State-dependent microstructural white matter changes in bipolar I depression

Abnormalities in fronto-limbic-striatal white matter (WM) have been reported in bipolar disorder (BD), but results have been inconsistent across studies. Furthermore, there have been no detailed investigations as to whether acute mood states contribute to microstructural changes in WM tracts. In order to compare fiber density and structural integrity within WM tracts between BD depression and remission, whole-brain fractional anisotropy (FA) and mean diffusivity (MD) were assessed in 37 bipolar I disorder (BD-I) patients (16 depressed and 21 remitted), and 26 healthy individuals with diffusion tensor imaging. Significantly decreased FA and increased MD in bilateral prefronto-limbic-striatal white matter and right inferior fronto-occipital, superior and inferior longitudinal fasciculi were shown in all BD-I patients versus controls, as well as in depressed BD-I patients compared to both controls and remitted BD-I patients. Depressed BD-I patients also exhibited increased FA in the ventromedial prefrontal cortex. Remitted BD-I patients did not differ from controls in FA or MD. These findings suggest that BD-I depression may be associated with acute microstructural WM changes.

Can we observe collective neuronal activity from macroscopic aggregate signals?

The fundamental problem faced by noninvasive neuroimaging techniques such as EEG/MEG1 is to elucidate functionally important aspects of the microscopic neuronal network dynamics from macroscopic aggregate measurements. Due to the mixing of the activities of large neuronal populations in the observed macroscopic aggregate, recovering the underlying network that generates the signal in the absence of any additional information represents a considerable challenge. Recent MEG studies have shown that macroscopic measurements contain sufficient information to allow the differentiation between patterns of activity, which are likely to represent different stimulus-specific collective modes in the underlying network (Hadjipapas, A., Adjamian, P., Swettenham, J.B., Holliday, I.E., Barnes, G.R., 2007. Stimuli of varying spatial scale induce gamma activity with distinct temporal characteristics in human visual cortex. NeuroImage 35, 518–530). The next question arising in this context is whether aspects of collective network activity can be recovered from a macroscopic aggregate signal. We propose that this issue is most appropriately addressed if MEG/EEG signals are to be viewed as macroscopic aggregates arising from networks of coupled systems as opposed to aggregates across a mass of largely independent neural systems. We show that collective modes arising in a network of simulated coupled systems can be indeed recovered from the macroscopic aggregate. Moreover, we show that nonlinear state space methods yield a good approximation of the number of effective degrees of freedom in the network. Importantly, information about hidden variables, which do not directly contribute to the aggregate signal, can also be recovered. Finally, this theoretical framework can be applied to experimental MEG/EEG data in the future, enabling the inference of state dependent changes in the degree of local synchrony in the underlying network.

Sensory and cortical activation of distinct glial cell subtypes in the somatosensory thalamus of young rats

The rodent ventrobasal (VB) thalamus receives sensory inputs from the whiskers and projects to the cortex, from which it receives reciprocal excitatory afferents. Much is known about the properties and functional roles of these glutamatergic inputs to thalamocortical neurons in the VB, but no data are available on how these afferents can affect thalamic glial cells. In this study, we used combined electrophysiological recordings and intracellular calcium ([Ca(2+)](i)) imaging to investigate glial cell responses to synaptic afferent stimulation. VB thalamus glial cells can be divided into two groups based on their [Ca(2+)](i) and electrophysiological responses to sensory and corticothalamic stimulation. One group consists of astrocytes, which stain positively for S100B and preferentially load with SR101, have linear current-voltage relations and low input resistance, show no voltage-dependent [Ca(2+)](i) responses, but express mGluR5-dependent [Ca(2+)](i) transients following stimulation of the sensory and/or corticothalamic excitatory afferent pathways. Cells of the other glial group, by contrast, stain positively for NG2, and are characterized by high input resistance, the presence of voltage-dependent [Ca(2+)](i) elevations and voltage-gated inward currents. There were no synaptically induced [Ca(2+)](i) elevations in these cells under control conditions. These results show that thalamic glial cell responses to synaptic input exhibit different properties to those of thalamocortical neurons. As VB astrocytes can respond to synaptic stimulation and signal to neighbouring neurons, this glial cell organization may have functional implications for the processing of somatosensory information and modulation of behavioural state-dependent thalamocortical network activities.

The C-terminus of Raf-1 acts as a 14-3-3-dependent activation switch

The Raf-1 protein kinase is a major activator of the ERK MAPK pathway, which links signaling by a variety of cell surface receptors to the regulation of cell proliferation, survival, differentiation and migration. Signaling by Raf-1 is regulated by a complex and poorly understood interplay between phosphorylation events and protein-protein interactions. One important mode of Raf-1 regulation involves the phosphorylation-dependent binding of 14-3-3 proteins. Here, we have examined the mechanism whereby the C-terminal 14-3-3 binding site of Raf-1, S621, controls the activation of MEK-ERK signaling. We show that phosphorylation of S621 turns over rapidly and is enriched in the activated pool of endogenous Raf-1. The phosphorylation on this site can be mediated by Raf-1 itself but also by other kinase(s). Mutations that prevent the binding of 14-3-3 proteins to S621 render Raf-1 inactive by specifically disrupting its capacity to bind to ATP, and not by gross conformational alteration as indicated by intact MEK binding. Phosphorylation of S621 correlates with the inhibition of Raf-1 catalytic activity in vitro, but 14-3-3 proteins can completely reverse this inhibition. Our findings suggest that 14-3-3 proteins function as critical cofactors in Raf-1 activation, which induce and maintain the protein in a state that is competent for both ATP binding and MEK phosphorylation.

Analysis of tissue transglutaminase function in the migration of Swiss 3T3 fibroblasts:the active-state conformation of the enzyme does not affect cell motility but is important for its secretion

Increasing evidence suggests that tissue transglutaminase (tTGase; type II) is externalized from cells, where it may play a key role in cell attachment and spreading and in the stabilization of the extracellular matrix (ECM) through protein cross-linking. However, the relationship between these different functions and the enzyme's mechanism of secretion is not fully understood. We have investigated the role of tTGase in cell migration using two stably transfected fibroblast cell lines in which expression of tTGase in its active and inactive (C277S mutant) states is inducible through the tetracycline-regulated system. Cells overexpressing both forms of tTGase showed increased cell attachment and decreased cell migration on fibronectin. Both forms of the enzyme could be detected on the cell surface, but only the clone overexpressing catalytically active tTGase deposited the enzyme into the ECM and cell growth medium. Cells overexpressing the inactive form of tTGase did not deposit the enzyme into the ECM or secrete it into the cell culture medium. Similar results were obtained when cells were transfected with tTGase mutated at Tyr(274) (Y274A), the proposed site for the cis,trans peptide bond, suggesting that tTGase activity and/or its tertiary conformation dependent on this bond may be essential for its externalization mechanism. These results indicate that tTGase regulates cell motility as a novel cell-surface adhesion protein rather than as a matrix-cross-linking enzyme. They also provide further important insights into the mechanism of externalization of the enzyme into the extracellular matrix.

Une étude générique du metteur en scène au théâtre:son émergence et son rôle moderne et contemporain

The theatre director (metteur en scene in French) is a relatively new figure in theatre practice. It was not until the I820s that the term 'mise en scene' gained currency. The term 'director' was not in general use until the I880s. The emergence and the role of the director has been considered from a variety of perspectives, either through the history of theatre (Allevy, Jomaron, Sarrazac, Viala, Biet and Triau); the history of directing (Chinoy and Cole, Boll, Veinstein, Roubine); semiotic approaches to directing (Whitmore, Miller, Pavis); the semiotics of performance (De Marinis); generic approaches to the mise en scene (Thomasseau, Banu); post-dramatic approaches to theatre (Lehmann); approaches to performance process and the specifics of rehearsal methodology (Bradby and Williams, Giannachi and Luckhurst, Picon-Vallin, Styan). What the scholarly literature has not done so far is to map the parameters necessarily involved in the directing process, and to incorporate an analysis of the emergence of the theatre director during the modem period and consider its impact on contemporary performance practice. Directing relates primarily to the making of the performance guided by a director, a single figure charged with the authority to make binding artistic decisions. Each director may have her/his own personal approaches to the process of preparation prior to a show. This is exemplified, for example, by the variety of terms now used to describe the role and function of directing, from producer, to facilitator or outside eye. However, it is essential at the outset to make two observations, each of which contributes to a justification for a generic analysis (as opposed to a genetic approach). Firstly, a director does not work alone, and cooperation with others is involved at all stages of the process. Secondly, beyond individual variation, the role of the director remains twofold. The first is to guide the actors (meneur de jeu, directeur d'acteurs, coach); the second is to make a visual representation in the performance space (set designer, stage designer, costume designer, lighting designer, scenographe). The increasing place of scenography has brought contemporary theatre directors such as Wilson, Castellucci, Fabre to produce performances where the performance space becomes a semiotic dimension that displaces the primacy of the text. The play is not, therefore, the sole artistic vehicle for directing. This definition of directing obviously calls for a definition of what the making of the performance might be. The thesis defines the making of the performance as the activity of bringing a social event, by at least one performer, providing visual and/or textual meaning in a performance space. This definition enables us to evaluate four consistent parameters throughout theatre history: first, the social aspect associated to the performance event; second, the devising process which may be based on visual and/or textual elements; third, the presence of at least one performer in the show; fourth, the performance space (which is not simply related to the theatre stage). Although the thesis focuses primarily on theatre practice, such definition blurs the boundaries between theatre and other collaborative artistic disciplines (cinema, opera, music and dance). These parameters illustrate the possibility to undertake a generic analysis of directing, and resonate with the historical, political and artistic dimensions considered. Such a generic perspective on the role of the director addresses three significant questions: an historical question: how/why has the director emerged?; a sociopolitical question: how/why was the director a catalyst for the politicisation of theatre, and subsequently contributed to the rise of State-funded theatre policy?; and an artistic one: how/why the director has changed theatre practice and theory in the twentieth-century? Directing for the theatre as an artistic activity is a historically situated phenomenon. It would seem only natural from a contemporary perspective to associate the activity of directing to the function of the director. This is relativised, however, by the question of how the performance was produced before the modern period. The thesis demonstrates that the rise of the director is a progressive and historical phenomenon (Dort) rather than a mere invention (Viala, Sarrazac). A chronological analysis of the making of the performance throughout theatre history is the most useful way to open the study. In order to understand the emergence of the director, the research methodology assesses the interconnection of the four parameters above throughout four main periods of theatre history: the beginning of the Renaissance (meneur de jeu), the classical age (actor-manager and stage designer-manager), the modern period (director) and the contemporary period (director-facilitator, performer). This allows us properly to appraise the progressive emergence of the director, as well as to make an analysis of her/his modern and contemporary role. The first chapter argues that the physical separation between the performance space and its audience, which appeared in the early fifteenth-century, has been a crucial feature in the scenographic, aesthetic, political and social organisation of the performance. At the end of the Middle Ages, French farces which raised socio-political issues (see Bakhtin) made a clear division on a single outdoor stage (treteau) between the actors and the spectators, while religious plays (drame fiturgique, mystere) were mostly performed on various outdoor and opened multispaces. As long as the performance was liturgical or religious, and therefore confined within an acceptable framework, it was allowed. At the time, the French ecclesiastical and civil authorities tried, on several occasions, to prohibit staged performances. As a result, practitioners developed non-official indoor spaces, the Theatre de fa Trinite (1398) being the first French indoor theatre recognized by scholars. This self-exclusion from the open public space involved breaking the accepted rules by practitioners (e.g. Les Confreres de fa Passion), in terms of themes but also through individual input into a secular performance rather than the repetition of commonly known religious canvases. These developments heralded the authorised theatres that began to emerge from the mid-sixteenth century, which in some cases were subsidised in their construction. The construction of authorised indoor theatres associated with the development of printing led to a considerable increase in the production of dramatic texts for the stage. Profoundly affecting the reception of the dramatic text by the audience, the distance between the stage and the auditorium accompanied the changing relationship between practitioners and spectators. This distance gave rise to a major development of the role of the actor and of the stage designer. The second chapter looks at the significance of both the actor and set designer in the devising process of the performance from the sixteenth-century to the end of the nineteenth-century. The actor underwent an important shift in function in this period from the delivery of an unwritten text that is learned in the medieval oral tradition to a structured improvisation produced by the commedia dell 'arte. In this new form of theatre, a chef de troupe or an experienced actor shaped the story, but the text existed only through the improvisation of the actors. The preparation of those performances was, moreover, centred on acting technique and the individual skills of the actor. From this point, there is clear evidence that acting began to be the subject of a number of studies in the mid-sixteenth-century, and more significantly in the seventeenth-century, in Italy and France. This is revealed through the implementation of a system of notes written by the playwright to the actors (stage directions) in a range of plays (Gerard de Vivier, Comedie de la Fidelite Nuptiale, 1577). The thesis also focuses on Leoni de' Sommi (Quatro dialoghi, 1556 or 1565) who wrote about actors' techniques and introduced the meneur de jeu in Italy. The actor-manager (meneur de jeu), a professional actor, who scholars have compared to the director (see Strihan), trained the actors. Nothing, however, indicates that the actor-manager was directing the visual representation of the text in the performance space. From the end of the sixteenth-century, the dramatic text began to dominate the process of the performance and led to an expansion of acting techniques, such as the declamation. Stage designers carne from outside the theatre tradition and played a decisive role in the staging of religious celebrations (e.g. Actes des Apotres, 1536). In the sixteenth-century, both the proscenium arch and the borders, incorporated in the architecture of the new indoor theatres (theatre a l'italienne), contributed to create all kinds of illusions on the stage, principally the revival of perspective. This chapter shows ongoing audience demands for more elaborate visual effects on the stage. This led, throughout the classical age, and even more so during the eighteenth-century, to grant the stage design practitioner a major role in the making of the performance (see Ciceri). The second chapter demonstrates that the guidance of the actors and the scenographic conception, which are the artistic components of the role of the director, appear to have developed independently from one another until the nineteenth-century. The third chapter investigates the emergence of the director per se. The causes for this have been considered by a number of scholars, who have mainly identified two: the influence of Naturalism (illustrated by the Meiningen Company, Antoine, and Stanislavski) and the invention of electric lighting. The influence of the Naturalist movement on the emergence of the modem director in the late nineteenth-century is often considered as a radical factor in the history of theatre practice. Naturalism undoubtedly contributed to changes in staging, costume and lighting design, and to a more rigorous commitment to the harmonisation and visualisation of the overall production of the play. Although the art of theatre was dependent on the dramatic text, scholars (Osborne) demonstrate that the Naturalist directors did not strictly follow the playwright's indications written in the play in the late nineteenth-century. On the other hand, the main characteristic of directing in Naturalism at that time depended on a comprehensive understanding of the scenography, which had to respond to the requirements of verisimilitude. Electric lighting contributed to this by allowing for the construction of a visual narrative on stage. However, it was a master technician, rather than an emergent director, who was responsible for key operational decisions over how to use this emerging technology in venues such as the new Bayreuth theatre in 1876. Electric lighting reflects a normal technological evolution and cannot be considered as one of the main causes of the emergence of the director. Two further causes of the emergence of the director, not considered in previous studies, are the invention of cinema and the Symbolist movement (Lugne-Poe, Meyerhold). Cinema had an important technological influence on the practitioners of the Naturalist movement. In order to achieve a photographic truth on the stage (tableau, image), Naturalist directors strove to decorate the stage with the detailed elements that would be expected to be found if the situation were happening in reality. Film production had an influence on the work of actors (Walter). The filmmaker took over a primary role in the making of the film, as the source of the script, the filming process and the editing of the film. This role influenced the conception that theatre directors had of their own work. It is this concept of the director which influenced the development of the theatre director. As for the Symbolist movement, the director's approach was to dematerialise the text of the playwright, trying to expose the spirit, movement, colour and rhythm of the text. Therefore, the Symbolists disengaged themselves from the material aspect of the production, and contributed to give greater artistic autonomy to the role of the director. Although the emergence of the director finds its roots amongst the Naturalist practitioners (through a rigorous attempt to provide a strict visual interpretation of the text on stage), the Symbolist director heralded the modem perspective of the making of performance. The emergence of the director significantly changed theatre practice and theory. For instance, the rehearsal period became a clear work in progress, a platform for both developing practitioners' techniques and staging the show. This chapter explores and contrasts several practitioners' methods based on the two aspects proposed for the definition of the director (guidance of the actors and materialisation of a visual space). The fourth chapter argues that the role of the director became stronger, more prominent, and more hierarchical, through a more political and didactic approach to theatre as exemplified by the cases of France and Germany at the end of the nineteenth-century and through the First World War. This didactic perspective to theatre defines the notion of political theatre. Political theatre is often approached by the literature (Esslin, Willett) through a Marxist interpretation of the great German directors' productions (Reinhardt, Piscator, Brecht). These directors certainly had a great influence on many directors after the Second World War, such as Jean Vilar, Judith Molina, Jean-Louis Barrault, Roger Planchon, Augusto Boal, and others. This chapter demonstrates, moreover, that the director was confirmed through both ontological and educational approaches to the process of making the performance, and consequently became a central and paternal figure in the organisational and structural processes practiced within her/his theatre company. In this way, the stance taken by the director influenced the State authorities in establishing theatrical policy. This is an entirely novel scholarly contribution to the study of the director. The German and French States were not indifferent to the development of political theatre. A network of public theatres was thus developed in the inter-war period, and more significantly after the Second World War. The fifth chapter shows how State theatre policies establish its sources in the development of political theatre, and more specifically in the German theatre trade union movement (Volksbiihne) and the great directors at the end of the nineteenth-century. French political theatre was more influenced by playwrights and actors (Romain Rolland, Louise Michel, Louis Lumet, Emile Berny). French theatre policy was based primarily on theatre directors who decentralised their activities in France during both the inter-war period and the German occupation. After the Second World War, the government established, through directors, a strong network of public theatres. Directors became both the artistic director and the executive director of those institutionalised theatres. The institution was, however, seriously shaken by the social and political upheaval of 1968. It is the link between the State and the institution in which established directors were entangled that was challenged by the young emerging directors who rejected institutionalised responsibility in favour of the autonomy of the artist in the 1960s. This process is elucidated in chapter five. The final chapter defines the contemporary role of the director in contrasting thework of a number of significant young theatre practitioners in the 1960s such as Peter Brook, Ariane Mnouchkine, The Living Theater, Jerzy Grotowski, Augusto Boal, Eugenio Barba, all of whom decided early on to detach their companies from any form of public funding. This chapter also demonstrates how they promoted new forms of performance such as the performance of the self. First, these practitioners explored new performance spaces outside the traditional theatre building. Producing performances in a non-dedicated theatre place (warehouse, street, etc.) was a more frequent practice in the 1960s than before. However, the recent development of cybertheatre questions both the separation of the audience and the practitioners and the place of the director's role since the 1990s. Secondly, the role of the director has been multifaceted since the 1960s. On the one hand, those directors, despite all their different working methods, explored western and non-western acting techniques based on both personal input and collective creation. They challenged theatrical conventions of both the character and the process of making the performance. On the other hand, recent observations and studies distinguish the two main functions of the director, the acting coach and the scenographe, both having found new developments in cinema, television, and in various others events. Thirdly, the contemporary director challenges the performance of the text. In this sense, Antonin Artaud was a visionary. His theatre illustrates the need for the consideration of the totality of the text, as well as that of theatrical production. By contrasting the theories of Artaud, based on a non-dramatic form of theatre, with one of his plays (Le Jet de Sang), this chapter demonstrates how Artaud examined the process of making the performance as a performance. Live art and autobiographical performance, both taken as directing the se(f, reinforce this suggestion. Finally, since the 1990s, autobiographical performance or the performance of the self is a growing practical and theoretical perspective in both performance studies and psychology-related studies. This relates to the premise that each individual is making a representation (through memory, interpretation, etc.) of her/his own life (performativity). This last section explores the links between the place of the director in contemporary theatre and performers in autobiographical practices. The role of the traditional actor is challenged through non-identification of the character in the play, while performers (such as Chris Burden, Ron Athey, Orlan, Franko B, Sterlac) have, likewise, explored their own story/life as a performance. The thesis demonstrates the validity of the four parameters (performer, performance space, devising process, social event) defining a generic approach to the director. A generic perspective on the role of the director would encompass: a historical dimension relative to the reasons for and stages of the 'emergence' of the director; a socio-political analysis concerning the relationship between the director, her/his institutionalisation, and the political realm; and the relationship between performance theory, practice and the contemporary role of the director. Such a generic approach is a new departure in theatre research and might resonate in the study of other collaborative artistic practices.

Spin dependent photoconductivity in silicon-on-sapphire

Resonant and non resonant spin dependent photoconductivity is observed in(100) silicon films grown on sapphire by CVD and MBE techniques. The CVD films are either in their as-grown state or have undergone single or double solid phase epitaxial regrowth. For all samples, a resonant decrease in photoconductivity is observed at a field of about 0.34 T for a microwave frequency of about 9.7 GHz and at about 3.3 mT when the frequency is about 92 MHz. For all samples the maximum fractional change in photoconductivity is approximately 10-4 independent of magnetic field strength.

Fully probabilistic control for stochastic nonlinear control systems with input dependent noise

Robust controllers for nonlinear stochastic systems with functional uncertainties can be consistently designed using probabilistic control methods. In this paper a generalised probabilistic controller design for the minimisation of the Kullback-Leibler divergence between the actual joint probability density function (pdf) of the closed loop control system, and an ideal joint pdf is presented emphasising how the uncertainty can be systematically incorporated in the absence of reliable systems models. To achieve this objective all probabilistic models of the system are estimated from process data using mixture density networks (MDNs) where all the parameters of the estimated pdfs are taken to be state and control input dependent. Based on this dependency of the density parameters on the input values, explicit formulations to the construction of optimal generalised probabilistic controllers are obtained through the techniques of dynamic programming and adaptive critic methods. Using the proposed generalised probabilistic controller, the conditional joint pdfs can be made to follow the ideal ones. A simulation example is used to demonstrate the implementation of the algorithm and encouraging results are obtained.

The development and growth of tissues derived from cranial neural crest and primitive mesoderm is dependent on the ligation status of retinoic acid receptor γ:evidence that retinoic acid receptor γ functions to maintain stem/progenitor cells in the absence of retinoic acid

Retinoic acid (RA) signaling is important to normal development. However, the function of the different RA receptors (RARs)-RARα, RARβ, and RARγ-is as yet unclear. We have used wild-type and transgenic zebrafish to examine the role of RARγ. Treatment of zebrafish embryos with an RARγ-specific agonist reduced somite formation and axial length, which was associated with a loss of hoxb13a expression and less-clear alterations in hoxc11a or myoD expression. Treatment with the RARγ agonist also disrupted formation of tissues arising from cranial neural crest, including cranial bones and anterior neural ganglia. There was a loss of Sox 9-immunopositive neural crest stem/progenitor cells in the same anterior regions. Pectoral fin outgrowth was blocked by RARγ agonist treatment. However, there was no loss of Tbx-5-immunopositive lateral plate mesodermal stem/progenitor cells and the block was reversed by agonist washout or by cotreatment with an RARγ antagonist. Regeneration of the caudal fin was also blocked by RARγ agonist treatment, which was associated with a loss of canonical Wnt signaling. This regenerative response was restored by agonist washout or cotreatment with the RARγ antagonist. These findings suggest that RARγ plays an essential role in maintaining stem/progenitor cells during embryonic development and tissue regeneration when the receptor is in its nonligated state.

Intracellular redox state modulates the T cell surface proteome – relevance to ageing

During ageing an altered redox balance has been observed in both intracellular and extracellular compartments, primarily due to glutathione depletion and metabolic stress. Maintaining redox homeostasis is important for controlling proliferation and apoptosis in response to specific stimuli for a variety of cells. For T cells, the ability to generate specific response to antigen is dependent on the oxidation state of cell surface and cytoplasmic protein-thiols. Here we describe the effects of depleting intracellular glutathione concentration for T cell exofacial expression of thioredoxin 1 and IL-2 production, and have determined the distribution of Trx1 with ageing. Using buthionine sulfoximine to deplete intracellular glutathione in Jurkat T cells we show using Western blotting that cell surface thioredoxin-1 is lowered and that the response to the lectin phytohaemagglutinin measured by ELISA as IL-2 production is also decreased. Using flow cytometry we show that the distribution of Trx1 on primary CD4+ T cells is age-dependent, with lower surface Trx1 expression and greater variability of surface expression observed with age. Together these data suggest that a relationship exists between the intracellular redox compartment and exofacial surface. Redox imbalance may be important for impaired T cell function during ageing.