Structural basis for receptor activity-modifying protein-dependent selective peptide recognition by a G protein-coupled receptor

Association of receptor activity-modifying proteins (RAMP1-3) with the G protein-coupled receptor (GPCR) calcitonin receptor-like receptor (CLR) enables selective recognition of the peptides calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) that have diverse functions in the cardiovascular and lymphatic systems. How peptides selectively bind GPCR:RAMP complexes is unknown. We report crystal structures of CGRP analog-bound CLR:RAMP1 and AM-bound CLR:RAMP2 extracellular domain heterodimers at 2.5 and 1.8 Å resolutions, respectively. The peptides similarly occupy a shared binding site on CLR with conformations characterized by a β-turn structure near their C termini rather than the α-helical structure common to peptides that bind related GPCRs. The RAMPs augment the binding site with distinct contacts to the variable C-terminal peptide residues and elicit subtly different CLR conformations. The structures and accompanying pharmacology data reveal how a class of accessory membrane proteins modulate ligand binding of a GPCR and may inform drug development targeting CLR:RAMP complexes.

Changes in brain activation during working memory and facial recognition tasks in patients with bipolar disorder with Lamotrigine monotherapy

Verbal working memory and emotional self-regulation are impaired in Bipolar Disorder (BD). Our aim was to investigate the effect of Lamotrigine (LTG), which is effective in the clinical management of BD, on the neural circuits subserving working memory and emotional processing. Functional Magnetic Resonance Imaging data from 12 stable BD patients was used to detect LTG-induced changes as the differences in brain activity between drug-free and post-LTG monotherapy conditions during a verbal working memory (N-back sequential letter task) and an angry facial affect recognition task. For both tasks, LGT monotherapy compared to baseline was associated with increased activation mostly within the prefrontal cortex and cingulate gyrus, in regions normally engaged in verbal working memory and emotional processing. Therefore, LTG monotherapy in BD patients may enhance cortical function within neural circuits involved in memory and emotional self-regulation. © 2007 Elsevier B.V. and ECNP.

Mycobacterium tuberculosis peptides presented by HLA-E molecules are targets for human CD8 T-cells with cytotoxic as well as regulatory activity

Tuberculosis (TB) is an escalating global health problem and improved vaccines against TB are urgently needed. HLA-E restricted responses may be of interest for vaccine development since HLA-E displays very limited polymorphism (only 2 coding variants exist), and is not down-regulated by HIV-infection. The peptides from Mycobacterium tuberculosis (Mtb) potentially presented by HLA-E molecules, however, are unknown. Here we describe human T-cell responses to Mtb-derived peptides containing predicted HLA-E binding motifs and binding-affinity for HLA-E. We observed CD8(+) T-cell proliferation to the majority of the 69 peptides tested in Mtb responsive adults as well as in BCG-vaccinated infants. CD8(+) T-cells were cytotoxic against target-cells transfected with HLA-E only in the presence of specific peptide. These T cells were also able to lyse M. bovis BCG infected, but not control monocytes, suggesting recognition of antigens during mycobacterial infection. In addition, peptide induced CD8(+) T-cells also displayed regulatory activity, since they inhibited T-cell proliferation. This regulatory activity was cell contact-dependent, and at least partly dependent on membrane-bound TGF-beta. Our results significantly increase our understanding of the human immune response to Mtb by identification of CD8(+) T-cell responses to novel HLA-E binding peptides of Mtb, which have cytotoxic as well as immunoregulatory activity.

Visual word recognition:The first half second

We used magnetoencephalography (MEG) to map the spatiotemporal evolution of cortical activity for visual word recognition. We show that for five-letter words, activity in the left hemisphere (LH) fusiform gyrus expands systematically in both the posterior-anterior and medial-lateral directions over the course of the first 500 ms after stimulus presentation. Contrary to what would be expected from cognitive models and hemodynamic studies, the component of this activity that spatially coincides with the visual word form area (VWFA) is not active until around 200 ms post-stimulus, and critically, this activity is preceded by and co-active with activity in parts of the inferior frontal gyrus (IFG, BA44/6). The spread of activity in the VWFA for words does not appear in isolation but is co-active in parallel with spread of activity in anterior middle temporal gyrus (aMTG, BA 21 and 38), posterior middle temporal gyrus (pMTG, BA37/39), and IFG. © 2004 Elsevier Inc. All rights reserved.

Pattern recognition analyses of brain activation elicited by happy and neutral faces in unipolar and bipolar depression

Objectives: Recently, pattern recognition approaches have been used to classify patterns of brain activity elicited by sensory or cognitive processes. In the clinical context, these approaches have been mainly applied to classify groups of individuals based on structural magnetic resonance imaging (MRI) data. Only a few studies have applied similar methods to functional MRI (fMRI) data. Methods: We used a novel analytic framework to examine the extent to which unipolar and bipolar depressed individuals differed on discrimination between patterns of neural activity for happy and neutral faces. We used data from 18 currently depressed individuals with bipolar I disorder (BD) and 18 currently depressed individuals with recurrent unipolar depression (UD), matched on depression severity, age, and illness duration, and 18 age- and gender ratio-matched healthy comparison subjects (HC). fMRI data were analyzed using a general linear model and Gaussian process classifiers. Results: The accuracy for discriminating between patterns of neural activity for happy versus neutral faces overall was lower in both patient groups relative to HC. The predictive probabilities for intense and mild happy faces were higher in HC than in BD, and for mild happy faces were higher in HC than UD (all p < 0.001). Interestingly, the predictive probability for intense happy faces was significantly higher in UD than BD (p = 0.03). Conclusions: These results indicate that patterns of whole-brain neural activity to intense happy faces were significantly less distinct from those for neutral faces in BD than in either HC or UD. These findings indicate that pattern recognition approaches can be used to identify abnormal brain activity patterns in patient populations and have promising clinical utility as techniques that can help to discriminate between patients with different psychiatric illnesses.

The effects of gender and COMT Val158Met polymorphism on fearful facial affect recognition:a fMRI study

The functional catechol-O-methyltransferase (COMT Val108/158Met) polymorphism has been shown to have an impact on tasks of executive function, memory and attention and recently, tasks with an affective component. As oestrogen reduces COMT activity, we focused on the interaction between gender and COMT genotype on brain activations during an affective processing task. We used functional MRI (fMRI) to record brain activations from 74 healthy subjects who engaged in a facial affect recognition task; subjects viewed and identified fearful compared to neutral faces. There was no main effect of the COMT polymorphism, gender or genotypegender interaction on task performance. We found a significant effect of gender on brain activations in the left amygdala and right temporal pole, where females demonstrated increased activations over males. Within these regions, Val/Val carriers showed greater signal magnitude compared to Met/Met carriers, particularly in females. The COMT Val108/158Met polymorphism impacts on gender-related patterns of activation in limbic and paralimbic regions but the functional significance of any oestrogen-related COMT inhibition appears modest. Copyright © 2008 CINP.

An activity theory approach to strategy as practice

This chapter introduces activity theory as an approach for studying strategy as practice. Activity theory conceptualizes the ongoing construction of activity as a product of activity systems, comprising the actor, the community with which that actor interacts and those symbolic and material tools that mediate between actors, their community and their pursuit of activity. The focus on the mediating role of tools and cultural artefacts in human activity seems especially promising for advancing the strategy-as-practice agenda, for example as a theoretical resource for the growing interest in sociomateriality and the role of tools and artefacts in (strategy) practice (for example, Balogun et al. 2014; Lanzara 2009; Nicolini 2009; Spee and Jarzabkowski 2009; Stetsenko 2005). Despite its potential, in a recent review Vaara and Whittington (2012) identified only three strategy-as-practice articles explicitly applying an activity theory lens. In the wider area of practice-based studies in organizations, activity theory has been slightly more popular (for example, Blackler 1993; 1995; Blackler, Crump and McDonald 2000; Engeström, Kerosuo and Kajamaa 2007; Groleau 2006; Holt 2008; Miettinen and Virkkunen 2005). It still lags behind its potential, however, primarily because of its origins as a social psychology theory developed in Russia with little initial recognition outside the Russian context, particularly in the area of strategy and organization theory, until recently (Miettinen, Samra-Fredericks and Yanow 2009). This chapter explores activity theory as a resource for studying strategy as practice as it is socially accomplished by individuals in interaction with their wider social group and the artefacts of interaction. In particular, activity theory’s focus on actors as social individuals provides a conceptual basis for studying the core question in strategy-as-practice research: what strategy practitioners do. The chapter is structured in three parts. First, an overview of activity theory is provided. Second, activity theory as a practice-based approach to studying organizational action is introduced and an activity system conceptual framework is developed. Third, the elements of the activity system are explained in more detail and explicitly linked to each of the core SAP concepts: practitioners, practices and praxis. In doing so, links are made to existing strategy-as-practice research, with brief empirical examples of topics that might be addressed using activity theory. Throughout the chapter, we introduce key authors in the development of activity theory and its use in management and adjacent disciplinary fields, as further resources for those wishing to make greater use of activity theory.

Functional connectivity of gamma EEG activity is modulated at low frequency during conscious recollection

We examined two subjectively distinct memory states that are elicited during recognition memory in humans and compared them in terms of the gamma oscillations (20–60 Hz) in the electroencepahalogram (EEG) that they induced. These subjective states, ‘recollection’ and ‘familiarity’ both entail correct recognition but one involves a clear and conscious recollection of the event including memory for contextual detail whilst the other involves a sense of familiarity without clear recollection. Here we show that during a verbal recognition memory test, the subjective experience of ‘recollection’ induced higher amplitude gamma oscillations than the subjective experience of ‘familiarity’ in the time period 300–500 ms after stimulus presentation. Recollection, but not familiarity, was also associated with greater functional connectivity in the gamma frequency range between frontal and parietal sites. Furthermore, the magnitude of the gamma functional connectivity varied over time and was modulated at 3 Hz. Previous studies in animals have shown local theta frequency modulation (3–7 Hz) of gamma-oscillations but this is the first time that a similar effect has been reported in the human EEG.