Non-peptidic antagonists of the CGRP receptor, BIBN4096BS and MK-0974, interact with the calcitonin receptor-like receptor via methionine-42 and RAMP1 via tryptophan-74

The receptor for calcitonin gene-related peptide (CGRP) has been the target for the development of novel small molecule antagonists for the treatment of migraine. Two such antagonists, BIBN4096BS and MK-0974, have shown great promise in clinical trials and hence a deeper understanding of the mechanism of their interaction with the receptor is now required. The structure of the CGRP receptor is unusual since it is comprised of a hetero-oligomeric complex between the calcitonin receptor-like receptor (CRL) and an accessory protein (RAMP1). Both the CLR and RAMP1 components have extracellular domains which interact with each other and together form part of the peptide-binding site. It seems likely that the antagonist binding site will also be located on the extracellular domains and indeed Trp-74 of RAMP1 has been shown to form part of the binding site for BIBN4096BS. However, despite a chimeric study demonstrating the role of the N-terminal domain of CLR in antagonist binding, no specific residues have been identified. Here we carry out a mutagenic screen of the extreme N-terminal domain of CLR (residues 23-63) and identify a mutant, Met-42-Ala, which displays 48-fold lower affinity for BIBN4096BS and almost 900-fold lower affinity for MK-0974. In addition, we confirm that the Trp-74-Lys mutation at human RAMP1 reduces BIBN4096BS affinity by over 300-fold and show for the first time a similar effect for MK-0974 affinity. The data suggest that the non-peptide antagonists occupy a binding site close to the interface of the N-terminal domains of CLR and RAMP1.

Die unvermeidlichen Sonette: Thomas Mann und Shakespeare

Thomas Mann empfand zeitlebens eine große Bewunderung für Shakespeare, die sich in der für seine literarische Arbeitsweise typischen Form der intertextuellen Bezugnahme auf die Werke des englischen Klassikers offenbart. Diese literarische Beziehung lässt sich anhand deutlicher Allusionen von den Anfängen bis ins Spätwerk verfolgen und kulminiert im Doktor Faustus. Innerhalb der Shakespeare-Anspielungen in diesem Roman nehmen Bezüge zu den Sonetten eine zentrale Rolle ein. Über Jahrzehnte hinweg zeigte sich Thomas Mann fasziniert von diesen Gedichten und setzte sich vielfach mit der in ihnen dargestellten Verbindung von hetero- und homosexueller Anziehung sowie der zentralen Thematik künstlerischer Verewigung auseinander. Diese beiden Themenkreise stehen auch hier im Vordergrund und bilden eine Folie für Aspekte der Beziehung zwischen Leverkühn und Rudi Schwerdtfeger, wobei Thomas Mann nicht nur Motive aus den Gedichten aufgriff, sondern ebenfalls auf die Entstehungssituation der Sonette und ihre vermutete autobiographische Dimension Bezug nahm: Leverkühn - seinerseits ein Selbstporträt seines Autors - nimmt so zugleich die Rolle einer Shakespeareschen Figur und die Position des englischen Dichters selbst ein. Darüber hinaus ist sich Thomas Manns Protagonist dieser literarischen Beziehungen in hohem Grade bewusst und gestaltet sie selbst entscheidend mit. Wie keine andere Mannsche Gestalt vor ihm greift Leverkühn als Hauptfigur in die Handlung ein, manipuliert und inszeniert das Romangeschehen anhand literarischer Vorlagen. Dadurch erhält Thomas Manns komplexe Verwendung von Intertextualität eine zusätzliche Dimension und nimmt in diesem späten Roman geradezu postmoderne Züge an.

Empowering, degrading or a 'mutually exploitative' exchange For women?: Characterising the power relations of the strip club

This paper seeks to characterise the gendered and sexualised power relations of both female and male strip clubs, and to signal what this means for establishing positive definitions of female desire. It is argued that while it is not useful to present female strippers, or female patrons of male strip clubs as purely passive victims of male heterosexism within these venues, it is equally damaging to assume that these venues represent a whole-scale challenge to conventional oppressive gender and sexual relations for women. Some research has even suggested that both strippers and their patrons are engaged in a 'mutually exploitative' power relationship. Moreover, further empirical research documents key points where female dancers have perhaps wielded 'more' power over patrons at certain moments, and female dancers have highlighted feelings of empowerment and highlighted potential for gender and sexual relations which position women as passive to be subverted within stripping. However, such feelings are often temporally specific and are not applicable to all women in the strip industry. It may be particularly hard for these to manifest in women concentrated in the least economically-rewarding areas of the industry who have less 'power' to resist compromising their bodily boundaries. Furthermore, it is argued that women watching male strippers does little to reverse the 'male gaze', and nor does this male occupation carry as much negative social stigma with it as female stripping suffers. It is thus argued that the overwhelming picture, stemming largely from accounts of former dancers and from empirical studies of individual clubs, suggests these venues in fact do very little to challenge normative hetero-oppressive sexual scripts.

Discourses of friendship between heterosexual women and gay men:mythical norms and an absence of desire

Gay men and heterosexual women may share some common interests in critiquing hetero-patriarchy. However feminism and gay liberationist politics do not always coincide and the role of individual subjectivities in recognising oppressive discourses of normativity remains debated. Interviews were conducted with seven friendship dyads of heterosexual women and gay men. Transcripts were subjected to discourse analysis, which suggested extensive management of heterosexist norms in the friends' accounts of friendship. The analysis highlighted ambiguity over the 'male' status of gay men, a concern with constructing the friendships as legitimately asexual, and the use of parody in the face of homophobia to disrupt normative assumptions. Although we primarily considered the role of heterosexist discourses, there is also evidence that other dimensions of non-normativity (for example, gender and ethnicity) are implicated in friendships constructed around shared otherness and mutual non-normativity. © 2010 SAGE.

Synthesis of novel and stable g-C3N4/N-doped SrTiO3 hybrid nanocomposites with improved photocurrent and photocatalytic activity under visible light irradiation

Hybrid nanocomposites based on N-doped SrTiO3 nanoparticles wrapped in g-C3N4 nanosheets were successfully prepared by a facile and reproducible polymeric citrate and thermal exfoliation method. The results clearly indicated that the N-doped SrTiO3 nanoparticles are successfully wrapped in layers of the g-C3N4 nanosheets. The g-C3N4/N-doped SrTiO3 nanocomposites showed absorption edges at longer wavelengths compared with the pure g-C3N4 as well as N-doped SrTiO3. The hybrid nanocomposites exhibit an improved photocurrent response and photocatalytic activity under visible light irradiation. Interestingly, the hybrid nanocomposite possesses high photostability and reusability. Based on experimental results, the possible mechanism for prolonged lifetime of the photoinduced charge carrier was also discussed. The high performance of the g-C3N4/N-doped SrTiO3 photocatalysts is due to the synergic effect at the interface of g-C3N4 and N-doped SrTiO3 hetero/nanojunction including the high separation efficiency of the charge carrier, band energy matching and the suppressed recombination rate. Therefore, the hybrid photocatalyst could be of potential interest for water splitting and environmental remediation under natural sunlight.

Queer sex work

Sex work is a subject of significant contestation across academic disciplines, as well as within legal, medical, moral, feminist, political and socio-cultural discourses. A large body of research exists, but much of this focuses on the sale of sex by women to men and ignores other performances, practices, meanings and embodiments in the contemporary sex industry. A queer agenda is important in order to challenge hetero-centric gender norms and to develop new insights into how gender, sex, power, crime, work, migration, space/place, health and intimacy are understood in the context of commercial sexual encounters. Queer Sex Work explores what it might mean to 'be', 'do' and 'think' queer(ly) in the study and practice of commercial sex. It brings together a multiplicity of empirical case studies - including erotic dance venues, online sex working, pornography, grey sexual economies, and BSDM - and offers a variety of perspectives from academic scholars, policy practitioners, activists and sex workers themselves. In so doing, the book advances a queer politics of sex work that aims to disrupt heteronormative logics whilst also making space for different voices in academic and political debates about commercial sex. This unique and multidisciplinary volume will be indispensable for scholars and students of the global sex trade and of gender, sexuality, feminism and queer theory more broadly, as well as policymakers, activists and practitioners interested in the politics and practice of sex work in local, national and international contexts.

Mediação biográfica: propostas para a formação docente

This work aims at studying the biographical mediation taken as the progress of people in formation process who develop a biographical work on their own experiences with the help of a former (PASSEGGI, 2006, 2011). The research was carried out on a curricular component from Curso de Formação Inicial e Continuada (initial and continuous process of formation of teachers) with teachers from public schools developed by Instituto Federal de Educação do Rio Grande do Norte (IFRN/ Ipanguaçu). The target audience featured diversity of professionals and experiences of formation. The general objective studied the potentials of procedures and devices used to mediate the reflection about the necessary knowledge to teaching practice based on their own experiences (auto-biographical) and the experience from the others (hetero-biographical). The study tried to respond to the following questions: how do teachers in formation relate themselves to the knowledge from experience? What procedures and devices contribute on the teachers‟ formation on the three different dimensions of biographical mediation (initiatory, maieutic, hermeneutics)? How to provide the auto-formation and hetero-formation? The theories and methods of this work are based on studies and researches that place the person in formation in the center of investigation and formation and analyze their reflective, re-inventive and self-re-inventive capacity. (FREIRE, 1987, 1996, 2001, 2011; JOSSO, 2008, 2010, 2012; DELORY-MONBERGER, 2006, 2008, 2012; CHARLLOT, 2000; CATANI, 2001; PASSEGGI, 2008; 2010; 2011; 2012). We selected six teachers who participate entirely on the meetings of the program. They discussed on the study topics, shared narrations that integrate their formation and the themes related to the course. The empirical material is composed by the narrations of the six participants and hearing boards done by themselves at the moment of the narration sharing process. The analysis followed three steps: a) the path of the program and the procedures of biographical mediation; b) the relations former/teacher on the three dimensions of biographical mediation; c) the hearing board as a device of biographical mediation. We concluded that the procedures and devices used for biographical mediation made possible specific learnings that are sources for the practice of initial and continuous teachers‟ formation, as well as for the formation of the former-researcher about the work with autobiographical narrations. Thus, it allow the co-investment of participants into the process of auto-formation and hetero-formation.

Caractérisation de l’activité Nur77 et de ses complexes en essais BRET par complémentation

Dans le système nerveux central, la dopamine joue un rôle crucial dans de nombreuses fonctions physiologiques telles que : l’apprentissage, le mouvement volontaire, la motivation, la cognition et la production hormonale. Il a été aussi démontré que le système de signalisation dopaminergique est altéré dans plusieurs maladies neurologiques et psychiatriques comme la maladie de Parkinson et la schizophrénie. Des études, effectuées dans le laboratoire du Dr.Daniel Lévesque (laboratoire d’accueil), ont montré que les récepteurs nucléaires Nur77 (NR4A1, NGFI-B) et RXRγ (retinoid X receptors γ) sont impliqués dans la régulation des effets de la dopamine dans le système nerveux central. De plus, ces données suggèrent que le complexe Nur77 et RXR joueraient un rôle crucial dans l’effet des médicaments antipsychotiques et antiparkinsoniens. Toutefois, très peu de médicaments ciblant Nur77 ont été identifiés à ce jour et les médicaments agissant sur RXRγ restent mal caractérisés. En outre, les analyses actuellement disponibles ne peuvent pas résumer la complexité des activités des NRs et génèrent des mesures indirectes des activités des drogues. Afin de mieux comprendre comment est régulée l’interaction Nur77/RXRγ dans ces processus, mon projet a été de mettre au point un essai BRET (Bioluminescence Resonance Energy Transfer) et PCA-BRET (Protein Complementation Assay-BRET) basé sur le recrutement d'un motif mimant un co-activateur fusionné avec la YFP. Nos différents essais ont été validés par courbes dose-réponse en utilisant différents composés RXR . Les EC50 (concentration efficace médiane, qui permet de mesurer l'efficacité d'un composé) obtenues étaient très semblables aux valeurs précédemment rapportées dans la littérature. Nous avons aussi pu identifier un composé le SR11237 (BMS649) qui semble posséder une sélectivité pour le complexe Nur77/RXRγ par rapport aux complexes Nurr1/RXRγ et RXRγ /RXRγ. Nos résultats indiquent que ces essais de BRET peuvent être utilisés pour évaluer la sélectivité de nouveaux composés pour les complexes Nur77/RXRγ, Nurr1/RXRγ et RXRγ /RXRγ. Un autre aspect de mon projet de doctorat a été de mettre en évidence par BRET l’importance de la SUMOylation dans la régulation de l'activité de Nur77 dans sa forme monomèrique, homodimèrique et hétérodimèrique. Nous avons ainsi identifié que Nur77 recrute principalement SUMO2 sur sa lysine 577. Il est intéressant de noté que le recrutement de la SUMO2 à Nur77 est potentialisé en présence de la SUMO E3 Ligase PIASγ. Aussi, la perte de la SUMOylation sur la lysine 577 entraîne l'incapacité de Nur77 de recruter divers motifs de co-activation mais pas pour ses formes homo- et hétérodimèrique. Cependant, la présence de PIASγ ne potentialise pas le recrutement du co-activateur, suggérant que cette SUMO E3 Ligase est seulement impliqué dans le processus de recrutement de la SUMO mais pas dans celui du co-activateur. Nous avons ainsi déterminé une nouvelle modification post-traductionnelle sur Nur77 régulant spécifiquement son activité monomérique Ces projets pourraient donc apporter de nouvelles données cruciales pour l’amélioration du traitement de la maladie de Parkinson ou de la schizophrénie, ainsi que d'obtenir une meilleure compréhension sur les mécanismes permettant la régulation de la fonction de Nur77

Unraveling the function of bacterial-type phosphoenolpyruvate carboxylase in vascular plants

Two distinct phosphoenolpyruvate carboxylase (PEPC) isozymes occur in vascular plants and green algae: plant-type PEPC (PTPC) and bacterial-type PEPC (BTPC). PTPC polypeptides typically form a tightly regulated cytosolic Class-1 PEPC homotetramer. BTPCs, however, appear to be less widely expressed and to exist only as catalytic and regulatory subunits that physically interact with co-expressed PTPC subunits to form hetero-octameric Class-2 PEPC complexes that are highly desensitized to Class-1 PEPC allosteric effectors. Yeast two-hybrid studies indicated that castor plant BTPC (RcPPC4) interacts with all three Arabidopsis thaliana PTPC isozymes, and that it forms stronger interactions with AtPPC2 and AtPPC3, suggesting that specific PTPCs are preferred for Class-2 PEPC formation. In contrast, Arabidopsis BTPC (AtPPC4) appeared to interact very weakly with AtPPC2 and AtPPC3, suggesting that BTPCs from different species may have different physical properties, hypothesized to be due to sequence dissimilarities within their ~10 kDa intrinsically disordered region. Recent RNA-seq and microarray data were analyzed to obtain a better understanding of BTPC expression patterns in different tissues of various monocot and dicot species. High levels of BTPC transcripts, polypeptides and Class-2 PEPC complexes were originally discovered in developing castor seeds, but the analysis revealed a broad range of diverse tissues where abundant BTPC transcripts are also expressed, such as the developing fruits of cucumber, grape, and tomato. Marked BTPC expression correlated well with the presence of ~116 kDa immunoreactive BTPC polypeptides, as well as Class-2 PEPC complexes in the immature fruit of cucumbers and tomatoes. It is therefore hypothesized that in vascular plants BTPC and thus Class-2 PEPC complexes maintain anaplerotic PEP flux in tissues with elevated malate levels that would potently inhibit ‘housekeeping’ Class-1 PEPCs. Elevated levels of malate can be used by biosynthetically active sink tissues such as immature tomatoes and cucumbers for rapid cell expansion, drought or salt stressed roots for osmoregulation, and developing seeds and pollen as a precursor for storage lipid and protein biosynthesis.

Simple heterogeneity parametrization for sea surface temperature and chlorophyll

Using satellite maps this paper offers a complex analysis of chlorophyll & SST heterogeneity in the shelf seas around the southwest of the UK. The heterogeneity scaling follows a simple power law and is consequently pa- rametrized by two parameters. It is shown that in most cases these two parameters vary only relatively little with time. The paper offers a detailed comparison of field heterogeneity between different regions. How much hetero- geneity is in each region preserved in the annual median data is also determined. The paper explicitly demon- strates how one can use these results to calculate representative measurement area for in situ networks.

Simple heterogeneity parametrization for sea surface temperature and chlorophyll

Using satellite maps this paper offers a complex analysis of chlorophyll & SST heterogeneity in the shelf seas around the southwest of the UK. The heterogeneity scaling follows a simple power law and is consequently pa- rametrized by two parameters. It is shown that in most cases these two parameters vary only relatively little with time. The paper offers a detailed comparison of field heterogeneity between different regions. How much hetero- geneity is in each region preserved in the annual median data is also determined. The paper explicitly demon- strates how one can use these results to calculate representative measurement area for in situ networks.

Crisis y creación. Las ambivalentes relaciones germano-españolas en la producción cinematográfica de la primera mitad del siglo veinte

Las épocas de crisis político-social propician en especial medida la creación y el afianzamiento de determinados auto y heteroestereotipos. Esta afirmación resulta concluyente cuando se analiza cómo las distintas fases políticas de España a lo largo de la historia han condicionado de manera definitiva su imagen en el extranjero, en especial en Alemania. Las imágenes y estereotipos románticos creados a partir de la Guerra de la Independencia (1808-1814) sirvieron durante la primera mitad del siglo veinte de instrumento de manipulación propagandística que debía contribuir a ensalzar la ejemplaridad del aliado español. Este artificio político, que buscaba la simpatía ideológica con el sistema de valores nacionalsocialista, se valió de manera particular de las producciones cinematográficas hispano-alemanas para lograr su objetivo.

Deterministic Switching in Bismuth Ferrite Nanoislands

We report deterministic selection of polarization variant in bismuth BiFeO3 nanoislands via a two-step scanning probe microscopy procedure. The polarization orientation in a nanoisland is toggled to the desired variant after a reset operation by scanning a conductive atomic force probe in contact over the surface while a bias is applied. The final polarization variant is determined by the direction of the inhomogeneous in-plane trailing field associated with the moving probe tip. This work provides the framework for better control of switching in rhombohedral ferroelectrics and for a deeper under- standing of exchange coupling in multiferroic nanoscale hetero- structures toward the realization of magnetoelectric devices.

Modular approach to select bacteriophages targeting Pseudomonas aeruginosa for their application to children suffering with cystic fibrosis

This review discusses the potential application of bacterial viruses (phage therapy) towards the eradication of antibiotic resistant Pseudomonas aeruginosa in children with cystic fibrosis (CF). In this regard, several potential relationships between bacteria and their bacteriophages are considered. The most important aspect that must be addressed with respect to phage therapy of bacterial infections in the lungs of CF patients is in ensuring the continuity of treatment in light of the continual occurrence of resistant bacteria. This depends on the ability to rapidly select phages exhibiting an enhanced spectrum of lytic activity among several well-studied phage groups of proven safety. We propose a modular based approach, utilizing both mono-species and hetero-species phage mixtures. With an approach involving the visual recognition of characteristics exhibited by phages of well studied phage groups on lawns of the standard P. aeruginosa PAO1 strain, the simple and rapid enhancement of the lytic spectrum of cocktails is permitted, allowing the development of tailored preparations for patients capable of circumventing problems associated with phage resistant bacterial mutants.

Développement de la polymérisation par (hétéro)arylation directe pour l’électronique organique

L’électronique organique suscite un intérêt grandissant en recherche grâce aux nouvelles possibilités qu’elle offre pour faciliter l’intégration de dispositifs électroniques dans nos vies. Grâce à elle, il est possible d’envisager des produits légers, flexibles et peu coûteux à produire. Les classes majeures de dispositifs étudiées sont les cellules photovoltaïques organiques (CPO) et les transistors organiques à effet de champ (TOEC). Dans les dernières années, une attention particulière a été portée sur les méthodes de polymérisation des matériaux organiques entrant dans la fabrication de ces dispositifs. La polymérisation par (hétéro)arylation directe (PHAD) catalysée au Pd offre une synthèse sans dérivé organométallique utilisant simplement un lien C-H aromatique, ce qui facilite la purification, diminue le nombre d’étapes et rend possible la production de matériaux à plus faible coût. De plus, la PHAD permet la préparation de matériaux qui était difficile, voire impossible, à obtenir auparavant. Cependant, l’inconvénient majeur de la PHAD reste sa limitation à certaines classes de polymères possédant des monomères ayant des positions bloquées favorisant qu’une seule paire de liaisons C-H. Dans le cadre de ces travaux de doctorat, l’objectif général est d’étudier la polymérisation par PHAD afin d’accéder à des classes de monomères qui n’étaient pas envisageables auparavant et à étendre l’application de cet outil dans le domaine des polymères conjugués. Plus spécifiquement, nous avons étudié l’utilisation de groupements protecteurs et partants sur des unités de benzodithiophènes et de bithiophène-silylés. Suivant ces résultats, nos travaux ont porté sur la polymérisation de dérivés de bithiophènes avec des bromo(aryle)s, une classe de polymères fréquemment utilisée en électronique organique mais qui était jugée impossible à polymériser par PHAD auparavant. Cette étude a montré l’importance de contrôler la PHAD afin d’obtenir le polymère souhaité. Finalement, nous avons étudié l’effet du système catalytique sur le taux de β−ramifications lors de la synthèse de polymères à base de thiophènes. Dans cette dernière étude, nous avons démontré l’importance d’utiliser des outils de caractérisation adéquats afin de confirmer la qualité des polymères obtenus.