Zugl.: Hannover, Universiẗat, Diss.

Techn. Univ., Diss--Berlin. / Literaturverz. S. 125 - 129.

Zugl.: Aachen, Techn. Hochsch., Diss., 2005.

Hannover, Universiẗat, Diss., 1999.

Le syndrome de Brugada est un trouble du rythme cardiaque héréditaire qui mène à l’apparition de fibrillations ventriculaires et à la mort subite cardiaque. Seulement 30% des cas atteints de ce syndrome sont liés à des mutations génétiques et ce à cause de la complexité du phénotype engendré. Le gène RRAD a été identifié dans une famille qui compte 5 membres atteints du syndrome de Brugada, tous porteurs du variant p.R211H. Ce gène code pour la protéine G monomérique Rad dont le rôle principal est de réguler le courant calcique de type L dans les cellules musculaires squelettiques et cardiaques. Cette étude associe trois modèles d’étude visant à discriminer l’implication de Rad dans le phénotype des patients atteints : Un modèle de surexpression pour étudier le rôle de Rad et l’impact de sa surexpression sur l’activité électrique et la structure des cardiomyocytes, des cardiomyocytes dérivés de cellules IPS reprogrammées des patients porteurs de la mutation pour en déterminer le phénotype cellulaire, et un modèle de souris knock in pour la mutation p.R211H généré dans le but d’intégrer le phénotype cellulaire à l’échelle de l’organe entier. Les résultats obtenus sur les trois modèles, montrent que Rad R211H provoque des troubles au niveau de l’activité électrique du coeur mais aussi au niveau de la structure des cellules différenciées et ces troubles se traduisent par des anomalies à l’ECG chez la souris. Cette étude est la première à démontrer l’implication de Rad GTPase dans le syndrome de Brugada et la seule à démontrer, à ce jour, des perturbations du cytosquelette dans cette pathologie qui est toujours considérée comme une pathologie exclusivement rythmique. / Brugada syndrome (BrS) is a rare inherited cardiac disorder linked to high risk of ventricular arrhythmias and sudden death. In the present day, only 30% of BrS cases have known genetic causes. Most of these mutations have been identified in the SCN5A gene that encodes the cardiac voltage-gated sodium channel NaV1.5. We identified a rare variant in the RRAD gene encoding for the small G protein Rad GTPase, in a familial case of BrS. The aim of this work was to elucidate the mechanisms by which the RRAD p.R211H variant could lead to BrS. First, an overexpressing model was developed using neonatal mouse cardiomyocytes to define the involvement of Rad in the electrical function of cardiomyocytes. Then, cardiac cells were derived from human induced pluripotent stem cells reprogrammed from the carriers of the Rad mutation in order to investigate the phenotype induced at the cellular level. Furthermore, a knock in mouse has been generated to study the impact of this same mutation on the organ level. The three models summarized in a complementary way the phenotype caused by the Rad mutation on the electrical activity at the cellular and the organ levels. The mutation seem to trigger structural defects in the cardiomyocytes that can be involved in the electrical defects related to the disease. The present study is the first report of the potential link between Rad GTPase and BrS. The phenotype reported recapitulates the classical electrophysiological signature of the disease but also associates cytoskeleton disturbances.

Herein we tested the repeatability of RAD-seq phylogeographic construction by creating a second, independent phylogeography of the pitcher-plant mosquito, Wyeomyia smithii. We sampled 25 populations drawn from different localities nearby previous collection sites and used these new data to construct a second, independent phylogeography to test the reproducibility of phylogenetic patterns. Our previous phylogeography was based on 3,741 phylogenetically informative markers from 21 populations and rooted with mitochondrial COI. The present phylogeography was based on 16,858 informative markers and rooted with RAD-seq. We found correspondence between clades at the extremes of W. smithii's distribution; however, there were several discrepancies between the trees, including the refugium that gave rise to all post-glacial populations. We observed that combining all 46 populations resolved these discrepancies and, equally importantly, that extensive taxon sampling in areas of historical importance is more valuable than increasing the number of informative sites in establishing an accurate, robust phylogeography. This thesis includes unpublished co-authored material.

Zugl.: Stuttgart, Univ., Diss., 2008

Zugl.: Duisburg, Essen, Univ., Diss., 2010

Techn. Universiẗat, Diss., 2004--Berlin.

While the rest of eighteenth century Europe, with the exception of England, was subject to- autocratic rule, Poland enjoyed a rare privilege—that of electing the sovereign . In other respects, however, she was not to be envied. Politically she was no longer of consequence except as a pawn in the hands of foreign interests. Her great nobles and lesser gentry alike were content to bask in the remembered glory of past ages; clergymen were, for the most part, lazy, corrupt and ignorant; yeomen had been reduced to serfdom; there was no army to speak of; the towns were in decline; wars had depleted the treasury and commerce and trade hardly existed. Worst of all was a general apathy combined with devotionalism rather than religious fervour, and the spurious belief that God was on the side of Poland and would take care of her whether the Poles helped themselves or not. For some time, however, thinking men had worried about this state of affairs and many wrote down their ideas on the subject. It remained for a Piarist father, Stanislas Konarski, to attack the very root of the evil—bad forms of government in general, and the iniquitous unanimity principle in particular. His four-volume work, "0 Skutecznym Rad Sposobie" ("On Effective Counsels in Government"), which appeared in the 1760's, not only subjected the problem to minute analysis, but also offered a "prescription" for Poland's ills: but by the time the nation was ready to act on Konarski's ideas it had only a scant four years of freedom left. The fruits of his work were seen only after the First Partition. / Arts, Faculty of / Central Eastern Northern European Studies, Department of / Graduate