The role of ECL2 in CGRP receptor activation:a combined modelling and experimental approach

The calcitonin gene-related peptide (CGRP) receptor is a complex of a cal-citonin receptor-like receptor (CLR), which is a family B G-protein-coupled receptor (GPCR) and receptor activity modifying protein 1. The role of the second extracellular loop (ECL2) of CLR in binding CGRP and coupling to Gs was investigated using a combination of mutagenesis and modelling. An alanine scan of residues 271-294 of CLR showed that the ability of CGRP to produce cAMP was impaired by point mutations at 13 residues; most of these also impaired the response to adrenomedullin (AM). These data were used to select probable ECL2-modelled conformations that are involved in agonist binding, allowing the identification of the likely contacts between the peptide and receptor. The implications of the most likely structures for receptor activation are discussed. © 2013 The Authors.

Attachment anxiety and friendship group identification under attachment threat:the moderating role of priming support network expectations

We examined the role of priming participants' own network expectations on their subsequent identification with their friendship group. We examined this prime alongside attachment anxiety and attachment threat, as predictors of friendship group identification. Previous research has suggested that attachment anxiety is associated with negative network expectations. In this study, we extended this work to show that when a network expectation prime was absent, higher attachment anxiety was associated with lower group identification under attachment threat, compared to a control condition. However, when expectations of support network were primed, attachment threat no longer affected group identification, so that only attachment anxiety predicted group identification. This suggests that priming participants who are high in attachment anxiety with their own network expectancies (which are negative), results in participants dis-identifying with their friendship group, regardless of whether or not they have experienced attachment threat. © 2012 Elsevier Ltd.

Interpersonal attachment predicts identification with groups

We propose a model documenting the relationship between interpersonal attachment style and identification with groups. We hypothesized that following threat to a romantic interpersonal relationship higher attachment anxiety would be associated with lowered tendencies to identify with groups. In two studies using varied social groups we observed support for this hypothesis. In Experiment 1 we found that participants higher in attachment anxiety identified less with a salient ingroup after imagining a distressing argument with their romantic partner. In Experiment 2 we replicated these findings using an implicit measure of social identification and additionally observed a moderating role for attachment avoidance. We discuss the implications of these findings for theoretical models of interpersonal attachment and social identification. © 2008 Elsevier Inc. All rights reserved.

Discovering biomarkers for antidepressant response:protocol from the Canadian biomarker integration network in depression (CAN-BIND) and clinical characteristics of the first patient cohort

Background: Major Depressive Disorder (MDD) is among the most prevalent and disabling medical conditions worldwide. Identification of clinical and biological markers ("biomarkers") of treatment response could personalize clinical decisions and lead to better outcomes. This paper describes the aims, design, and methods of a discovery study of biomarkers in antidepressant treatment response, conducted by the Canadian Biomarker Integration Network in Depression (CAN-BIND). The CAN-BIND research program investigates and identifies biomarkers that help to predict outcomes in patients with MDD treated with antidepressant medication. The primary objective of this initial study (known as CAN-BIND-1) is to identify individual and integrated neuroimaging, electrophysiological, molecular, and clinical predictors of response to sequential antidepressant monotherapy and adjunctive therapy in MDD. Methods: CAN-BIND-1 is a multisite initiative involving 6 academic health centres working collaboratively with other universities and research centres. In the 16-week protocol, patients with MDD are treated with a first-line antidepressant (escitalopram 10-20 mg/d) that, if clinically warranted after eight weeks, is augmented with an evidence-based, add-on medication (aripiprazole 2-10 mg/d). Comprehensive datasets are obtained using clinical rating scales; behavioural, dimensional, and functioning/quality of life measures; neurocognitive testing; genomic, genetic, and proteomic profiling from blood samples; combined structural and functional magnetic resonance imaging; and electroencephalography. De-identified data from all sites are aggregated within a secure neuroinformatics platform for data integration, management, storage, and analyses. Statistical analyses will include multivariate and machine-learning techniques to identify predictors, moderators, and mediators of treatment response. Discussion: From June 2013 to February 2015, a cohort of 134 participants (85 outpatients with MDD and 49 healthy participants) has been evaluated at baseline. The clinical characteristics of this cohort are similar to other studies of MDD. Recruitment at all sites is ongoing to a target sample of 290 participants. CAN-BIND will identify biomarkers of treatment response in MDD through extensive clinical, molecular, and imaging assessments, in order to improve treatment practice and clinical outcomes. It will also create an innovative, robust platform and database for future research. Trial registration: ClinicalTrials.gov identifier NCT01655706. Registered July 27, 2012.

Receptor activity-modifying proteins 2 and 3 generate adrenomedullin receptor subtypes with distinct molecular properties

Adrenomedullin (AM) is a peptide hormone with numerous effects in the vascular systems. AM signals through the AM1 and AM2 receptors formed by the obligate heterodimerization of a G protein-coupled receptor, the calcitonin receptor-like receptor (CLR), and receptor activity-modifying proteins (RAMP) 2 and 3, respectively. These different CLR-RAMP interactions yield discrete receptor pharmacology and physiological effects. The effective design of therapeutics that target the individual AM receptors is dependent on understanding the molecular details of the effects of RAMPs on CLR. To understand the role of RAMPs 2 and 3 on the activation and conformation of the CLR subunit of AM receptors we mutated 68 individual amino acids in the juxtamembrane region of CLR, a key region for activation of AM receptors and determined the effects on cAMP signalling. Sixteen CLR mutations had differential effects between the AM1 and AM2 receptors. Accompanying this, independent molecular modelling of the full-length AM-bound AM1 and AM2 receptors predicted differences in the binding pocket, and differences in the electrostatic potential of the two AM receptors. Druggability analysis indicated unique features that could be used to develop selective small molecule ligands for each receptor. The interaction of RAMP2 or RAMP3 with CLR induces conformational variation in the juxtamembrane region, yielding distinct binding pockets, probably via an allosteric mechanism. These subtype-specific differences have implications for the design of therapeutics aimed at specific AM receptors and for understanding the mechanisms by which accessory proteins affect G protein-coupled receptor function.

The Structure and Optical Properties of Sr1-xCaxMoO3

We acknowledge the University of Aberdeen for provision of a studentship for Harriet Hopper.

Homeless women waiting for bus to take them to women's shelter

General note: Title and date provided by Bettye Lane.

An allosteric role for receptor activity-modifying proteins in defining GPCR pharmacology

G protein-coupled receptors are allosteric proteins that control transmission of external signals to regulate cellular response. Although agonist binding promotes canonical G protein signalling transmitted through conformational changes, G protein-coupled receptors also interact with other proteins. These include other G protein-coupled receptors, other receptors and channels, regulatory proteins and receptor-modifying proteins, notably receptor activity-modifying proteins (RAMPs). RAMPs have at least 11 G protein-coupled receptor partners, including many class B G protein-coupled receptors. Prototypic is the calcitonin receptor, with altered ligand specificity when co-expressed with RAMPs. To gain molecular insight into the consequences of this protein–protein interaction, we combined molecular modelling with mutagenesis of the calcitonin receptor extracellular domain, assessed in ligand binding and functional assays. Although some calcitonin receptor residues are universally important for peptide interactions (calcitonin, amylin and calcitonin gene-related peptide) in calcitonin receptor alone or with receptor activity-modifying protein, others have RAMP-dependent effects, whereby mutations decreased amylin/calcitonin gene-related peptide potency substantially only when RAMP was present. Remarkably, the key residues were completely conserved between calcitonin receptor and AMY receptors, and between subtypes of AMY receptor that have different ligand preferences. Mutations at the interface between calcitonin receptor and RAMP affected ligand pharmacology in a RAMP-dependent manner, suggesting that RAMP may allosterically influence the calcitonin receptor conformation. Supporting this, molecular dynamics simulations suggested that the calcitonin receptor extracellular N-terminal domain is more flexible in the presence of receptor activity-modifying protein 1. Thus, RAMPs may act in an allosteric manner to generate a spectrum of unique calcitonin receptor conformational states, explaining the pharmacological preferences of calcitonin receptor-RAMP complexes. This provides novel insight into our understanding of G protein-coupled receptor-protein interaction that is likely broadly applicable for this receptor class.

Politics and Poetics of the Novel: Using Domesticity to Create the Nation

This thesis examines how the depiction of the family during war reinforces or challenges societal values in three nineteenth-century novels. The primary focus lies in three novels by Sir Walter Scott, Leo Tolstoy, and Harriet Beecher Stowe that represent the perspectives of England, Russia, and the United States, respectively, and their evolving nationalism as the roots of the Napoleonic Wars and the American Civil War became visible. By investigating the interaction between economic classes, it can be concluded that the preservation of the family is inherently dependent on social status in some nations, while in others, it is integral to daily life regardless of class. The backdrop of impending war only serves to heighten national differences, overturn the organization of the family hierarchy, and redefine the idea of the modern household.

El PCE y el movimiento comunista internacional (1969-1977)

El artículo se centra en la actividad internacional del Partido Comunista de España (PCE) desde las secuelas de la represión de la Primavera de Praga hasta 1977. Fue un período caracterizado por el principio del declive definitivo del movimiento comunista internacional. El análisis abarca múltiples cuestiones. Examina las crecientes críticas del PCE hacia el modelo soviético, y sus repercusiones en las relaciones entre el partido liderado por Santiago Carrillo y el movimiento comunista. Además, el artículo explora el intento del PCE de promover un nuevo tipo de internacionalismo en Europa occidental, auspiciando una renovada colaboración entre comunistas y socialistas y aprovechando las condiciones brindadas por la distensión. En este contexto tuvo lugar el surgimiento del eurocomunismo, que el ensayo analiza ilustrando los factores internos y externos que determinaron su crisis en la segunda mitad de los setenta.

Renta feudal, ejercicio del poder y diferenciación social campesina en el marco del señorío del cabildo salmantino en la Edad Media

El presente trabajo analiza la evolución del señorío eclesiástico en el largo plazo, para sumar al conocimiento de las formas señoriales de la Extremadura leonesa. Consideramos específicamente el caso del cabildo catedralicio salmantino entre los siglos XII y XV. Buscamos demostrar que no poseyó idéntica estructura durante todo el período y que sus transformaciones se explican por una compleja conjunción de variables. Dichas transformaciones incidieron sobre las estructuras sociales del agro, en especial sobre el desarrollo de procesos de diferenciación social campesina. Demostramos que la forma concreta en que se realizaba la renta podía alterar las estructuras sociales de las comunidades y que el desarrollo de las relaciones sociales asalariadas se encontraba muy vinculado a las coyunturas económicas y a las posibilidades y límites de la gestión señorial. Finalmente, ponemos de relieve que la transformación social no siempre fue irreversible y que su consolidación dependió de la incapacidad de los señores de ejercer sus poderes políticos.

Sister Practices: Non-Normative Experiences of Time and Technology

This chapter summarises some of the learning from a material practice that sits in a sisterly manner next to architecture. Drawing on feminist writing and the experiences of women in professional life more generally, the chapter will examine how mainstream understanding of time and technology limit the engagement of those people in society who do not fit given norms. The chapter argues that when we examine such concepts in more detail and expand them to reflect diverse experiences those very same concepts offer new potentials and innovative openings for the progression of disciplines such as architecture.

Lost and Found? A Parable of the Architect (Male) and the Academic (Female)

The following text captures an interview, conducted over three evenings, between a practicing architect (male) and an architecture academic (female and feminist). This is a conversation between two long-standing friends who did their Part 3 professional exam together more than twenty-five years ago. Since then, they have taken different career paths and lived lives at different paces and in different places. Every so often they meet over coffee to laugh and argue about architecture, bemoan failures, and share successes.

The academic initiated the interview in order to hear an honest and open account of the career experience of a male architect. She hoped that their longstanding friendship would lead to less guarded responses. The answers to the questions were always going to be personally challenging to the interviewer and possibly to their friendship. The interview is a form of ethnographic study: a structured, qualitative process within a long term, immersed context. But when ‘the immersed context’ is a much-valued friendship, it is a precarious action. Nevertheless, for the future of gendered relationships both protagonists accepted the risks.

Reducing waste of food left on plates : interventions based on means-end chain analysis of customers in foodservice sector

Parallel ruptures: Jews of Bessarabia and Transnistria between Romanian nationalism and Soviet communism, 1918-1940

“Parallel Ruptures: Jews of Bessarabia and Transnistria between Romanian Nationalism and Soviet Communism, 1918-1940,” explores the political and social debates that took place in Jewish communities in Romanian-held Bessarabia and the Moldovan Autonomous Soviet Socialist Republic during the interwar era. Both had been part of the Russian Pale of Settlement until its dissolution in 1917; they were then divided by the Romanian Army’s occupation of Bessarabia in 1918 with the establishment of a well-guarded border along the Dniester River between two newly-formed states, Greater Romania and the Soviet Union. At its core, the project focuses in comparative context on the traumatic and multi-faceted confrontation with these two modernizing states: exclusion, discrimination and growing violence in Bessarabia; destruction of religious tradition, agricultural resettlement, and socialist re-education and assimilation in Soviet Transnistria. It examines also the similarities in both states’ striving to create model subjects usable by the homeland, as well as commonalities within Jewish responses on both sides of the border. Contacts between Jews on either side of the border remained significant after 1918 despite the efforts of both states to curb them, thereby necessitating a transnational view in order to examine Jewish political and social life in borderland regions. The desire among Jewish secular leaders to mold their co-religionists into modern Jews reached across state borders and ideological divides and sought to manipulate respective governments to establish these goals, however unsuccessful in the final analysis. Finally, strained relations between Jews in peripheral borderlands with those at national/imperial cores, Moscow and Bucharest, sheds light on the complex circumstances surrounding the inclusion versus exclusion debates at the heart of all interwar European states and the complicated negotiations that took place within all minority communities that responded to state policies.