Dokument-ID Dokumenttyp Verfasser/Autoren Herausgeber Haupttitel Abstract Auflage Verlagsort Verlag Erscheinungsjahr Seitenzahl Schriftenreihe Titel Schriftenreihe Bandzahl ISBN Quelle der Hochschulschrift Konferenzname Quelle:Titel Quelle:Jahrgang Quelle:Heftnummer Quelle:Erste Seite Quelle:Letzte Seite URN DOI Abteilungen OPUS4-13132 Wissenschaftlicher Artikel Staiger, Christine; Cadot, Sidney; Kooter, Raul; Dittrich, Marcus; Müller, Tobias; Klau, Gunnar W.; Wessels, Lodewyk F. A. A Critical Evaluation of Network and Pathway-Based Classifiers for Outcome Prediction in Breast Cancer Recently, several classifiers that combine primary tumor data, like gene expression data, and secondary data sources, such as protein-protein interaction networks, have been proposed for predicting outcome in breast cancer. In these approaches, new composite features are typically constructed by aggregating the expression levels of several genes. The secondary data sources are employed to guide this aggregation. Although many studies claim that these approaches improve classification performance over single genes classifiers, the gain in performance is difficult to assess. This stems mainly from the fact that different breast cancer data sets and validation procedures are employed to assess the performance. Here we address these issues by employing a large cohort of six breast cancer data sets as benchmark set and by performing an unbiased evaluation of the classification accuracies of the different approaches. Contrary to previous claims, we find that composite feature classifiers do not outperform simple single genes classifiers. We investigate the effect of (1) the number of selected features; (2) the specific gene set from which features are selected; (3) the size of the training set and (4) the heterogeneity of the data set on the performance of composite feature and single genes classifiers. Strikingly, we find that randomization of secondary data sources, which destroys all biological information in these sources, does not result in a deterioration in performance of composite feature classifiers. Finally, we show that when a proper correction for gene set size is performed, the stability of single genes sets is similar to the stability of composite feature sets. Based on these results there is currently no reason to prefer prognostic classifiers based on composite features over single genes classifiers for predicting outcome in breast cancer. 2012 e34796 PLoS One 7 4 urn:nbn:de:bvb:20-opus-131323 10.1371/journal.pone.0034796 Theodor-Boveri-Institut für Biowissenschaften OPUS4-13066 Wissenschaftlicher Artikel Weiße, Sebastian; Heddergott, Niko; Heydt, Matthias; Pflästerer, Daniel; Maier, Timo; Haraszti, Tamas; Grunze, Michael; Engstler, Markus; Rosenhahn, Axel A Quantitative 3D Motility Analysis of Trypanosoma brucei by Use of Digital In-line Holographic Microscopy We present a quantitative 3D analysis of the motility of the blood parasite Trypanosoma brucei. Digital in-line holographic microscopy has been used to track single cells with high temporal and spatial accuracy to obtain quantitative data on their behavior. Comparing bloodstream form and insect form trypanosomes as well as mutant and wildtype cells under varying external conditions we were able to derive a general two-state-run-and-tumble-model for trypanosome motility. Differences in the motility of distinct strains indicate that adaption of the trypanosomes to their natural environments involves a change in their mode of swimming. 2012 e37296 PLoS One 7 5 urn:nbn:de:bvb:20-opus-130666 10.1371/journal.pone.0037296 Theodor-Boveri-Institut für Biowissenschaften OPUS4-12728 Wissenschaftlicher Artikel Jahn, Daniel; Schramm, Sabine; Schnölzer, Martina; Heilmann, Clemens J.; de Koster, Chris G.; Schütz, Wolfgang; Benavente, Ricardo; Alsheimer, Manfred A truncated lamin A in the Lmna\(^{−/−}\) mouse line: Implications for the understanding of laminopathies During recent years a number of severe clinical syndromes, collectively termed laminopathies, turned out to be caused by various, distinct mutations in the human LMNA gene. Arising from this, remarkable progress has been made to unravel the molecular pathophysiology underlying these disorders. A great benefit in this context was the generation of an A-type lamin deficient mouse line (Lmna\(^{−/−}\)) by Sullivan and others,1 which has become one of the most frequently used models in the field and provided profound insights to many different aspects of A-type lamin function. Here, we report the unexpected finding that these mice express a truncated Lmna gene product on both transcriptional and protein level. Combining different approaches including mass spectrometry, we precisely define this product as a C-terminally truncated lamin A mutant that lacks domains important for protein interactions and post-translational processing. Based on our findings we discuss implications for the interpretation of previous studies using Lmna\(^{−/−}\) mice and the concept of human laminopathies. 2012 463-474 Nucleus 3 5 urn:nbn:de:bvb:20-opus-127281 10.4161/nucl.21676 Theodor-Boveri-Institut für Biowissenschaften OPUS4-12375 Wissenschaftlicher Artikel Zirkel, J.; Cecil, A.; Schäfer, F.; Rahlfs, S.; Ouedraogo, A.; Xiao, K.; Sawadogo, S.; Coulibaly, B.; Becker, K.; Dandekar, T. Analyzing Thiol-Dependent Redox Networks in the Presence of Methylene Blue and Other Antimalarial Agents with RT-PCR-Supported in silico Modeling BACKGROUND: In the face of growing resistance in malaria parasites to drugs, pharmacological combination therapies are important. There is accumulating evidence that methylene blue (MB) is an effective drug against malaria. Here we explore the biological effects of both MB alone and in combination therapy using modeling and experimental data. RESULTS: We built a model of the central metabolic pathways in P. falciparum. Metabolic flux modes and their changes under MB were calculated by integrating experimental data (RT-PCR data on mRNAs for redox enzymes) as constraints and results from the YANA software package for metabolic pathway calculations. Several different lines of MB attack on Plasmodium redox defense were identified by analysis of the network effects. Next, chloroquine resistance based on pfmdr/and pfcrt transporters, as well as pyrimethamine/sulfadoxine resistance (by mutations in DHF/DHPS), were modeled in silico. Further modeling shows that MB has a favorable synergism on antimalarial network effects with these commonly used antimalarial drugs. CONCLUSIONS: Theoretical and experimental results support that methylene blue should, because of its resistance-breaking potential, be further tested as a key component in drug combination therapy efforts in holoendemic areas. 2012 287-302 Bioinformatics and Biology Insights 6 urn:nbn:de:bvb:20-opus-123751 10.4137/BBI.S10193 Theodor-Boveri-Institut für Biowissenschaften OPUS4-12683 Wissenschaftlicher Artikel Tomei, Sara; Adams, Sharon; Uccellini, Lorenzo; Bedognetti, Davide; De Giorgi, Valeria; Erdenebileg, Narnygerel; Libera Ascierto, Maria; Reinboth, Jennifer; Liu, Qiuzhen; Bevilacqua, Generoso; Wang, Ena; Mazzanti, Chiara; Marincola, Francesco M. Association between HRAS rs12628 and rs112587690 polymorphisms with the risk of melanoma in the North American population HRAS belongs to the RAS genes superfamily. RAS genes are important players in several human tumors and the single-nucleotide polymorphism rs12628 has been shown to contribute to the risk of bladder, colon, gastrointestinal, oral, and thyroid carcinoma. We hypothesized that this SNP may affect the risk of cutaneous melanoma as well. HRAS gene contains a polymorphic region (rs112587690), a repeated hexanucleotide -GGGCCT- located in intron 1. Three alleles of this region, P1, P2, and P3, have been identified that contain two, three, and four repeats of the hexanucleotide, respectively. We investigated the clinical impact of these polymorphisms in a case-control study. A total of 141 melanoma patients and 118 healthy donors from the North America Caucasian population were screened for rs12628 and rs112587690 polymorphisms. Genotypes were assessed by capillary sequencing or fragment analysis, respectively, and rs12628 CC and rs112587690 P1P1 genotypes significantly associated with increased melanoma risk (OR = 3.83, p = 0.003; OR = 11.3, p = 0.033, respectively), while rs112587690 P1P3 frequency resulted significantly higher in the control group (OR = 0.5, p = 0.017). These results suggest that rs12628 C homozygosis may be considered a potential risk factor for melanoma development in the North American population possibly through the linkage to rs112587690. 2012 3456-3461 Medical Oncology 29 5 urn:nbn:de:bvb:20-opus-126834 dx.doi.org/10.1007/s12032-012-0255-3 Theodor-Boveri-Institut für Biowissenschaften OPUS4-13081 Wissenschaftlicher Artikel El-Keredy, Amira; Schleyer, Michael; König, Christian; Ekim, Aslihan; Gerber, Bertram Behavioural Analyses of Quinine Processing in Choice, Feeding and Learning of Larval Drosophila Gustatory stimuli can support both immediate reflexive behaviour, such as choice and feeding, and can drive internal reinforcement in associative learning. For larval Drosophila, we here provide a first systematic behavioural analysis of these functions with respect to quinine as a study case of a substance which humans report as "tasting bitter". We describe the dose-effect functions for these different kinds of behaviour and find that a half-maximal effect of quinine to suppress feeding needs substantially higher quinine concentrations (2.0 mM) than is the case for internal reinforcement (0.6 mM). Interestingly, in previous studies (Niewalda et al. 2008, Schipanski et al 2008) we had found the reverse for sodium chloride and fructose/sucrose, such that dose-effect functions for those tastants were shifted towards lower concentrations for feeding as compared to reinforcement, arguing that the differences in dose-effect function between these behaviours do not reflect artefacts of the types of assay used. The current results regarding quinine thus provide a starting point to investigate how the gustatory system is organized on the cellular and/or molecular level to result in different behavioural tuning curves towards a bitter tastant. 2012 e40525 PLoS One 7 7 urn:nbn:de:bvb:20-opus-130811 10.1371/journal.pone.0040525 Theodor-Boveri-Institut für Biowissenschaften OPUS4-13201 Wissenschaftlicher Artikel Kessler, Michael; Hertel, Dietrich; Jungkunst, Hermann F.; Kluge, Jürgen; Abrahamczyk, Stefan; Bos, Merijn; Buchori, Damayanti; Gerold, Gerhard; Gradstein, S. Robbert; Köhler, Stefan; Leuschner, Christoph; Moser, Gerald; Pitopang, Ramadhanil; Saleh, Shahabuddin; Schulze, Christian H.; Sporn, Simone G.; Steffan-Dewenter, Ingolf; Tjitrosoedirdjo, Sri S.; Tscharntke, Teja Can Joint Carbon and Biodiversity Management in Tropical Agroforestry Landscapes Be Optimized? Managing ecosystems for carbon storage may also benefit biodiversity conservation, but such a potential 'win-win' scenario has not yet been assessed for tropical agroforestry landscapes. We measured above-and below-ground carbon stocks as well as the species richness of four groups of plants and eight of animals on 14 representative plots in Sulawesi, Indonesia, ranging from natural rainforest to cacao agroforests that have replaced former natural forest. The conversion of natural forests with carbon stocks of 227-362 Mg C ha\(^{-1}\) to agroforests with 82-211 Mg C ha\(^{-1}\) showed no relationships to overall biodiversity but led to a significant loss of forest-related species richness. We conclude that the conservation of the forest-related biodiversity, and to a lesser degree of carbon stocks, mainly depends on the preservation of natural forest habitats. In the three most carbon-rich agroforestry systems, carbon stocks were about 60% of those of natural forest, suggesting that 1.6 ha of optimally managed agroforest can contribute to the conservation of carbon stocks as much as 1 ha of natural forest. However, agroforestry systems had comparatively low biodiversity, and we found no evidence for a tight link between carbon storage and biodiversity. Yet, potential win-win agroforestry management solutions include combining high shade-tree quality which favours biodiversity with cacao-yield adapted shade levels. 2012 e47192 PLoS One 7 10 urn:nbn:de:bvb:20-opus-132016 10.1371/journal.pone.0047192 Theodor-Boveri-Institut für Biowissenschaften OPUS4-13444 Wissenschaftlicher Artikel Schokraie, Elham; Warnken, Uwe; Hotz-Wagenblatt, Agnes; Grohme, Markus A.; Hengherr, Steffen; Förster, Frank; Schill, Ralph O.; Frohme, Marcus; Dandekar, Thomas; Schnölzer, Martina Comparative proteome analysis of Milnesium tardigradum in early embryonic state versus adults in active and anhydrobiotic state Tardigrades have fascinated researchers for more than 300 years because of their extraordinary capability to undergo cryptobiosis and survive extreme environmental conditions. However, the survival mechanisms of tardigrades are still poorly understood mainly due to the absence of detailed knowledge about the proteome and genome of these organisms. Our study was intended to provide a basis for the functional characterization of expressed proteins in different states of tardigrades. High-throughput, high-accuracy proteomics in combination with a newly developed tardigrade specific protein database resulted in the identification of more than 3000 proteins in three different states: early embryonic state and adult animals in active and anhydrobiotic state. This comprehensive proteome resource includes protein families such as chaperones, antioxidants, ribosomal proteins, cytoskeletal proteins, transporters, protein channels, nutrient reservoirs, and developmental proteins. A comparative analysis of protein families in the different states was performed by calculating the exponentially modified protein abundance index which classifies proteins in major and minor components. This is the first step to analyzing the proteins involved in early embryonic development, and furthermore proteins which might play an important role in the transition into the anhydrobiotic state. 2012 e45682 PLoS One 7 9 urn:nbn:de:bvb:20-opus-134447 10.1371/journal.pone.0045682 Theodor-Boveri-Institut für Biowissenschaften OPUS4-6550 Wissenschaftlicher Artikel Schartl, Manfred; Kneitz, Susanne; Wilde, Brigitta; Wagner, Toni; Henkel, Christiaan V.; Spaink, Hermann P.; Meierjohann, Svenja Conserved expression signatures between medaka and human pigment cell tumors Aberrations in gene expression are a hallmark of cancer cells. Differential tumor-specific transcript levels of single genes or whole sets of genes may be critical for the neoplastic phenotype and important for therapeutic considerations or useful as biomarkers. As an approach to filter out such relevant expression differences from the plethora of changes noted in global expression profiling studies, we searched for changes of gene expression levels that are conserved. Transcriptomes from massive parallel sequencing of different types of melanoma from medaka were generated and compared to microarray datasets from zebrafish and human melanoma. This revealed molecular conservation at various levels between fish models and human tumors providing a useful strategy for identifying expression signatures strongly associated with disease phenotypes and uncovering new melanoma molecules. 2012 urn:nbn:de:bvb:20-opus-75848 Theodor-Boveri-Institut für Biowissenschaften OPUS4-12364 Wissenschaftlicher Artikel Krueger, Beate; Friedrich, Torben; Förster, Frank; Bernhardt, Jörg; Gross, Roy; Dandekar, Thomas Different evolutionary modifications as a guide to rewire two-component systems Two-component systems (TCS) are short signalling pathways generally occurring in prokaryotes. They frequently regulate prokaryotic stimulus responses and thus are also of interest for engineering in biotechnology and synthetic biology. The aim of this study is to better understand and describe rewiring of TCS while investigating different evolutionary scenarios. Based on large-scale screens of TCS in different organisms, this study gives detailed data, concrete alignments, and structure analysis on three general modification scenarios, where TCS were rewired for new responses and functions: (i) exchanges in the sequence within single TCS domains, (ii) exchange of whole TCS domains; (iii) addition of new components modulating TCS function. As a result, the replacement of stimulus and promotor cassettes to rewire TCS is well defined exploiting the alignments given here. The diverged TCS examples are non-trivial and the design is challenging. Designed connector proteins may also be useful to modify TCS in selected cases. 2012 97-128 Bioinformatics and Biology Insights 6 urn:nbn:de:bvb:20-opus-123647 10.4137/BBI.S9356 Theodor-Boveri-Institut für Biowissenschaften