wild who acted as both thief and surrogate policeman; and third, it was also marked by a surge in interests on the part of writers like Daniel Defoe and Bernard Mandeville in the related matters of crime and punishment. This article explores the ways in which accounts of crime and punishment in this period deployed and in some instances interrogated the rhetoric of social contract theory and writings on statecraft, particularly by Thomas Hobbes and Mandeville. But while the criminal biographies and gallows sermons produced by the Newgate prison’s ‘ordinaries’ provided crude and reductive accounts of the efficacy of the state, the article shows how two accounts of the life of Jonathan Wild (by Defoe and H.D) responded in highly complex ways to the issues of crime and policing and provided a consistently and self-consciously ambivalent reading of the state and state power. To conclude, I suggest that this ambivalence can be read as a critique of the impartial or neutral state and that it constitutes one of the key features of what we would later understand to be crime writing as a dedicated literary genre.

“Authentic Reproductions”: Staging the “Wild West” in Modern Irish Drama

This article examines two metatheatrical plays written by playwrights from the north of Ireland that bookend the twentieth century. The first is Ulster Literary Theatre (ULT) playwright Gerald MacNamara’s parodic, “proto-Pirandellian”4 The Mist That Does Be on the Bog (1909), which satirizes the peasant aesthetic of the “Abbey play” of the Irish Revival.5 The second is Marie Jones’s international hit, Stones in His Pockets (1999), a “play-full,” postmodern deconstruction of the commodification of Irish culture in the era of the Celtic Tiger. Although separated by exactly ninety years, the two plays can be connected through their critiques of the cultural politics of nationalism and globalization during the periods of the Irish Revival and the Celtic Tiger, respectively. Moreover, both plays are distinguished by their dramaturgical form, as the political critique of each is corporeally embodied in metatheatrical performance.

Wild-type measles virus infection of primary epithelial cells occurs via the basolateral surface without syncytium formation or release of infectious virus

The lymphotropic and myelotropic nature of wild-type measles virus (wt-MV) is well recognized, with dendritic cells and lymphocytes expressing the MV receptor CD150 mediating systemic spread of the virus. Infection of respiratory epithelial cells has long been considered crucial for entry of MV into the body. However, the lack of detectable CD150 on these cells raises the issue of their importance in the pathogenesis of measles. This study utilized a combination of in vitro, ex vivo and in vivo model systems to characterize the susceptibility of epithelial cells to wt-MV of proven pathogenicity. Low numbers of MV-infected epithelial cells in close proximity to underlying infected lymphocytes or myeloid cells suggested infection via the basolateral side of the epithelium in the macaque model. In primary cultures of human bronchial epithelial cells, foci of MV-infected cells were only observed following infection via the basolateral cell surface. The extent of infection in primary cells was enhanced both in vitro and in ex vivo cornea rim tissue by disrupting the integrity of the cells prior to the application of virus. This demonstrated that, whilst epithelial cells may not be the primary target cells for wt-MV, areas of epithelium in which tight junctions are disrupted can become infected using high m.o.i. The low numbers of MV-infected epithelial cells observed in vivo in conjunction with the absence of infectious virus release from infected primary cell cultures suggest that epithelial cells have a peripheral role in MV transmission.