Die Quantifizierung der Genotoxizität Selbstinaktivierender Retroviraler Vektoren für die Gentherapie

Die retrovirale Gentherapie wurde bereits in mehreren klinischen Studien erfolgreich zur Behandlung monogenetischer Erkrankungen eingesetzt. Die vektorassoziierte Aktivierung zellulärer Protoonkogene (z.B. MDS1/EVI1) und die Manifestation maligner Transformation in einzelnen Patienten verdeutlichten jedoch das Risiko, das mit dem Einsatz integrierender Vektorsysteme verbunden ist. Neben der Protoonkogen-Aktivierung existieren noch weitere vektorassoziierte Ereignisse mit potentiell toxischen Auswirkungen (z.B. Haploinsuffizienz, Inaktivierung von Tumorsuppressorgenen, aberrante Transkripte und veränderte Proteine). Ein genaues Verständnis der unterschiedlichen Aspekte der Genotoxizität gentherapeutischer retroviraler Vektoren ist daher von größter Wichtigkeit für deren klinische Anwendung. In dieser Arbeit wurden sicherheitsrelevante Parameter der Funktion SIN-retroviraler Vektoren für die Gentherapie der Septischen Granulomatose (X-CGD) systematisch quantifiziert. Vergleichende Integromanalysen wurden verwendet, um ein Aktivitätsprofil genetischer Nebenwirkungen in vitro und im präklinischen Mausmodell zu erheben. Die Vektoren verursachten keine vektorvermittelte klonale Selektion und wiesen eine signifikant geringere Inzidenz von Integraten im MDS1/EVI1 Lokus auf als die herkömmlichen Vektoren mit vollständigen ‚Long Terminal Repeats‘ (LTR). Die Untersuchung viral-zellulärer Spleißprodukte mit einem gammaretroviralen SIN-Vektor zeigte nur vereinzelte aberrante Fusionstranskripte. Klonalitätsanalysen der frühen Hämatopoese nach klinischer SIN-lentiviraler Gentherapie (University College London) zeigten eine polyklonale genkorrigierte Repopulation, wobei die unzureichende Konditionierung des Patienten nach 6 Monaten zum Verlust der Genmarkierung führte. Im Gegensatz zu bisherigen X-CGD Gentherapiestudien fand hier keine bevorzugte Integration in den Genlokus MDS1/EVI1 statt. Somit konnte gezeigt werden, dass der genetische Hintergrund der X-CGD keinen offensichtlichen Einfluss auf die präferentielle Integration in diesen Lokus oder andere ausübt. In primären hämatopoetischen Zellen und in einem Genotoxizitätsassay mit einer IL-3 abhängigen Zelllinie wurden die Auswirkungen verschiedener lentiviraler Vektoren untersucht. Die Art und Aktivität des internen Promotors in SIN-lentiviralen Vektoren bestimmt maßgeblich das Integrationsprofil sowie die Bildung chimärer Transkripte. Es wurde gezeigt, dass der interne Promotor die Restaktivität des 5’-SIN-LTRs und somit das Risiko zur Bildung viral-zellulärer Fusionstranskripte unter Beteiligung des kanonischen Spleißdonors erhöht. Mit einem schwachen Promotor sinkt hingegen die Wahrscheinlichkeit zur Ausbildung aberranter Transkripte. Durch den Genotoxizitätsassay wurde die Bedeutung der Inzidenz viral-zellulärer Fusionstranskripte für das genotoxische Potential lentiviraler Vektoren bestätigt. Die in dieser Arbeit erzielten Ergebnisse zeigen, dass durch hochauflösende funktionelle Integromanalysen eine fundierte Einschätzung der biologischen Sicherheit gentherapeutischer retroviraler Vektoren möglich ist. Der Einfluss neuer struktureller Vektorelemente auf das Sicherheitsprofil wurde definiert und dessen biologische Relevanz anhand der generierten Transkripte und in angeschlossenen Genotoxizitätsassays bestimmt. Detaillierte präklinische Analysen gammaretro- und lentiviraler SIN-Vektoren ermöglichten den Nachweis der sicheren und effizienten retroviralen X-CGD Gentherapie und deren Translation in die Klinik. Ein sicherheitsoptimierter SIN-gammaretroviraler Vektor wurde für eine klinische Phase I/II X-CGD Studie zugelassen

Enhanced light emission from top-emitting organic light-emitting diodes by optimizing surface plasmon polariton losses

We demonstrate enhanced light extraction for monochrome top-emitting organic light-emitting diodes (OLEDs). The enhancement by a factor of 1.2 compared to a reference sample is caused by the use of a hole transport layer (HTL) material possessing a low refractive index (1.52). The low refractive index reduces the in-plane wave vector of the surface plasmon polariton (SPP) excited at the interface between the bottom opaque metallic electrode (anode) and the HTL. The shift of the SPP dispersion relation decreases the power dissipated into lost evanescent excitations and thus increases the outcoupling efficiency, although the SPP remains constant in intensity. The proposed method is suitable for emitter materials owning isotropic orientation of the transition dipole moments as well as anisotropic, preferentially horizontal orientation, resulting in comparable enhancement factors. Furthermore, for sufficiently low refractive indices of the HTL material, the SPP can be modeled as a propagating plane wave within other organic materials in the optical microcavity. Thus, by applying further extraction methods, such as micro lenses or Bragg gratings, it would become feasible to obtain even higher enhancements of the light extraction.Comment: 11 pages, 6 figures, will be submitted to PR

Satisfying the Need for Relatedness Among Teachers: Benefits of Searching for Social Support

The satisfaction of teachers’ need for relatedness is an important pre-condition for teachers’ wellbeing. Receiving social support plays an important role in satisfying the need for relatedness. Following job crafting theory, the present study aims to examine (1) whether searching for social support results in an increase in the satisfaction of the need for relatedness and (2) whether this effect is mediated by an increase of received social support from the school principal and from colleagues. Using longitudinal data (N = 1071) we calculated residualized change scores and applied structural equation modeling to test the hypothesized mediation model. Results confirmed the beneficial effect of searching for social support on the satisfaction of the need for relatedness. This effect included a direct effect and an indirect effect through the receipt of social support from colleagues. The receipt of social support from the school principal was positively related to searching for social support but was unrelated to the satisfaction of the need for relatedness. These findings emphasize the importance that teachers build strong and supportive relationships within the school team, as this helps to satisfy their need for relatedness, which in turn contributes to better wellbeing among teachers

School principals’ social support and teachers’ basic need satisfaction: The mediating role of job demands and job resources

Many teachers report high levels of occupational stress. Teachers’ basic need satisfaction is essential for teachers’ well-being at work. Social support from school principals is assumed to play an important role for teachers’ basic need satisfaction. However, the underlying mechanisms of the relationship between social support from school principals and teachers’ basic need satisfaction are mostly unknown. Previous research suggests that job demands and job resources may play an important mediating role. Therefore, we examine whether teachers’ perceived job demands and job resources serve as mediators between social support from the school principal and teachers’ basic need satisfaction. Using longitudinal data of N = 1071 teachers over the course of one school year, we applied structural equation modelling to test the hypothesised mediation model. Results showed that the relationship between social support from the school principal and teachers’ basic need satisfaction was mediated by teachers’ perceived job demands and job resources. Particularly, the job demand ‘unclear organisational conditions’ and job resource ‘social support from colleagues’ indicated the strongest effects on teachers’ basic need satisfaction. These findings emphasise the responsibility of school principals to provide social support to their teachers and create a well-structured and supportive workplace. In doing so, school principals contribute to a work environment in which teachers can thrive

Videoprojekt 'Mein geheimes Porto": Anwendung eines Modells für handlungsorientiertes Lernen im universitären Kontext Anette

DE: 2017 wurde Porto zum dritten Mal in der Online-Abstimmung European BestDestinations zum beliebtesten Reiseziel Europas gewählt. Vor diesem Hintergrundwurden im Studienjahr 2016/2017 alle Studierenden der germanistischen Studiengängeder Universität Porto zur Teilnahme an einem Videoprojekt eingeladen. Ziel des Projektsbestand darin, versteckte Winkel ihrer Universitätsstadt zu entdecken und diese auspersönlicher Sicht jenseits des touristischen Mainstreams in selbstproduziertenKurzvideos in deutscher Sprache zu präsentieren.Das Projekt sollte den Studierenden die Möglichkeit bieten, einerseitsfremdsprachliche und mediale Kompetenzen gesamtheitlich und ziel- undhandlungsorientiert anzuwenden, sich andererseits darin eigeninitiativ und konstruktiveinzubringen. Durch die subjektive inhaltliche Relevanz, die Möglichkeit der medialenPartizipation - durch Online-Veröffentlichung der Projektergebnisse - und nicht zuletztdurch die Aussicht auf eine Prämierung wurde eine hohe Resonanz angestrebt, was sichdann auch in der Teilnehmer*innenzahl widerspiegelte.Vor dem Hintergrund einer kommunikativen Fremdsprachendidaktik möchten wir mitdiesem Artikel aufzeigen, inwiefern durch eine handlungs- und aufgabenorientierteVorgehensweise im universitären Fremdsprachenunterricht ein Beitrag zur Förderung selbstverantwortlicher Lernprozesse und fremdsprachlichen Handelns durch einenkonstruktiven, kreativen und produktiven Umgang mit digitalen Ressourcen in einemauthentischen Szenario geleistet werden kann.In 2017, Porto was voted Europe's most popular tourist destination for the third timein the European Best Destinations online poll. Against this background, in the academicyear 2016/2017, all students of German Studies at the University of Porto were invitedto participate in a video project. The aim of the project was to discover hidden corners oftheir university city and to present them from a personal point of view beyond the touristmainstream through self-produced short videos in German.The project was intended to offer students the opportunity to apply foreign-languageand media-related competences in a holistic, goal-oriented and action-oriented manner.In addition, students were invited to take the initiative, making an individual andconstructive contribution. Due to the subjective content relevance, the possibility ofmedia participation - by publishing the project results online - and not least by theprospect of an award, a high level of response was sought. This was reflected in theconsiderable number of participants.Within a framework of communicative approaches to foreign language teaching, wewould like to use this article to show to what extent a contribution to the promotion ofself-reliant learning processes and foreign-language tasks through a constructive,creative and productive use of digital resources in an authentic scenario is achieved,through an action-oriented and task-oriented approach in university language teaching

Conflicting results of prenatal FISH with different probes for Down's Syndrome critical regions associated with mosaicism for a de novo del(21)(q22) characterised by molecular karyotyping: Case report

For the rapid detection of common aneuploidies either PCR or Fluorescence in situ hybridisation (FISH) on uncultured amniotic fluid cells are widely used. There are different commercial suppliers providing FISH assays for the detection of trisomies affecting the Down's syndrome critical regions (DSCR) in 21q22. We present a case in which rapid FISH screening with different commercial probes for the DSCR yielded conflicting results. Chromosome analysis revealed a deletion of one chromosome 21 in q22 which explained the findings. Prenatally an additional small supernumerary marker chromosome (sSMC) was discovered as well, which could not be characterised. Postnatal chromosome analysis in lymphocytes of the infant revealed complex mosaicism with four cell lines. By arrayCGH the sSMC was provisionally described as derivative chromosome 21 which was confirmed by targeted FISH experiments

Teachers' perceived time pressure, emotional exhaustion and the role of social support from the school principal

Many teachers experience high levels of work-related strain due to time pressure, which over time can lead to various health problems, such as emotional exhaustion. However, there is growing evidence that this could be a reciprocal effect. Moreover, it is known that perceived social support can buffer the negative effects of stress, such as time pressure, on health outcomes. Less is known about buffering effects of received social support. Based on longitudinal data of n = 1071 Swiss primary and secondary school teachers over the course of one school year, the present study examined the reciprocal relationship between teachers’ perceived time pressure and emotional exhaustion and whether received social support from the school principal buffers this relationship. Results of a random intercept cross-lagged panel model show a strong relationship between teachers’ perceived time pressure and emotional exhaustion at the between-person level, but no effects at the within-person level. Further, received social support was directly related to less perceived time pressure and less emotional exhaustion. The results showed neither evidence for reciprocal effects between perceived time pressure and emotional exhaustion nor for a buffering effect of received social support from the school principal. Concluding, present findings indicate that the receipt of social support from the school principal is a central job resource that beneficially relates to teachers’ experience of time pressure and emotional exhaustion

Transformationale Führung und positive Emotionen bei Lehrpersonen – die Rolle der sozialen Unterstützung und der psychologischen Bedürfnisbefriedigung

Positive Emotionen gelten als Schlüsselfaktor zur Steigerung des Wohlbefindens und der Arbeitsleistung. Die vorliegende Studie beleuchtet den Zusammenhang zwischen transformationalem Führungsverhalten der Schulleitung und dem Erleben positiver Emotionen von Lehrpersonen. Es wird untersucht, ob dabei (a) die erhaltene soziale Unterstützung aus dem Team und (b) die Befriedigung der psychologischen Grundbedürfnisse als vermittelnde Mechanismen wirken. Basierend auf Längsschnittdaten von N = 1 217 Lehrpersonen zeigte sich, dass das individuelle transformationale Führungsverhalten die Bedürfnisse nach Autonomie und sozialer Eingebundenheit befriedigt, was zu einer Erhöhung der positiven Emotionen der Lehrpersonen beiträgt. Für die kollektive transformationale Führung waren die Ergebnisse weniger eindeutig. Sie weisen aber darauf hin, dass diese zu mehr sozialer Unterstützung innerhalb des Teams führt. Dadurch werden die Bedürfnisse nach Autonomie und sozialer Eingebundenheit stärker befriedigt, was wiederum zur Steigerung der positiven Emotionen der Lehrpersonen beiträgt. Schulleitungen können folglich positive Emotionen von Lehrpersonen über zwei verschiedene Wege fördern: Indem sie (1) die psychologischen Grundbedürfnisse der Lehrpersonen befriedigen und (2) die Voraussetzungen für ein unterstützendes Teamklima schaffen

Satisfying the Need for Relatedness Among Teachers: Benefits of Searching for Social Support

The satisfaction of teachers’ need for relatedness is an important pre-condition for teachers’ wellbeing. Receiving social support plays an important role in satisfying the need for relatedness. Following job crafting theory, the present study aims to examine (1) whether searching for social support results in an increase in the satisfaction of the need for relatedness and (2) whether this effect is mediated by an increase of received social support from the school principal and from colleagues. Using longitudinal data (N = 1071) we calculated residualized change scores and applied structural equation modeling to test the hypothesized mediation model. Results confirmed the beneficial effect of searching for social support on the satisfaction of the need for relatedness. This effect included a direct effect and an indirect effect through the receipt of social support from colleagues. The receipt of social support from the school principal was positively related to searching for social support but was unrelated to the satisfaction of the need for relatedness. These findings emphasize the importance that teachers build strong and supportive relationships within the school team, as this helps to satisfy their need for relatedness, which in turn contributes to better wellbeing among teachers

Dual-Focused Transformational Leadership, Teachers’ Satisfaction of the Need for Relatedness, and the Mediating Role of Social Support

Basic psychological need satisfaction is essential for the wellbeing of teachers and motivation at work. Transformational leadership contributes to the development and maintenance of a respectful, constructive atmosphere, a supportive working climate, and has been suggested to be a crucial factor for the satisfaction of the need for relatedness of employees. Transformational leadership is also considered as an ideal leadership style in the school setting, but most studies did not distinguish between individual and team effects of this leadership behavior. In the present study, we applied the dual-focused model of transformational leadership and focused on social processes to address the question of whether individual- and group-focused transformational leadership behavior contribute differently to satisfaction of the need for relatedness of teachers. Based on longitudinal data with three measurement points across one school year of N = 1,217 teachers, results of structural equational models supported the notion of the dual effects of transformational leadership: Individual-focused transformational leadership was directly positively related to change in satisfaction of the need for relatedness of teachers. The relationship between group-focused transformational leadership and change in satisfaction of the need for relatedness was mediated by received social support from team members. These findings emphasize the importance of school leadership behavior of principals for satisfaction of the need for relatedness of teachers. The satisfaction of the need for relatedness is, therefore, not only satisfied through the direct interaction between the school principal and the individual teacher but also through interactions of the school principal with the whole team. Our results confirm that school principals should focus their leadership behavior both on individual need satisfaction of teachers as well as on team development