Molekulargenetische Untersuchungen zur Pathogenese des Mammakarzinoms

Das Kandidatengen MGEA5 auf Chromosom 10q24.1-q24.3, dem bereits onkogenes Potential bei der Pathogenese anderer Tumorentitäten (Meningeomen) nachgewiesen werden konnte, wurde mittels LOH-Analysen auf Allelverluste in dieser Region untersucht. Insgesamt wurden 66 Probenpaare aus sporadischen Mammakarzinomen und Blut (bzw. Normalgewebe) mit Mikrosatellitenmarkern in der genannten Region auf Verluste von Allelen hin untersucht. Die Ergebnisse dieser Analysen deuten darauf hin,dass das gewählte Kandidatengen in der Tumorgenese des sporadischen Mammakarzinoms keine kausale Rolle spielt. Es bedarf demnach weiteren Untersuchungen an anderen Kandidatengenen, um zuverlässige genetische Marker für die Diagnostik, Prognostik und Therapie des Brustkrebses zu finden und einsetzen zu können

A FRET-based approach for studying desensitization of G protein-activated K+^{+} (GIRK) channels

In der vorliegenden Arbeit wurde die schnelle Desensitisierung von Agonisten-aktivierten GIRK-Kanälen analysiert. Simultane FRET- und Ganzzell-Ableitungen wurden durchgeführt, um zugrunde liegende molekulare Ereignisse innerhalb von Millisekunden zu untersuchen. Mittels elektrophysiologischer Messungen von fusionierten Kanaluntereinheiten konnte gezeigt werden, dass kinetische Eigenschaften der GIRK-Ströme sowohl von der Stöchiometrie der G-Protein-Untereinheiten als auch von der GIRK-Kanal Zusammensetzung abhängig sind. Diese Ergebnisse deuten auf zwei unterschiedliche, aber additive Mechanismen hin. Beide Mechanismen werden durch RGS4 vermittelt, unterscheiden sich aber in ihrem zeitlichen Verlauf. Die schnellere Komponente wird durch Strom-abhängige Veränderungen der elektrochemischen Triebkraft verursacht. Die langsamere Komponente dagegen spiegelt eine Desensitisierungskomponente wieder, die durch die GTPase-Aktivität des RGS Proteins vermittelt wird.In the present study, a FRET-based approach was used for studying acute desensitization of agonist-activated GIRK current. Simultaneous FRET-recordings and whole-cell measurements of current were performed to analyse underlying molecular events in a range of milliseconds. Whole-cell recordings using tagged channel subunits revealed that current kinetics depend on the stoichiometry of G protein subunits and on the composition of GIRK channels. We suggest that two distinct, but additive mechanisms contribute to acute desensitization of GIRK current. Both mechanisms depend on RGS4, but differ in their time course. The fast desensitizing component is caused by current-dependent changes in the electrochemical driving force for potassium ions. The slower desensitizing component, a $\textit {bona fide}$ signalling mechanism, could be detected on protein level in the presence of RGS4 and corresponds to previous publications suggesting that acute desensitization is promoted by the GTPase activity of RGS4

Spatial Coding as a Function of Handedness and Responding Hand: Theoretical and Methodological Implications

The Simon effect shows that choice reactions are faster if the location of the stimulus and the response correspond, even when stimulus location is task-irrelevant. The Simon effect raises the question of what factors influence spatial coding. Until now, the effects of handedness, responding hand, and visual field were addressed in separate studies that used bimanual and unimanual tasks, providing inconclusive results. Here we aimed to close this empirical gap by looking at the effects of these variables in the same study. We used a unimanual version of a Simon task with four groups of participants: left-handed and right-handed, responding with the dominant or nondominant hand. Our results show that the Simon effect is substantially reduced in the field of the responding hand for all groups of participants, except for left-handed individuals responding with the left-hand. These findings highlight the importance of attention mechanisms in stimulus-response coding. They reflect that stimulus-response interference is influenced by hierarchical activation of response units. At a practical level, these findings call for a number of methodological considerations (e.g., handedness, responding hand, and visual field) when using stimulus-response conflict to address spatial coding and cognitive control functions in neurological populations

Apraxia and inattention dissociate in chronic left hemisphere stroke.

Apraxia and inattention dissociate in chronic left hemisphere stroke D.C. Timpert, P.H. Weiss-Blankenhorn, A. Dovern, S. Vossel, G.R. Fink (Jülich, Köln) Theories of lateralized cognitive functions in the human brain propose (for right- handers) a dominance of the left hemisphere for motor control and language, and a dominance of the right hemisphere for attention. Accordingly, neglect is more frequently observed after right-hemispheric stroke, while apraxia and aphasia are a common sequela of left-hemispheric stroke. However, there are also – often neglected - clinical reports of attentional deficits after left hemisphere stroke. To elucidate the neural basis of such atypically lateralized attentional deficits, we here assessed - for the first time - the relationship of inattention and apraxia in chronic left-hemisphere stroke using behavioural and lesion analyses. Attention and apraxic deficits were each characterized by five neuropsychological tests. Voxel-based lesion-symptom mapping (VLSM) was performed on the basis of clinical imaging. Apraxic deficits were observed in 46.5% of the patients with chronic left-hemisphere stroke (n= 71). The prevalence of inattention (lateralized and non-lateralized inattention combined) was 18.3%. Interestingly, the severity of attentional and apraxic deficits did not correlate. Apraxic imitation and object use deficits were significantly associated with left parietal and temporal lesions, respectively. The severity of attentional deficits was related to lesions in vicinity of the left intraparietal sulcus (IPS). Attentional deficits after chronic left-hemisphere stroke are hence more prevalent as commonly assumed, dissociate from apraxic deficits, and are associated with lesions of the left posterior parietal cortex. These findings challenge theories of strictly lateralized attentional functions in the human brain