Behavioral adaptation and cognitive control are crucial for goal-reaching behaviors. Every creature is ubiquitously faced with choices between behavioral alternatives. Common sense suggests that errors are an important source of information in the regulation of such processes. Several theories exist regarding cognitive control and the processing of undesired outcomes. However, most of these models focus on the consequences of an error, and less attention has been paid to the mechanisms that underlie the commissioning of an error. In this article, we present an integrative review of neuro-cognitive models that detail the determinants of the occurrence of response errors. The factors that may determine the likelihood of committing errors are likely related to the stability of task-representations in prefrontal networks, attentional selection mechanisms and mechanisms of action selection in basal ganglia circuits. An important conclusion is that the likelihood of committing an error is not stable over time but rather changes depending on the interplay of different functional neuro-anatomical and neuro-biological systems. We describe factors that might determine the time-course of cognitive control and the need to adapt behavior following response errors. Finally, we outline the mechanisms that may proof useful for predicting the outcomes of cognitive control and the emergence of response errors in future research.

We study anomalous diffusion on fractals with a static external field applied. We utilise the master equation to calculate particle distributions and from that important quantities as for example the mean square displacement <r^2(t)>. Applying different bias amplitudes on several regular Sierpinski carpets we obtain maximal drift velocities for weak field strengths. According to <r^2(t)>~t^(2/d_w), we determine random walk dimensions of d_w<2 for applied external fields. These d_w corresponds to superdiffusion, although diffusion is hindered by the structure of the carpet, containing dangling ends. This seems to result from two competing effects arising within an external field. Though the particles prefer to move along the biased direction, some particles get trapped by dangling ends. To escape from there they have to move against the field direction. Due to the by the bias accelerated particles and the trapped ones the probability distribution gets wider and thus d_w<2. / In dieser Arbeit untersuchen wir anomale Diffusion auf Fraktalen unter Einwirkung eines statisches äußeres Feldes. Wir benutzen die Mastergleichung, um die Wahrscheinlichkeitsverteilung der Teilchen zu berechnen, um daraus wichtige Größen wie das mittlere Abstandsquadrat <r^2(t)> zu bestimmen. Wir wenden unterschiedliche Feldstärken bei verschiedenen regelmäßigen Sierpinski-Teppichen an und erhalten maximale Driftgeschwindigkeiten für schwache Feldstärken. Über <r^2(t)>~t^{2/d_w} bestimmen wir die Random-Walk-Dimension d_w als d_w<2. Dieser Wert für d_w entspricht der Superdiffusion, obwohl der Diffusionsprozess durch Strukturen des Teppichs, wie Sackgassen, behindert wird. Es schient, dass dies das Ergebnis zweier konkurrierender Effekte ist, die durch das Anlegen eines äußeren Feldes entstehen. Einerseits bewegen sich die Teilchen bevorzugt entlang der Feldrichtung. Andererseits gelangen einige Teilchen in Sackgassen. Um die Sackgassen, die in Feldrichtung liegen, zu verlassen, müssen sich die Teilchen entgegen der Feldrichtung bewegen. Somit sind die Teilchen eine gewisse Zeit in der Sackgasse gefangen. Infolge der durch das äußere Feld beschleunigten und der gefangenen Teilchen, verbreitert sich die Wahrscheinlichkeitsverteilung der Teilchen und somit ist d_w<2.

DRM is a conserved transcription factor complex that includes E2F/DP and pRB family proteins and plays important roles in the cell cycle and cancer. Recent work has unveiled a new aspect of DRM function in regulating genes involved in development and differentiation. These studies, however, were performed with cultured cells and a genome-wide study involving intact organisms undergoing active proliferation and differentiation was lacking. Our goal was to extend the knowledge of the role of DRM in gene regulation through development and in multiple tissues. To accomplish this, we employed genomic approaches to determine genome-wide targets of DRM using the nematode Caenorhabditis elegans as a model system. In this dissertation, I focus on the DRM component LIN-54 since it was proposed to exhibit DNA-binding activity. First, we confirmed the DNA-binding activity of C.elegans LIN-54 in vivo, and showed it is essential to recruit the DRM complex to its target genes. Next, chromatin immunoprecipitation and gene expression profiling revealed that LIN-54 controls transcription of genes implicated in cell division, development and reproduction. This work identified an interesting contrast in DRM function in soma vs. germline: DRM promotes transcription of germline-specific genes in the germline, but prevents their ectopic expression in the soma. Furthermore, we discovered a novel characteristic of DRM, sex chromosome-biased binding and function. We demonstrated that C. elegans DRM preferentially binds autosomes, yet regulates X-chromosome silencing by counteracting the H3K36 histone methyltransferase MES-4. By using genomics, cytology, and genetics, we defined DRM as an important player in the regulation of germline X-chromosome gene expression, and addressed molecular mechanisms vii behind the antagonistic interactions between DRM and MES-4. I present a model to explain the interplay of DRM and MES-4, and propose a novel function of DRM and MES-4 in maintaining proper chromosome gene expression dosage. This work extends our knowledge of the conserved roles of DRM in development, and provides a new view of differing DRM functions in soma versus germline. Furthermore, we defined a novel chromosome-specific aspect of DRM-mediated regulation.

No description available.

This thesis focuses on the question of preferential treatment by U.S. national newsmagazines of presidential candidates in the 2004 election as evidenced by their visual coverage. Using content analysis, all the visual depictions of candidates George W. Bush and John Kerry were analyzed for 10 visual attributes to determine whether one had received better pictorial treatment. This study asked if the newsmagazines had printed greater amounts of visuals overall for one candidate and if one candidate's visuals were more or less positive than the other. The author concludes that more coverage was given to Bush over Kerry in a 60/40 ratio in all three magazines, and overall, the pictures published for each candidate were positive and neither candidate was given preferential treatment by any of the magazines. The newsmagazines were not deemed biased for publishing more visuals of Bush because, though more visuals were of the president during September, the newsmagazines published nearly equal numbers of visuals in October and November, often pairing them in layouts. The magazines were also not biased in their selection of visuals. All three tended to publish more positive or neutral visuals and rarely did any significantly differing patterns emerge to show that the editors favored one candidate over the other. Those attributes that did reach significance had weak associations. This study is a replication and a continuation of visual media content analyses of the 1984, 1988, and 1996 campaign coverage by Moriarty and Garramone (1986), Moriarty and Poppovich (1989), and Waldman and Devitt (1998) respectively. This research adds to the body of media bias and agenda-setting among newspapers and magazines and visual media.

No description available.

Src family kinases (SFKs) are key regulators of cell proliferation, differentiation, and survival. The expression of these non-receptor tyrosine kinases is strongly correlated with cancer development and tumor progression. Thus, this family of proteins serves as an attractive drug target. The activation of SFKs can occur via multiple signaling pathways, yet many of them are poorly understood. Here, we summarize the current knowledge on G protein-coupled receptor (GPCR)- mediated regulation of SFKs, which is of considerable interest because GPCRs are among the most widely used pharmaceutical targets. This type of activation can occur through a direct interaction between the two proteins or be allosterically regulated by arrestins and G proteins. We postulate that a rearrangement of binding motifs within the active conformation of arrestin-3 mediates Src regulation by comparison of available crystal structures. Therefore, we hypothesize a potentially different activation mechanism compared to arrestin-2. Furthermore, we discuss the probable direct regulation of SFK by GPCRs and investigate the intracellular domains of exemplary GPCRs with conserved polyproline binding motifs that might serve as scaffolding domains to allow such a direct interaction. Large intracellular domains in GPCRs are often understudied and, in general, not much is known of their contribution to different signaling pathways. The suggested direct interaction between a GPCR and a SFK could allow for a potential immediate allosteric regulation of SFKs by GPCRs and thereby unravel a novel mechanism of SFK signaling. This overview will help to identify new GPCR–SFK interactions, which could serve to explain biological functions or be used to modulate downstream effectors.

<p>The following thesis will focus on understanding the downstream behavioral effects of δORmediated β-arrestinsignaling. δORagonists have been implicated as effective targets for a variety of diseases, however detrimental side effects of opioid-targeting agonists limit their clinical use. δORagonists specifically can induce seizures, however the underlying mechanism contributing to this  behavior  is  unknown.  We  review  this  phenomenon  in  more  detail,  highlighting  current agonists known to induce seizures and potential circuits and pathways involved. Our work suggests β-arrestinsignaling  is  involved,  specifically β-arrestin2  mediated  signaling  may  be  largely contributing  to δORagonist-induced  seizure  behavior.  As  it  is  possible  the β-arrestinisoforms have unique roles in seizure behavior, we also analyzed methods in which to provoke β-arrestinisoform bias of δORtargeting compounds. Though the full mechanism relating δORagonists with seizures remains unknown, our work provides foundational detail of this behavior, implicating the importance of β-arrestinisoform signaling through δOR; allowing for future studies to full define this seizure pathway and develop δORsafer agonists.  </p>

Les opioïdes restent encore à l’heure actuelle les composés pharmacologiques les plus efficaces pour traiter les différentes formes de douleurs, et donc fournir une analgésie thérapeutique. Cependant, l’administration répétée de ces composés entraîne des effets secondaires majeurs comme la dépression respiratoire, la tolérance, mais également, il a été montré que certains de ces opioïdes pouvaient engendrer des états proépileptiques. D’un point de vue thérapeutique, il existe donc un réel besoin pour de nouveaux et meilleurs traitements analgésiques, n’élicitant pas ces effets secondaires. Notre laboratoire étudie la signalétique des récepteurs couplés aux protéines G comme les récepteurs opioïdes et leur capacité de sélectivité fonctionnelle depuis des années, et en particulier celle du récepteur delta opioïde (DOP). En effet, celui-ci présenterait moins d’effets indésirables que le récepteur mu opioïde (MOP) qui est la cible principale des opioïdes classiques comme la morphine. Cependant, il semblerait que le DOP justement soit à l’origine des états proépileptiques précédemment décrits. Ainsi malgré la promesse initiale des agonistes delta par rapport à la diminution des effets secondaires, les effets proépileptiques de certains ont notamment contribué à une baisse d’intérêt vers le DOP et aucun de ses agonistes n’a pu passer les phases de tests cliniques. Cependant, il a été démontré que certains agonistes delta n’entraînaient pas d’effet proépileptique; tandis que d’autres oui. Comment expliquer un tel phénomène ? Ceci est la question que pose la présente recherche. Ainsi notre objectif sera d’obtenir et de comparer les signatures pharmacologiques des agonistes connus pour être proépileptiques versus ceux qui ne le sont pas ; par rapport à la transduction de signal via le récepteur delta opioïde et sa protéine G hétérotrimérique ; et par rapport à un de ses effecteurs principaux pour l’analgésie, un canal potassique rectifiant entrant. Cette comparaison se fera selon les paramètres du modèle classique de la pharmacologie, comme l’efficacité et la puissance ; mais également avec un outil plus récent appelé modèle opérationnel, utilisant des paramètres comme l’affinité et le coefficient de transduction. Pour se faire, le transfert d'énergie par résonance de bioluminescence ou BRET sera utilisé afin de caractériser les différentes voies signalétiques impliquées. Cette recherche s’inscrit dans un vaste contexte de collaboration entre différents laboratoires, et au sein de chacun d’entre eux, dans l’espoir de pouvoir synthétiser un jour, de meilleurs composés pharmacologiques, capables de cibler uniquement les voies médiatrices des effets thérapeutiques voulus, ici l’analgésie ; sans éliciter celles entraînant les effets secondaires associés, ici, les états proconvulsifs. L’aboutissement de cette recherche permettrait donc d’impacter la vie de millions de gens en souffrance, et c’est pourquoi il nous semble plus qu’important de continuer à l’entreprendre. / Opioids are still nowadays the most efficacious pharmacological compounds available to treat the different types of pain, and therefore provide a therapeutic analgesia. However, repeated administration of those compounds lead to major secondary effects like respiratory depression, tolerance, but also it was shown that some opioid compounds could induce seizures. From a therapeutical point of view, there is a serious need for new and better analgesic treatments that do not elicit such adverse effects. Our lab has been studying for years the signaletics of G-protein coupled receptors like the opioid receptors, and their capacity for functional selectivity, especially more recently the one of the delta opioid receptor (DOP). Indeed, this receptor elicits fewer adverse effects compared to the mu opioid receptor (MOP) that is the main target of all clinically used opioids such as morphine. However, it seems like the DOP itself would be responsible for the pro-epileptic states previously described. Thus, despite initial promises of the delta agonists towards reducing adverse effects whilst providing analgesia, the pro-convulsive effects that some seem to elicit have induced a loss of interest towards the DOP, and so far none of its agonists have gone further than pre-clinical trials. However, it has been shown that not all of those DOP agonists had those pro-convulsive adverse effects. How to explain such a phenomenon? This is the question which the present research will be asking. Thus our goal is to obtain and compare pharmacological signatures of the agonists known for being pro-convulsive versus those that are not ; regarding the transduction of signals through the delta opioid receptor and its heterotrimeric G-Protein ; and also regarding one of its main effectors to induce analgesia, an inwardly rectifying potassium channel. This comparison will be done according to the classical parameters of pharmacology, such as efficacy and potency ; but also according to the newest operational model, with parameters such as affinity and transduction coefficients. In order to do so, bioluminescence resonance energy transfer or BRET, will be used in order to characterize and quantify the signalling pathways there implicated. This research is embedded in a vast collaboration context, in between laboratories around the world, and within those laboratories as well, in hope to be able to one day synthesize, better pharmacological compounds, capable of targeting only the pathways responsible for the desired effects, here analgesia ; without triggering the associated adverse effects, here pro-convulsive states. The culmination of this research could allow to impact the lives of millions of people throughout the world, and this is why it is more than important for us to keep on pursuing it.

A substantial number of works have aimed at modeling the receptive field properties of the primary visual cortex (V1). Their evaluation criterion is usually the similarity of the model response properties to the recorded responses from biological organisms. However, as several algorithms were able to demonstrate some degree of similarity to biological data based on the existing criteria, we focus on the robustness against loss of information in the form of occlusions as an additional constraint for better understanding the algorithmic level of early vision in the brain. We try to investigate the influence of competition mechanisms on the robustness. Therefore, we compared four methods employing different competition mechanisms, namely, independent component analysis, non-negative matrix factorization with sparseness constraint, predictive coding/biased competition, and a Hebbian neural network with lateral inhibitory connections. Each of those methods is known to be capable of developing receptive fields comparable to those of V1 simple-cells. Since measuring the robustness of methods having simple-cell like receptive fields against occlusion is difficult, we measure the robustness using the classification accuracy on the MNIST hand written digit dataset. For this we trained all methods on the training set of the MNIST hand written digits dataset and tested them on a MNIST test set with different levels of occlusions. We observe that methods which employ competitive mechanisms have higher robustness against loss of information. Also the kind of the competition mechanisms plays an important role in robustness. Global feedback inhibition as employed in predictive coding/biased competition has an advantage compared to local lateral inhibition learned by an anti-Hebb rule.