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Acknowledgements: Acknowledgements: We acknowledge support from the Carlsberg Foundation for logistics to carry out two expeditions to Kap København in 2006 and 2012 (S. Funder, principal investigator for Carlsberg foundation grant to LongTerm and Kap København—the age). The fieldwork in 2016 was supported by a grant to N.K.L. from the Villum Foundation. We highly appreciate the collaborative support by Illumina Inc. that was crucial for the success of the project. E.W. and K.H.K. thank the Danish National Research Foundation (DNRF) and the Lundbeck Foundation (R302-2018-2155) for providing long-term funds to develop the necessary DNA technology that eventually made it possible to retrieve environmental DNA from these ancient deposits in the Kap København Formation. E.W. also acknowledges the Wellcome Trust (UNS69906), the Carlsberg Foundation (CF18-0024), Novo Foundation (NNF18SA0035006), Leverhume (RPG-2016-235) and GRF EXC CRS Chair - Cluster of Excellence (44113220) for their support. M.W.P. acknowledges support from the Carlsberg Foundation (CF17-0275). K.K.S. and S.J. acknowledge support from VILLUM FONDEN (00025352). I.G.A. and E.C. have received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 819192). B.D.S. acknowledges support from the Wellcome Trust programme in Mathematical Genomics and Medicine (WT220023). J.Å.K. was supported by the Carlsberg Foundation (CF20-0238). C.B. acknowledges ERC Advanced Award Diatomic (grant agreement no. 835067). J.C.G. was supported by Natural Science and Engineering Research Council of Canada–Discovery Grant 06785 and Canada Foundation for Innovation grant 21305. M.J.C. acknowledges support from the Danish National Research Foundation DNRF128. We thank G. Yang for cosmogenic isotope AMS target chemistry; S. Funder for introducing us to the Kap København Formation and generating much of the platform that enabled us to conduct our research; T. O. Delmont for providing data and guidance on the SMAGs analysis; Minik Rosing for providing talc minerals; T. B. Zunic for providing tremolite, orthoclase and chlorite; Z. Vardanyan for help with the DNA extractions and library build; and L. B. Levy and D. Skov for their help collecting samples in 2016. This work was prepared in part by Lawrence Livermore National Laboratory under contract DE-AC52-07NA27344; LLNL-JRNL-830653. E.W. thanks St Johns College, Cambridge for providing him with a stimulating environment for scientific thoughts and discussion., Late Pliocene and Early Pleistocene epochs 3.6 to 0.8 million years ago1 had climates resembling those forecasted under future warming2. Palaeoclimatic records show strong polar amplification with mean annual temperatures of 11-19 °C above contemporary values3,4. The biological communities inhabiting the Arctic during this time remain poorly known because fossils are rare5. Here we report an ancient environmental DNA6 (eDNA) record describing the rich plant and animal assemblages of the Kap København Formation in North Greenland, dated to around two million years ago. The record shows an open boreal forest ecosystem with mixed vegetation of poplar, birch and thuja trees, as well as a variety of Arctic and boreal shrubs and herbs, many of which had not previously been detected at the site from macrofossil and pollen records. The DNA record confirms the presence of hare and mitochondrial DNA from animals including mastodons, reindeer, rodents and geese, all ancestral to their present-day and late Pleistocene relatives. The presence of marine species including horseshoe crab and green algae support a warmer climate than today. The reconstructed ecosystem has no modern analogue. The survival of such ancient eDNA probably relates to its binding to mineral surfaces. Our findings open new areas of genetic research, demonstrating that it is possible to track the ecology and evolution of biological communities from two million years ago using ancient eDNA.

Proteins of the Fanconi Anemia (FA) complementation group are required for crosslink (CL) repair in humans and their loss leads to severe pathological phenotypes. Here we characterize a homolog of the Fe-S cluster helicase FANCJ in the model plant Arabidopsis, AtFANCJB, and show that it is involved in interstrand CL repair. It acts at a presumably early step in concert with the nuclease FAN1 but independently of the nuclease AtMUS81, and is epistatic to both error-prone and error-free post-replicative repair in Arabidopsis. The simultaneous knock out of FANCJB and the Fe-S cluster helicase RTEL1 leads to induced cell death in root meristems, indicating an important role of the enzymes in replicative DNA repair. Surprisingly, we found that AtFANCJB is involved in safeguarding rDNA stability in plants. In the absence of AtRTEL1 and AtFANCJB, we detected a synergetic reduction to about one third of the original number of 45S rDNA copies. It is tempting to speculate that the detected rDNA instability might be due to deficiencies in G-quadruplex structure resolution and might thus contribute to pathological phenotypes of certain human genetic diseases., Author summary The Fanconi Anemia and Hoyeraal-Hreidarsson syndromes are severe human genetic diseases that are correlated with DNA repair deficiencies. Interestingly, plants harbour homologues of factors in their genome that are causative for the respective diseases upon mutation. Using the model plant Arabidopsis, we analysed in detail the role of two helicases that are causing one or the other syndrome when defective in humans. We found that the simultaneous loss of both helicases leads to synergistic defects of plant cells in response to induced but also natural DNA damage, indicating that they act in different repair pathways. Most surprisingly, we found a drastic reduction of rDNA copies, in the double mutant, that are required for ribosome formation and thus protein synthesis. Such a phenotype has not been reported before—neither for humans nor animals—but this finding might significantly contribute to specificities of the respective diseases.

The accelerated metabolism of tumor cells, inevitable for maintaining high proliferation rates, is an emerging target for tumor therapy. Increased glucose and lipid metabolism as well as mitochondrial activity have been shown in solid tumors but also in leukemic cells. As tumor cells are able to escape the blockade of one metabolic pathway by a compensatory increase in other pathways, treatment strategies simultaneously targeting metabolism at different sites are currently developed. However, the number of clinically applicable anti-metabolic drugs is still limited. Here, we analyzed the impact of the anti-diabetic drug metformin alone or in combination with two non-steroidal anti-inflammatory drugs (NSAIDs) diclofenac and diflunisal on acute myeloid leukemia (AML) cell lines and primary patient blasts. Diclofenac but not diflunisal reduced lactate secretion in different AML cell lines (THP-1, U937, and KG-1) and both drugs increased respiration at low concentrations. Despite these metabolic effects, both NSAIDs showed a limited effect on tumor cell proliferation and viability up to a concentration of 0.2 mM. In higher concentrations of 0.4–0.8 mM diflunisal alone exerted a clear effect on proliferation of AML cell lines and blocked respiration. Single treatment with the anti-diabetic drug metformin blocked mitochondrial respiration, but proliferation and viability were not affected. However, combining all three drugs exerted a strong cytostatic and cytotoxic effect on THP-1 cells. Comparable to the results obtained with THP-1 cells, the combination of all three drugs significantly reduced proliferation of primary leukemic blasts and induced apoptosis. Furthermore, NSAIDs supported the effect of low dose chemotherapy with cytarabine and reduced proliferation of primary AML blasts. Taken together we show that low concentrations of metformin and the two NSAIDs diclofenac and diflunisal exert a synergistic inhibitory effect on AML proliferation and induce apoptosis most likely by blocking tumor cell metabolism. Our results underline the feasibility of applying anti-metabolic drugs for AML therapy.

vorgelegt von: Astrid Schmidt Zusammenfassung in englischer Sprache Masterarbeit FH Campus Wien 2016

Erzählen und Rollenspiel – zwei Sprechhandlungssituationen, die an Kinder im Vorschulalter hohe sprachliche, kognitive sowie soziale Anforderungen stellen und gleichzeitig eine große Faszination auf Kinder die-ser Altersgruppe ausüben. Der Beitrag stellt Ergebnisse aus dem Flensburger Projekt zum Erzählen und Rollenspiel dar und gibt einen Einblick in die Entwicklung und Erprobung einer forschungsbasierten sprachpädagogischen Förderkonzeption für den Elementarbereich. Dabei liegt ein besonderes Augenmerk auf den während der Erprobungsphase aufgetretenen Problemen und deren erfolgreicher Lösung durch die Einbindung von Schrift in die Konzeption.

In der vorliegenden retrospektiven Arbeit wurden die Ergebnisse des Frühzeitigen Totalen Muttermundverschluss (FTMV) und der Notcerclage, zwei Operationsverfahren bei wiederholten Spätaborten und bei Vorliegen eines Fruchtblasenprolapses (FBP), ausgewertet. Bei wiederholten Spätaborten wird in der Frauenklinik der Charité Campus Mitte ein FTMV durchgeführt. Dieses Verfahren soll aszendierende Infektionen verhindern, dafür wird der äußere Muttermund nach Entfernung der Schleimhaut durch Nähte fest verschlossen. Zur Schleimhautentfernung wurden eine rotierende Drahtbürste und ein CO2 Laser verwendet. Die Ergebnisse des FTMV mittels Laser werden mit denen bei Einsatz einer Drahtbürste verglichen. Zwischen 1993 - 2004 erhielten 101 Patientinnen einen FTMV. In 72 Fällen erfolgte die Wundauffrischung mit einem Laser und in 29 Fällen mit einer Drahtbürste. Der FTMV wurde im Mittel in der 17/0 SSW durchgeführt. Vor dem Eingriff endeten nur 21,5% aller Schwangerschaften mit Erfolg, das heißt, mit einem lebenden Kind, mit dem FTMV konnten 95% erfolgreich beendet werden. Die Geburtsgewichte lagen in 75% der Fälle bei 2500g oder darüber. Beim Vergleich der Verfahren zur Wundauffrischung (Drahtbürste vs. Laser) bestand kein signifikanter Unterschied (p=0,101). Ein weiteres Ziel dieser Arbeit war es, die Ergebnisse nach einer Notcerclage zu analysieren. Im gleichen Zeitraum von 1993 bis 2004 wurden 116 Notcerclagen durchgeführt. Die 116 Patientinnen wurden nach den Schweregraden des FBP in 3 Gruppen eingeteilt. Gruppe I (n=33): FBP im Niveau des äußeren Muttermundes, Gruppe II (n=55): FBP über den äußeren Muttermund hinaus und Gruppe III (n=28): Fruchtblase füllt gesamte Vagina ballonartig aus oder Sanduhrprolaps. Mit Erfolg endeten 81% der Schwangerschaften. Im Mittel konnte die Schwangerschaft um 35 d verlängert werden (Qu: 11d; Qo; 72d), wobei 33% der Kinder 2500g oder mehr wogen, 80,1% der Kinder konnten die Klinik nach der Notcerclage lebend verlassen. Zwischen den Gruppen der verschiedenen Grade des FBP gab es signifikante Unterschiede bezüglich der Schwangerschaftsverlängerung nach der Notcerclage (p=0,012). In Gruppe I konnte die Schwangerschaft im Mittel um 56 d, in Gruppe II um 31d und in Gruppe III noch um 25 d verlängert werden. Beide Operationsverfahren scheinen eine Therapieoption bei wiederholten Spätaborten und Frühgeburten und bei Auftreten eines FBP darzustellen., This retrospective study evaluates the results of the Early Total Cervix Occlusion (ETCO) and the Emergency cerclage, two methods perfomed for recurrent late abortions and bulging membranes. At the Department of Obstetrics of the Charité Campus Mitte an ETCO is performed at recurrent late abortions. This procedure should avoid ascending genital infections, therefor the glandular epithelium of the external os of uteri is removed and then closed with sutures. For removing the epithelium a rotating wire brush and a carbon dioxide laser was used. The results of the ETCO with a laser and with the wire brush were compared. From 1993 until 2004 101 women underwent an ETCO. In 72 cases the removing of the epithelium was performed with a laser und in 29 cases with a wire brush. The ETCO was performed in mean at 17/0 weeks of gestation. Before the procedure only 21,5 % of the pregnancies end with success, that means, with a surviving infant, with the ETCO 95% end successfully. In 75% of all cases the birth weights were 2500g or more. There was no significant difference between the two methods of removing the epithelium (wire brush vs. laser) (p=0,101). Another purpose of this study was to evaluate the results after an emergency cerclage. During the same period from 1993 until 2004 116 emergency cerclages were performed. The patients were divided into three groups depending on the grade of bulging membranes. Group I (n=33): bulging membranes at the external os, group II (n=55): bulging membranes into the vagina and group III (n=28): bulging membranes fulfill the whole vagina or hourglass prolapsed membranes. 81% of the pregnancies ended with success. The mean prolangation of pregnancy was 35 days (Qu: 11d; Qo; 72d), in 33% the birth weight of the infants was 2500g or more, 80,1% of the infants were admitted at home alive. Between the groups with different grades of bulging membranes, the prolongation of pregnancy after the emergency cerclage was significantly different. (p=0,012). In group I the mean prolongation of pregnancy was 56 days, in group II 31 days and in group III 25 days. Both methods seem to be an option of therapy at recurrent abortions, premature birth and bulging membranes.