Characterization of the FKBP12-Encoding Genes in Aspergillus fumigatus.

Invasive aspergillosis, largely caused by Aspergillus fumigatus, is responsible for a growing number of deaths among immunosuppressed patients. Immunosuppressants such as FK506 (tacrolimus) that target calcineurin have shown promise for antifungal drug development. FK506-binding proteins (FKBPs) form a complex with calcineurin in the presence of FK506 (FKBP12-FK506) and inhibit calcineurin activity. Research on FKBPs in fungi is limited, and none of the FKBPs have been previously characterized in A. fumigatus. We identified four orthologous genes of FKBP12, the human FK506 binding partner, in A. fumigatus and designated them fkbp12-1, fkbp12-2, fkbp12-3, and fkbp12-4. Deletional analysis of the four genes revealed that the Δfkbp12-1 strain was resistant to FK506, indicating FKBP12-1 as the key mediator of FK506-binding to calcineurin. The endogenously expressed FKBP12-1-EGFP fusion protein localized to the cytoplasm and nuclei under normal growth conditions but also to the hyphal septa following FK506 treatment, revealing its interaction with calcineurin. The FKBP12-1-EGFP fusion protein didn't localize at the septa in the presence of FK506 in the cnaA deletion background, confirming its interaction with calcineurin. Testing of all deletion strains in the Galleria mellonella model of aspergillosis suggested that these proteins don't play an important role in virulence. While the Δfkbp12-2 and Δfkbp12-3 strains didn't show any discernable phenotype, the Δfkbp12-4 strain displayed slight growth defect under normal growth conditions and inhibition of the caspofungin-mediated "paradoxical growth effect" at higher concentrations of the antifungal caspofungin. Together, these results indicate that while only FKBP12-1 is the bona fide binding partner of FK506, leading to the inhibition of calcineurin in A. fumigatus, FKBP12-4 may play a role in basal growth and the caspofungin-mediated paradoxical growth response. Exploitation of differences between A. fumigatus FKBP12-1 and human FKBP12 will be critical for the generation of fungal-specific FK506 analogs to inhibit fungal calcineurin and treat invasive fungal disease.

Greek-Turkish Dilemmas and the Cyprus-EU Accession Process

This article compares the processes of foreign policymaking in Greece and Turkey in order to examine why the incentives and pressures of the enlargement process have failed until now to initiate a settlement in the Cyprus bicommunal negotiations. While most studies on the Cyprus problem have focused on the two communities of the island, little at-tention has been paid to the policies of the two â??motherlandsâ??, namely Greece and Turkey. Yet their leverage on the two Cypriot communities and their conflicting expectations with regard to an enlarged Europe in the Eastern Mediterranean constitute a complex security puzzle. The Republic of Cyprus stands as a champion candidate member for the next enlargement, amid fears of Turkish reprisals and hopes for a po-litical settlement on the island. With the benefits of settlement overwhelming the benefits of any other alternative, it is paradoxical that the parties seem to be about to fail to reach a last-minute, mutually beneficial compromise. I try to resolve this paradox by supplementing rational choice theory with cognitivist theories of international relations. While rational choice predicts a direct relationship between external environment and foreign policy shifts, the case of Cyprus suggests that this relationship is actually indirect. Without understanding how the external environment is framed in the domestic political discourse of Greece and Turkey, it is impossible to demonstrate how outside pressure and incentives affect foreign policy shifts.

Discourses on Modernization in the Employment Public Services: Towards a New Form of Governance?

The “crisis of the social issue” in the EU has led to a certain consensus in the need to renew the organizational and institutional model of public administration. The core of the reform implies important administrative changes in most of the European welfare states. Those changes are inspired on theories such as the new public management, management by objectives or partnership. Such changes involve both semantic (“sharing responsibilities”, “effective costs”, or the substitution of “citizen under an administration” by “consumer”) and political (predominance of scattered forms of power and the individualization of responsibilities) transformations which operate in the framework of individuals and State relations. The paradigms of activation and flexicurity have been central in this public administration modernization project. This commitment with new forms of governance of social issues has important consequences for the political and moral foundations of social cohesion, and the Spanish case is not an exception. This paper aims at looking at those representations of “modernization” (as they appear in debates about the employment services restructuring policies) in detail as well as providing references to the trajectory of such reforms of public services since the early eighties to the beginning of the crisis.

Crossing the threshold: exile and literature in "El Canto del peregrino" (1999) by Angelina Muñiz-Huberman

This paper analyses the relation between exile and literature in Angelina Muñiz-Huberman’s work El canto del peregrino. In this collection of essays, the Spanish-Mexican writer, member of the second generation of Spanish Republican exiles in Mexico, outlines a poetics of exile. From the outset, the relation between exile and literature is presented in terms of identity: while defining exile as “literary form”, the book tends to prefer a metaphorical concept of exile over ‘merely’ historical or referential approaches to it. More in particular, this paper will examine how the author constructs an identity of ‘exiled writer’ based on the close association between exile and literature on the one hand, and on the view of exile as ‘home’ or ‘dwelling’, on the other hand. A second point of interest concerns the discursive impact of this literary and metaphorical concept of exile and the author’s personal experience. A brief analysis of the essayist’s discursive voice and her writing practice shows how Muñiz-Huberman gives shape to an intrinsically complex and paradoxical view on exile.

Sufrimiento y pesimismo en Schopenhauer

El presente artículo investiga de qué forma la centralidad del sufrimiento en la filosofía de Schopenhauer sirve para fundamentar su pesimismo. Tres son los argumentos analizados: el lugar del sufrimiento en el mundo, su lugar en la conciencia humana y su lugar frente a la felicidad. A la luz de estos tres argumentos, se destaca que el vínculo indisoluble entre el sufrimiento y la esencia del mundo, la determinación del sufrimiento en la conciencia, tanto en su génesis como en su intensidad, y su anterioridad ontológica frente a la felicidad hacen del pesimismo una categoría necesaria. Finalmente, se señala una posible contribución del pesimismo schopenhaueriano a la crítica social contemporánea, considerando la idea de mundo que el capitalismo tardío promueve.

Self-perception of dentofacial attractiveness among patients requiring orthognathic surgery

Objective: To test the hypothesis that the self-perception of dental and facial attractiveness among patients requiring orthognathic surgery is no different from that of control patients.

Materials and Methods: Happiness with dental and facial appearance was assessed using questionnaires completed by 162 patients who required orthognathic treatment and 157 control subjects. Visual analog scale, binary, and open response data were collected. Analysis was carried out using a general linear model, logistic regression, and chi-square tests.

Results: Orthognathic patients were less happy with their dental appearance than were controls. Class II patients and women had lower happiness scores for their dental appearance. Among orthognathic patients, the "shape" and "prominence" of their teeth were the most frequent causes of concern. Older subjects, women, and orthognathic patients were less happy with their facial appearance. Class III orthognathic patients, older subjects, and women were more likely to have looked at their own face in profile. A greater proportion of Class II subjects than Class III subjects wished to change their appearance.

Conclusions: The hypothesis is rejected. The findings indicate that women and patients requiring orthognathic surgery had lower levels of happiness with their dentofacial appearance. Although Class II patients exhibited the lowest levels of happiness with their dental appearance, there was some evidence that concerns and awareness about their facial profile were more pronounced among the Class III patients.

Museums and youth: between misunderstanding and disappointment. Youth perceptions and arguments about the cultural consumption of museums in Chile

Young people are less explored in museum audience research; this is a paradoxical situation when considering its strategic location in the cultural reproduction and if considering the high performing cultural consumption compared with other sectors. The phenomenon of museums consumption by young Chileans who are self recognized as public and non-public museums is explored from a qualitative approach. It was conducted with focus groups in the three largest cities in Chile (Santiago, Valparaíso and Concepción). They identify the museum as a cultural institution in full force. However, in questioning museums activity youth reveal the specificity of their cultural matrix. This is referred to a social temporality based on the fragment, the discourse of familiarity, proximity and instead of breaking and critical. They claim a museum aesthetic / historical experience based on pleasure and enjoyment. An overview is proposed to further clarify the youth cultural consumption to characterize more precisely the place of the museum in the set, to design more effective policies museums.

China’s New Approach to CSR in Congo: Is the leverage turning to China?

China has been the world’s fastest growing economy in the past 30 years with its enterprises rapidly emerging and becoming leading players globally. In particular, the progressive integration into the international system has been spurred by China’s entry into the global trading regime of the World Trade Organization (WTO) in 2001. The 'go global' policy has been facilitating the rapidly growing engagement on the African continent of Chinese multinational companies (MNCs). As a promising tri-polar global economic entity, its growth of relations with Africa has been both unprecedented and impressive. As the Sino-Africa economic and business partnership surges forward, the matter of corporate social responsibility (CSR) is increasingly becoming an imperative ingredient for any successful business. It is noteworthy that responsible corporate citizens should take account of the impact of their investment on both economic and social arenas. However, it still remains uncertain what role Chinese MNCs have been playing in the continent’s sustainable development.
A Sino-Congo deal seems a positive way forward, accelerating the Democratic Republic of Congo’s (hereinafter referred to as Congo) regional economy, depressed due to years of war. Meanwhile, the escalating investment into Congo has raised controversies for its no-attachment policy, with increasing pressure imposed on China’s MNCs to take CSR more seriously. Particular concerns are focused on the multinationals’ inadequate environmental and human rights protection. The recent massive infrastructure investment is arguably perceived as a different interpretation of CSR, which has aroused a hot debate about whether China is heading for status as a responsible stakeholder in the international community. It is conducive to clarifying the paradoxical issue by addressing whether China’s recent approaches have the potential to facilitate CSR initiatives or hinder them in the long run.

Wnt-β-catenin-Tcf-4 signalling-modulated invasiveness is dependent on osteopontin expression in breast cancer.

Background:We have previously demonstrated that Tcf-4 regulates osteopontin (OPN) in rat breast epithelial cells, Rama37. In this report, we have examined the importance of this regulation in human breast cancer.Methods:The regulatory roles of Tcf-4 on cell invasion and OPN expression were investigated. The mRNA expression of Tcf-4 and OPN, and survival of breast cancer patients were correlated.Results:Tcf-4 enhanced cell invasion in both MCF10AT and MDA MB 231 breast cancer cells by transcriptionally activating OPN expression. Osteopontin was activated by Wnt signalling in MDA MB 231 cells. Paradoxical results on Tcf-4-regulated OPN expression in MCF10AT (activation) and Rama37 (repression) cells were shown to be a result of differential Wnt signalling competency in MCF10AT and Rama37 cells. High levels of OPN and Tcf-4 mRNA expression were significantly associated with survival in breast cancer patients. Most importantly, Tcf-4-positive patients had a poorer prognosis when OPN was overexpressed, while OPN-negative patients had a better prognosis when Tcf-4 was overexpressed.Conclusion:Our results suggest that Tcf-4 can act as a repressor or activator of breast cancer progression by regulating OPN expression in a Wnt-dependent manner and that Tcf-4 and OPN together may be a novel prognostic indicator for breast cancer progression.

Bereavement: A behavioural process

Sixty-seven widows whose husbands had been killed in the context of sectarian violence in Northern Ireland were assessed in relation to the cause of death, the quality of their marital relationship and the level of worry prior to the loss. Results reported here show that the violent cause of death led to a greater level of long-term psychological distress than other causes of death. Furthermore, widows who reported happiness regarding their marital relationship showed more signs of distress after the loss than those who reported less happiness. Widows who had not worried about their husband showed less signs of psychological distress after the loss than those who had worried. The interpretation of the findings is based on recent thinking in behaviour analysis.

Is everybody happy? The politics and measurement of national wellbeing

This article explores the political and intellectual influences behind the growth of interest in happiness and the emergence of the new 'science of happiness'. It offers a critique of the use of subjective wellbeing indicators within indexes of social and economic progress, and argues that the proposed United Kingdom's National Well-being Index is over-reliant on subjective measures. We conclude by arguing that the mainstreaming of happiness indicators reflects and supports the emergence of 'behavioural social policy'.

AßPP over-expressing transgenic rat model of Alzheimer's disease utilizing the Tg2576 mouse protocol.

The current study examined behavioral and histological effects of amyloid-ß (Aß) protein precursor (AßPP) overexpression in transgenic (Tg) rats created using the same gene, mutation, and promoter as the Tg2576 mouse model of Alzheimer's disease (AD). Male Tg+ rats were bred with female wild-type rats to generate litters of hemizygous Tg+ and Tg- offspring. Tg+ rats and Tg- littermates were tested for memory deficits at 4, 8, and 12 months old using a water-maze procedure. There were no significant behavioral differences between Tg+ rats and Tg- littermates at 4 months old but there were significant differences at 8 and 12 months old, and in probe trials at 8 and 12 months old, the Tg+ rats spent significantly less time and covered less distance in the platform zone. Under acquisition of a fixed-consecutive number schedule at 3 months old, Tg- littermates demonstrated a longer latency to learning the response rule than Tg+ rats; while this might seem paradoxical, it is consistent with the role of overexpression of AßPP in learning. Histological analyses revealed activated astrocytes in brains of Tg+ rats but not Tg- littermates at 6 months old, and thioflavin-S positive staining in the hippocampus and cortex of 17-month old Tg+ rats but not Tg- littermates. Quantification of Aß load in the brain at 22 months indicated high levels of Aß38, Aß40, and Aß42 in the Tg+ rats. These data suggest this model might provide a valuable resource for AD research.

Time to get a move on:Overcoming bradykinetic movement in Parkinson's disease with artificial sensory guidance generated from biological motion

Paradoxical kinesia describes the motor improvement in Parkinson's disease (PD) triggered by the presence of external sensory information relevant for the movement. This phenomenon has been puzzling scientists for over 60 years, both in neurological and motor control research, with the underpinning mechanism still being the subject of fierce debate. In this paper we present novel evidence supporting the idea that the key to understanding paradoxical kinesia lies in both spatial and temporal information conveyed by the cues and the coupling between perception and action. We tested a group of 7 idiopathic PD patients in an upper limb mediolateral movement task. Movements were performed with and without a visual point light display, travelling at 3 different speeds. The dynamic information presented in the visual point light display depicted three different movement speeds of the same amplitude performed by a healthy adult. The displays were tested and validated on a group of neurologically healthy participants before being tested on the PD group. Our data show that the temporal aspects of the movement (kinematics) in PD can be moderated by the prescribed temporal information presented in a dynamic environmental cue. Patients demonstrated a significant improvement in terms of movement time and peak velocity when executing movement in accordance with the information afforded by the point light display, compared to when the movement of the same amplitude and direction was performed without the display. In all patients we observed the effect of paradoxical kinesia, with a strong relationship between the perceptual information prescribed by the biological motion display and the observed motor performance of the patients. © 2013 Elsevier B.V. All rights reserved.

K-Contagion: Sound, Space and Speed in Psy's 'Gangnam Style'

Park Jae-Sang’s (otherwise known as PSY) bewilderingly successful pop contagion ‘Gangnam Style’ needs no introduction. As of January 2013, it has become the most watched video in YouTube’s history and has garnered over 1.23 billion hits since. ‘Gangnam Style’ has also become a rapid global pop phenomenon with multiple parodic reproductions, imitations and adaptations; Rapper PSY himself has become an international name and styled as the ‘anti-hero’ of the glamour-driven K-pop scene. His fame has transcended the social sphere and permeated the political stratosphere with politicians such as Barrack Obama and David Cameron being among the many whom PSY has exchanged pleasantries with. Apart from breaking ground and creating social and media history in many ways, ‘Gangnam Style’ has even been purported by UN Secretary-General Ban Ki Moon to be a “force for world peace” – cultural barriers are demolished as the world dances. Underlying this sentiment is the video’s almost universal appeal that assumes a supracultural yet equally paradoxical translatability: Korea’s neoteric ‘K-Wave’ phenomenon is at once local yet global, and where the latter is predicated on the former quality. The paper’s concern is thus two-fold. It will consider the dromological aspects of this musical contagion as it exemplifies and performs quite literally Paul Virilio’s thesis that the modern condition is driven by speed yet arrested to a dictatorship of movement. While many theories have been put forward for this astounding pop peculiarity, this paper would also examine the intercultural currents that advocate such a global (pop) cultural response. Through an analysis of sonic qualities – digital techno-beat rhythms, synth-based musicality, cyclical lyrics, horse-galloping movements – and acoustic receptions, it will consider the simultaneous and dichotomous currents of glocalisation and globalisation as it relates to the ways in which sonic ‘hyper-links’ establish new concepts of global-cultural identities even as these seem to be interrogated in the borderless worlds of hyper-mediatised realities and cultural technologies.

Anxiolytic-like effects observed in rats exposed to the elevated zero-maze following treatment with 5-HT2/5-HT3/5-HT4 ligands

The present study examined the effects of administering selective 5-HT antagonists and agonists to rats tested in the elevated zero-maze (EZM) model of anxiety. The EZM paradigm has advantages over the elevated plus-maze (EPM) paradigm with respect to measuring anxiety, yet has been utilized less frequently. Three experiments were conducted each with a diazepam control (0.25, 0.5 and 0.75 mg/kg). In the first experiment, we administered the 5-HT_2C antagonist RS 102221 (0.5, 1.0, and 2.0 mg/kg) and 5-HT_2C agonist MK-212 (0.25, 0.5 and 0.75 mg/kg); in the second experiment, we administered the 5-HT₃ antagonist Y-25130 (0.1, 1.0 and 3.0 mg/kg) and 5-HT₃ agonist SR 57227A (0.1, 1.0 and 3.0 mg/kg), and in the third experiment, we administered the 5-HT₄ antagonist RS 39604 (0.01, 0.1, 1.0 mg/kg) and 5-HT₄ agonist RS 67333 (0.01, 0.1 and 0.5 mg/kg). The administration of 5-HT_2/3/4 subtype antagonists all generated behavioral profiles indicative of anxiolytic-like effects in the EZM, which was apparent from examination of both traditional and ethological measures. While little effect was observed from 5-HT₂ and 5-HT₃ agonists, the 5-HT₄ agonist RS 67333 was found to produce a paradoxical anxiolytic-like effect similar to that produced by the 5-HT₄ antagonist RS 39604. We conclude by discussing the implications of these findings.