Effects of Transmitters and Amyloid-Beta Peptide on Calcium Signals in Rat Cortical Astrocytes: Fura-2AM Measurements and Stochastic Model Simulations

BACKGROUND: To better understand the complex molecular level interactions seen in the pathogenesis of Alzheimer's disease, the results of the wet-lab and clinical studies can be complemented by mathematical models. Astrocytes are known to become reactive in Alzheimer's disease and their ionic equilibrium can be disturbed by interaction of the released and accumulated transmitters, such as serotonin, and peptides, including amyloid- peptides (A). We have here studied the effects of small amounts of A25-35 fragments on the transmitter-induced calcium signals in astrocytes by Fura-2AM fluorescence measurements and running simulations of the detected calcium signals. METHODOLOGY/PRINCIPAL FINDINGS: Intracellular calcium signals were measured in cultured rat cortical astrocytes following additions of serotonin and glutamate, or either of these transmitters together with A25-35. A25-35 increased the number of astrocytes responding to glutamate and exceedingly increased the magnitude of the serotonin-induced calcium signals. In addition to A25-35-induced effects, the contribution of intracellular calcium stores to calcium signaling was tested. When using higher stimulus frequency, the subsequent calcium peaks after the initial peak were of lower amplitude. This may indicate inadequate filling of the intracellular calcium stores between the stimuli. In order to reproduce the experimental findings, a stochastic computational model was introduced. The model takes into account the major mechanisms known to be involved in calcium signaling in astrocytes. Model simulations confirm the principal experimental findings and show the variability typical for experimental measurements. CONCLUSIONS/SIGNIFICANCE: Nanomolar A25-35 alone does not cause persistent change in the basal level of calcium in astrocytes. However, even small amounts of A25-35, together with transmitters, can have substantial synergistic effects on intracellular calcium signals. Computational modeling further helps in understanding the mechanisms associated with intracellular calcium oscillations. Modeling the mechanisms is important, as astrocytes have an essential role in regulating the neuronal microenvironment of the central nervous system

Plasma Brain-Derived Neurotrophic Factor Levels Predict the Clinical Outcome of Depression Treatment in a Naturalistic Study

Remission is the primary goal of treatment for major depressive disorder (MDD). However, some patients do not respond to treatment. The main purpose of this study was to determine whether brain-derived neurotrophic factor (BDNF) levels are correlated with treatment outcomes. In a naturalistic study, we assessed whether plasma BDNF levels were correlated with clinical outcomes by measuring plasma BDNF in patients with depressive syndrome (MADRS score ≥18), and subsequently comparing levels between the subgroup of patients who underwent remission (MADRS score ≤8) and the subgroup who were refractory to treatment (non-responders). Patients with depressive syndrome who underwent remission had significantly higher plasma BDNF levels (p<0.001), regardless of age or sex. We also found a significant negative correlation between MADRS scores and plasma BDNF levels within this group (ρ = –0.287, p = 0.003). In contrast, non-responders had significantly lower plasma BDNF levels (p = 0.029). Interestingly, plasma BDNF levels in the non-responder group were significantly higher than those in the remission group in the initial stage of depressive syndrome (p = 0.002). Our results show that plasma BDNF levels are associated with clinical outcomes during the treatment of depression. We suggest that plasma BDNF could potentially serve as a prognostic biomarker for depression, predicting clinical outcome

A game for all seasons: lessons and learnings from the JRC’s scenario exploration system

The European Commission Joint Research Centre’s (JRC) Scenario Exploration System (SES) is a foresight gaming system developed to facilitate the application of futures thinking to policy-making. It was originally geared at engaging EU policy-makers with scenarios in a facilitated process with a low learning curve. Specifically, the SES was designed to help participants, in less than three hours, to engage in systemic thinking with a long-term perspective and to explore alternative futures on specific issues and themes. When applied in various contexts, the SES proved to have a broader range of applications, which led to communities of practice emerging around the tool. Successful responses to various requests to apply the tool beyond its original focus demonstrated the versatility of the SES. Specifically, we discovered its ability to accommodate a large array of scenarios to discuss a very diverse range of issues. The experience accumulated through several adaptations of the SES allows the analysis of the various strengths and weaknesses of the tool as a platform for futures thinking and sharing more broadly the know-how for the creation and application of new versions. Ultimately, this article seeks to contribute a series of design suggestions for futures practitioners seeking to develop a playful mode of interaction with scenarios, or those seeking to repurpose the original SES system for use in their own project

Regulation of GSK-3 Activity as A Shared Mechanism in Psychiatric Disorders

Serin/Treonin kinaz ailesinin üyelerinden bir kinaz olarak ilk kez glikojen sentaz’ı inhibe ettiği keşfedilen glikojen sentaz kinaz-3 (GSK-3), günümüzde bilinen 50’den fazla substratı ile birçok hücre içi düzenleyici mekanizmada görev alan geniş etki spektrumlu bir enzim olarak kabul edilmektedir. GSK-3’ün memelilerde GSK-3α ve GSK-3β olmak üzere yapısal olarak yüksek homoloji gösteren iki izoformu bulunmaktadır. Her iki izoform birçok dokuda yaygın dağılım göstermekle beraber, en yüksek oranda beyinde bulunmakta ve genellikle benzer fonksiyonlar göstermektedirler. Diğer protein kinazların aksine GSK-3 uyarılmamış hücrede yapısal olarak aktif yani defosforile halde bulur. Protein kinaz A (PKA), protein kinaz B (PKB;AKT) ve protein kinaz C (PKC) gibi diğer protein kinazlarla fosforilasyona uğrayarak olarak inaktive edilir. Günümüzde artmış GSK-3 aktivitesinin major depresyon, bipolar bozukluk, hiperaktivite bozuklukları gibi hastalıklar ve şizofreni oluşumunda rol oynayabileceğine ilişkin önemli bulgular mevcuttur. Bu nedenle söz konusu psikiyatrik hastalıklarda arttığı gösterilen GSK-3 aktivitesinin azaltılmasının tedavide umut verici bir yaklaşım olabileceği kabul edilebilir. Bu gözden geçirme çalışmasında yukarıda sözü edilen psikiyatrik hastalıkların oluşmasında görev alan GSK-3 aracılı mekanizmalara kısaca değinilerek GSK-3’ün aktivitesinin düzenlenmesinde rol oynadığı gösterilen klinikte kullanılan ilaçlara yer verilmiştir. Anahtar sözcükler: GSK-3, depresyon, bipolar bozukluk, şizofren

Manipulating the Hype: contemporary art's response to media cliches

Manipulating the Hype addresses art’s reaction to the barrage of signs produced by the media. The paper researches contemporary art’s response to clichéd media stereotypes and elucidates artists’ multifaceted perspective on overtly obvious yet widely embraced paradigms marketed by the media. Contemporary art’s strategic reconfiguration of media stereotypes is a valuable introspection upon the superficiality and impracticability of advertising and entertainment industry constructs. By reconsidering the mediated image, art has the ability to inspire reevaluation of cultural values. The thesis additionally attempts to ascertain the reinterpretation of media stereotypes as a common thread linking principal art movements and historically significant artworks from around the world since 1960. How does contemporary art respond to the extensive cultural influence of the media? Is a reaction to mass media a thematic commonality linking contemporary artists in the age of globalization? Manipulating the Hype is a dual outcome investigation comprised of written thesis and studio practice. The written thesis combines experience from a lengthy professional practice with historical and theoretical research. The visual thesis consists of twelve photographic works taken at on the Big Island of Hawaii. The images juxtapose artificial icons of power from popular culture with the natural force of the active lava flow. The process of research discloses how the advertising and entertainment industries capitalize upon innate human desires through the manipulative proliferation of archetypal imagery. Furthermore, the thesis establishes the widespread retort to media clichés as a palpable commonality in studio practices worldwide. The findings in the research make evident that although contemporary art does not have sufficient influence to reform the media, it can heighten public awareness of media tactics