Molekulare Pathologie und Embryologie von Hoxd13- assoziierten Fehlbildungen der Extremitäten

Zusammenfassung: Patienten mit erblich bedingter Synpolydactylie (SPD) entwickeln Skelettfehlbildungen, wie einen oder mehrere, zusätzliche Finger oder Zehen und deren Fusionierung. Eine Mutation in Hoxd13, die zur Verlängerung eines Polyalaninrepeats führt, verursacht SPD; wobei die Schwere des entstehenden Phänotyps mit der Länge der Expansion korreliert ist. Hoxd13 gehört zur Familie der hoch konservierten Hox-Gene; Transkriptionsfaktoren, die während der embryonalen Entwicklung eine essentielle Rolle in der Achsenbildung spielen. In dieser Arbeit wurde das spontan entstandene Mausmodell spdh (synpolydactyly homolog) untersucht, um den Pathomechanismus der Hoxd13-assoziierten SPD aufzuklären. Spdh Tiere tragen eine Verlängerung um sieben zusätzliche Alanine in Hoxd13 und weisen einen SPD ähnlichen Phänotyp mit zusätzlichen Fingern und Zehen, deren Fusionierung, sowie defiziente Gelenkentwicklung und einen Verknöcherungsdefekt auf. Transgene Tiere und verschiedene Verkreuzungsexperimente lieferten Hinweise darauf, dass die Mutation in Hoxd13 eine Kombination aus Funktionsverlust und negativem Funktionsgewinn nach sich zieht, zumal auch Tiere mit inaktiviertem Hoxd13 keine SPD entwickeln. Zum einen ist es mit dieser Arbeit gelungen, Anhaltspunkte dafür zu finden, dass in spdh Tieren das Perichondrium als wesentlicher Signalgeber während der Ossifikation verloren geht, die verzögerte Verknöcherung nicht endochondral verläuft, und es sich hierbei um eine homeotische Transformation der Mittelhandknochen zu Handwurzelknochen handelt. Diese Effekte kommen vermutlich durch den Einfluss von mutiertem Hoxd13 auf Hoxa13 zustande. Zum anderen wird der Pathomechanismus aufgeklärt, der zu zusätzlichen, fusionierten Kondensationen führt. Mangelhafte BMP-Aktivierung und falsch regulierte Ephrin-vermittelte Signalübertragung führen zu mangelnder Apoptose und unausreichender Zell-Zellabgrenzung. Dies könnte für die Fusionierungen der chondrogenen Anlagen verantwortlich gemacht werden. Ausschlaggebend für die zusätzlichen Kondensationen ist der gestörte Retinsäuresignalweg. Hier wird gezeigt, dass Hoxd13 wt direkt an den Raldh2 Promotor binden und diesen aktivieren kann. Raldh2 ist das einzige Enzym, das in der entstehenden Extremitätenknospe Retinsäure (RA) produziert, die wiederum im interdigitalen Mesenchym die Chondrogenese unterdrückt. In spdh Tieren wird zuwenig Raldh2 aktiviert, daher zuwenig RA produziert; die Chondrogenese im interdigitalen Mesenchym wird nicht ausreichend unterdrückt und die Zellen dort erhalten falsche Differenzierungssignale. Die ungenügende RA-Konzentration konnte substituiert werden und behandelte Tiere entwickelten in allen Fällen fünf Finger. So konnte ein erblich bedingter Entwicklungsdefekt behoben werden. Daher wird hier ein neuer Pathomechanismus für Polydactylie vorgeschlagen, der im Gegensatz zu den bisher bekannten Mechanismen kein Defekt in der Musterbildung ist, sondern dem ein Prozess der unkontrollierten Differenzierung zugrunde liegt

A multilevel longitudinal study of experiencing virtual presence in adolescence: the role of anxiety and openness to experience in the classroom

Presence describes the feeling of reality and immersion that users of virtual/internet environments have. Importantly, it has been suggested that there are individual and contextual differences regarding susceptibility to presence. These aspects of presence have been linked to both beneficial and disadvantageous uses of the internet, such as online therapeutic applications and addictive internet behaviours. In the present study, presence was studied in relation to individual anxiety symptoms and classroom-level openness to experience (OTE) using a normative sample of 648 adolescents aged between 16 and 18 years. Presence was assessed with the Presence II questionnaire, anxiety symptoms with the relevant subscales of the SCL-90-R, and OTE with the Five Factor Questionnaire. A three-level hierarchical linear model was calculated. Results showed that experiencing presence in virtual environments dropped between the ages of 16 and 18 years. Additionally, although anxiety symptoms were associated with higher presence at 16 years, this association decreased with age. Results also demonstrated that adolescents in classrooms higher on OTE reported reduced level of experiencing presence. The practical and theoretical implications of these findings are discussed

Association of CD69 Up-Regulation on CD4+ CLA+ T cells versus patch test, strip patch test and clinical history in nickel sensitization

<p>Abstract</p> <p>Objective</p> <p>The patch test (PT) with its modification - the strip patch test (SPT) - is the standard in vivo procedure to diagnose an allergic contact dermatitis (ACD). To date, none of the in vitro tests for the diagnosis of ACD fulfils the requirements of an easy, valid and reliable test. To investigate the prediction ability of a flow cytometric assay of CD69 up-regulation on CD4+ CLA+ T cells in nickel-sensitive and non-nickel-sensitive patients.</p> <p>Methods</p> <p>In a prospective, investigator-blinded, clinical study a total of 85 nickel-sensitive (n = 44; 51.8%) and non-nickel-sensitive patients (n = 41; 48.2%) were enrolled. The association between CD69 up-regulation on CD4+ CLA+ T cells on the one hand and PT, SPT, and clinical history on the other hand was measured. Association is expressed with c statistic values (receiver operating characteristic analysis) and corresponding 95% CIs.</p> <p>Results</p> <p>The associations were c = 0.57 (95% CI: 0.42-0.72) between CD69 up-regulation and PT, c = 0.49 (95% CI: 0.36-0.62) between CD69 up-regulation and SPT, and c = 0.51 (95% CI: 0.37-0.64) between CD69 up-regulation and clinical history.</p> <p>Conclusions</p> <p>CD69 up-regulation on CD4+ CLA+ T cells in vitro could not predict neither a positive PT or SPT result nor a positive clinical history to nickel sulfate. The combination of clinical history and patch testing still remains the basis for diagnosing ACD.</p

Communication and Control of Electric Vehicles Supporting Renewables: Preprint

Discusses the technologies needed, potential scenarios, limitations, and opportunities for using grid-connected renewable energy to fuel the electric vehicles of the future

Generalized estimating equations to estimate the ordered stereotype logit model for panel data

By modeling the effects of predictor variables as a multiplicative function of regression parameters being invariant over categories, and category-specific scalar effects, the ordered stereotype logit model is a flexible regression model for ordinal response variables. In this article, we propose a generalized estimating equations (GEE) approach to estimate the ordered stereotype logit model for panel data based on working covariance matrices, which are not required to be correctly specified. A simulation study compares the performance of GEE estimators based on various working correlation matrices and working covariance matrices using local odds ratios. Estimation of the model is illustrated using a real-world dataset. The results from the simulation study suggest that GEE estimation of this model is feasible in medium-sized and large samples and that estimators based on local odds ratios as realized in this study tend to be less efficient compared with estimators based on a working correlation matrix. For low true correlations, the efficiency gains seem to be rather small and if the working covariance structure is too flexible, the corresponding estimator may even be less efficient compared with the GEE estimator assuming independence. Like for GEE estimators more generally, if the true correlations over time are high, then a working covariance structure which is close to the true structure can lead to considerable efficiency gains compared with assuming independence.Peer ReviewedPostprint (published version

Simulating the High Energy Gamma-ray sky seen by the GLAST Large Area Telescope

This paper presents the simulation of the GLAST high energy gamma-ray telescope. The simulation package, written in C++, is based on the Geant4 toolkit, and it is integrated into a general framework used to process events. A detailed simulation of the electronic signals inside Silicon detectors has been provided and it is used for the particle tracking, which is handled by a dedicated software. A unique repository for the geometrical description of the detector has been realized using the XML language and a C++ library to access this information has been designed and implemented. A new event display based on the HepRep protocol was implemented. The full simulation was used to simulate a full week of GLAST high energy gamma-ray observations. This paper outlines the contribution developed by the Italian GLAST software group.Comment: 6 pages, 4 figures, to be published in the Proceedings of the 6th International Symposium ''Frontiers of Fundamental and Computational Physics'' (FFP6), Udine (Italy), Sep. 26-29, 200

Methods to estimate the between-study variance and its uncertainty in meta-analysis

Meta‐analyses are typically used to estimate the overall/mean of an outcome of interest. However, inference about between‐study variability, which is typically modelled using a between‐study variance parameter, is usually an additional aim. The DerSimonian and Laird method, currently widely used by default to estimate the between‐study variance, has been long challenged. Our aim is to identify known methods for estimation of the between‐study variance and its corresponding uncertainty, and to summarise the simulation and empirical evidence that compares them. We identified 16 estimators for the between‐study variance, seven methods to calculate confidence intervals, and several comparative studies. Simulation studies suggest that for both dichotomous and continuous data the estimator proposed by Paule and Mandel and for continuous data the restricted maximum likelihood estimator are better alternatives to estimate the between‐study variance. Based on the scenarios and results presented in the published studies, we recommend the Q‐profile method and the alternative approach based on a ‘generalised Cochran between‐study variance statistic’ to compute corresponding confidence intervals around the resulting estimates. Our recommendations are based on a qualitative evaluation of the existing literature and expert consensus. Evidence‐based recommendations require an extensive simulation study where all methods would be compared under the same scenarios. © 2015 The Authors. Research Synthesis Methods published by John Wiley & Sons Ltd

The Equivalence Theorem and Effective Lagrangians

We point out that the equivalence theorem, which relates the amplitude for a process with external longitudinally polarized vector bosons to the amplitude in which the longitudinal vector bosons are replaced by the corresponding pseudo-Goldstone bosons, is not valid for effective Lagrangians. However, a more general formulation of this theorem also holds for effective interactions. The generalized theorem can be utilized to determine the high-energy behaviour of scattering processes just by power counting and to simplify the calculation of the corresponding amplitudes. We apply this method to the phenomenologically most interesting terms describing effective interactions of the electroweak vector and Higgs bosons in order to examine their effects on vector-boson scattering and on vector-boson-pair production in $f\bar{f}$ annihilation. The use of the equivalence theorem in the literature is examined.Comment: 20 pages LaTeX, BI-TP 94/1

Resposta de antena de machos de Spodoptera frugiperda (Lepidoptera: noctuidae) a compostos feromonais sintéticos.

Poster

The (co-)occurrence of problematic video gaming, substance use, and psychosocial problems in adolescents

Aims. The current study explored the nature of problematic (addictive) video gaming and the association with game type, psychosocial health, and substance use. Methods. Data were collected using a paper and pencil survey in the classroom setting. Three samples were aggregated to achieve a total sample of 8478 unique adolescents. Scales included measures of game use, game type, the Video game Addiction Test (VAT), depressive mood, negative self-esteem, loneliness, social anxiety, education performance, and use of cannabis, alcohol and nicotine (smoking). Results. Findings confirmed problematic gaming is most common amongst adolescent gamers who play multiplayer online games. Boys (60%) were more likely to play online games than girls (14%) and problematic gamers were more likely to be boys (5%) than girls (1%). High problematic gamers showed higher scores on depressive mood, loneliness, social anxiety, negative self-esteem, and self-reported lower school performance. Nicotine, alcohol, and cannabis using boys were almost twice more likely to report high PVG than non-users. Conclusions. It appears that online gaming in general is not necessarily associated with problems. However, problematic gamers do seem to play online games more often, and a small subgroup of gamers – specifically boys – showed lower psychosocial functioning and lower grades. Moreover, associations with alcohol, nicotine, and cannabis use are found. It would appear that problematic gaming is an undesirable problem for a small subgroup of gamers. The findings encourage further exploration of the role of psychoactive substance use in problematic gaming