@article{OnoSonoyamaNemaetal.2014,
  author    = {Ono, Mitsuaki and Sonoyama, Wataru and Nema, Kazuki and Hara, Emilio Satoshi and Oida, Yasutaka and Pham, Hai Thanh and Yamamoto, Katushi and Hirota, Kazuo and Sugama, Kazushige and Sebald, Walter and Kuboki, Takuo},
  title     = {Regeneration of calvarial defects with Escherichia coli-derived rhBMP-2 adsorbed in PLGA membrane},
  series = {Cells Tissues Organs},
  volume    = {198},
  journal   = {Cells Tissues Organs},
  number    = {5},
  issn      = {1422-6405},
  doi       = {10.1159/000356947},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-196680},
  pages     = {367 -- 376},
  year      = {2014},
  abstract  = {Objective: Escherichia coli-derived recombinant human bone morphogenetic protein-2 (E-BMP-2) has been shown to be as effective as mammalian cell-derived BMP-2. However, several in vitro and in vivo experiments are still necessary to validate the effectiveness of E-BMP-2 due to the difference in synthesis process, mainly related to protein nonglycosylation. The objective of this study was to investigate whether biodegradable polylactide-co-glycolide (PLGA) membrane is a suitable carrier for E-BMP-2 delivery for bone regeneration of critical-sized defects in rat calvaria. Materials and Methods: First, the osteoinductive effect of E-BMP-2 was confirmed in vitro in mouse bone marrow stromal cells by analysis of osteocalcin mRNA levels, and calcium deposition was detected by alizarin red staining. Before in vivo experiments, the release profile of E-BMP-2 from PLGA membranes was determined by ELISA. E-BMP-2 (0, 1, 5 and 10 μg/μl) was applied for ectopic and orthotopic bone formation and was analyzed by X-ray, micro-CT and histology. Results: Release-profile testing showed that PLGA membrane could retain 94\% of the initially applied E-BMP-2. Ectopic bone formation assay revealed that combination of E-BMP-2/PLGA membrane strongly induced bone formation. Stronger osteoinductivity with complete repair of critical-sized defects was observed only with PLGA membranes adsorbed with 5 and 10 μg/μl of E-BMP-2, whereas no bone formation was observed in the groups that received no membrane or 0-μg/μl dose of E-BMP-2. Conclusion: PLGA membrane was shown to be a suitable carrier for sustained release of E-BMP-2, and the E-BMP-2/PLGA membrane combination was demonstrated to be efficient in bone regeneration in a model of critical-sized defects.},
  language  = {en}
}
@phdthesis{Schwarze2014,
  author    = {Schwarze, Simone},
  title     = {Untersuchung von Faltungs- und Funktionsdynamik isolierter Proteindom{\"a}nen mittels Fluoreszenzl{\"o}schung},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-107080},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {Proteine bestehen aus einer spezifischen Sequenz verschiedener Aminos{\"a}uren, die ihre charakteristische Funktion bestimmt. Die große Variabilit{\"a}t an Aminos{\"a}uresequenzen erm{\"o}glichte die Evolution einer nahezu unbegrenzten Anzahl an Proteinen. Meistens nehmen diese Schl{\"u}sselpositionen ein, von robusten Baustoffen bis hin zu molekularen Maschinen. Daher kann eine Fehlfunktion gravierende Auswirkungen auf das Leben haben, z.B. Krankheiten wie Alzheimer oder Epilepsi. Um die Funktionen und Fehlfunktionen zu verstehen, ist eine umfassende Kenntnis der Proteinfaltung, der Protein-Protein Assoziation, sowie den Dynamiken innerhalb von Proteinen erforderlich. Diese Vorg{\"a}nge wurden in dieser Arbeit an drei isolierten Proteindom{\"a}nen durch die Anwendung der Fluoreszenzl{\"o}schmechanismen der H-Dimerbildung und des photoinduzierten Elektronentransfers untersucht. Der entfaltete Zustand der Bindungsdom{\"a}ne BBL, das Teil des 2-oxo-acid Dehydrogenasekomplexes ist, wurde unter physiologischen Bedingungen mit Zirkulardichroismus (CD) und einer Kombination aus photoinduziertem Elektronentransfer und Fluoreszenzkorrelationsspektroskopie analysiert. Beide Methoden zeigten {\"u}bereinstimmend anhand von 20 in BBL einzeln eingef{\"u}gten konservativen Punktmutationen, dass Seitenketteninteraktionen keine Auswirkungen auf die Sekund{\"a}rstruktur des denaturierten Zustandes, den Ausgangspunkt der Faltung, haben. Mit Hilfe der Dekonvolation der CD-Spektren wurde zudem gezeigt, dass die Reststruktur im denaturierten Zustand der helikalen Proteindom{\"a}ne von β-Str{\"a}ngen und β-Kehren dominiert wird, die eine entscheidende Funktion bei der Faltung in den nativen Zustand haben k{\"o}nnten. Die N-terminale Dom{\"a}ne (NTD), der f{\"u}r die Materialforschung hochinteressanten Spinnen-seidenfaser, ist f{\"u}r die Polymerisation des Spinnenseidenfadens auf den pH-Wechsel von pH 7 auf pH 6 hin verantwortlich. Dieser f{\"u}r die Proteinfunktion wichtige Prozess wurde durch die Einbringung eines extrinsischen Fluoreszenzschalters, basierend auf der H-Dimerbildung, mit der Stopped-Flow-Technik untersucht. Es wurde gezeigt, dass die NTDs 104 mit einer Rate von 3 x 10^8 M-1 s-1 assoziieren und somit nahezu das Geschwindigkeitslimit der Protein-Protein Assoziation erreicht wird. Zwei geladenen Seitenketten, der D39 und D40, kommt eine entscheidende Funktion in dem Prozess zu, da eine Mutation dieser die Assoziation verhindert. Des Weiteren wurde gezeigt, dass sich die NTD auf eine Erh{\"o}hung der Ionenst{\"a}rke entgegengesetzt zu anderen Proteinen verh{\"a}lt: die Dissoziation wird beschleunigt, die Assoziation nicht beeinflusst. Gleiches Verhalten wurde auf den einzelnen Austausch der {\"u}brigen protonierbaren Aminos{\"a}ureseitenketten hin beobachtet, ausgenommen die Mutation der E119, welche die Dissoziation verlangsamt. Daher scheint der makromolekulare Dipol, der auf Grund der Ladungsverteilung in der NTD entsteht, die Assoziation maßgeblich zu beeinflussen. Glutamatrezeptoren sind an der schnellen synaptischen Signalweiterleitung im Nervensys-tem von Vertebraten beteiligt. Die Konformationen der Ligandenbindungsdom{\"a}ne (LBD) haben dabei entscheidende Auswirkungen auf die Funktion des Gesamtrezeptors. Diese wurden mit einer Kombination aus photoinduziertem Elektronentransfer und Fluoreszenzkorrelationsspektroskopie untersucht. Mit dieser Methode wurde ein dynamisches Bild der gebundenen sowie ungebundenen Form der AMPA-spezifischen Glutamatrezeptor 2-LBD gezeigt. Es wurde zudem gezeigt, dass sich die Dynamiken in Abh{\"a}ngigkeit der Bindung von den Agonisten Glutamat und AMPA, dem partiellen Agonisten Kainate oder Cyclothiazid (CTZ), welches eine Dimerisierung der LBDs bewirkt, unterschiedlich ver{\"a}ndern. Dies k{\"o}nnte eine Auswirkung auf die Funktion der Rezeptoren haben. Die Anwendung der Fluoreszenzl{\"o}schmechanismen der H-Dimerbildung und des photoinduzierten Elektronentransfers in dieser Arbeit hat gezeigt, dass diese die M{\"o}glichkeit bieten, unterschiedlichste Fragestellungen zu beantworten und so Einblicke in dynamische Funktionsweisen von Proteinen er{\"o}ffnen. Kombiniert mit etablierten Fluoreszenzmethoden ist es so m{\"o}glich quantitativ Kinetiken auf unterschiedlichen Zeitskalen zu untersuchen.},
  subject      = {Protein-Protein-Wechselwirkung},
  language  = {de}
}
@phdthesis{Classen2014,
  author    = {Claßen, Alice},
  title     = {Diversity, traits and ecosystem services of pollinators along climate and land use gradients on Mount Kilimanjaro},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-101292},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {Since more than two centuries naturalists are fascinated by the profound changes in biodiversity observed along climatic gradients. Although the theories explaining changes in the diversity and the shape of organisms along climatic gradients belong to the foundations of modern ecology, our picture on the spatial patterns and drivers of biodiversity is far from being complete. Ambiguities in theory and data are common and past work has been strongly concentrated on plants and vertebrates. In the last two decades, interest in the fundamental processes structuring diversity along climatic gradients gained new impetus as they are expected to improve our understanding about how ecosystems will respond to global environmental changes. Global temperatures are rising faster than ever before; natural habitats are transformed into agricultural land and existing land use systems get more and more intensified to meet the demands of growing human populations. The fundamental shifts in the abiotic and biotic environment are proclaimed to affect ecosystems all over the world; however, precise predictions about how ecosystems respond to global changes are still lacking. We investigated diversity, traits and ecosystem services of wild bees along climate and land use gradients on Mount Kilimanjaro (Tanzania, East Africa). Wild bees play a major role in ecosystems, as they contribute to the reproduction and performance of wild and crop plants. Their responsiveness to environmental changes is therefore of high ecological and economic importance. Temperature and energy resources have often been suggested to be the main determinants of global and local species richness, but the mechanisms behind remain poorly understood. In the study described in chapter II we analyzed species richness patterns of wild bees along climate and land use gradients on Mount Kilimanjaro and disentangled the factors explaining most of the changes in bee richness. We found that floral resources had a weak but significant effect on pollinator abundance, which in turn was positively related to species richness. However, temperature was the strongest predictor of species richness, affecting species richness both directly and indirectly by positively influencing bee abundances. We observed higher levels of bee-flower-interactions at higher temperatures, independently of flower and bee abundances. This suggests that temperature restricts species richness by constraining the exploitation of resources by ectotherms. Current land use did not negatively affect species richness. We conclude that the richness of bees is explained by both temperature and resource availability, whereas temperature plays the dominant role as it limits the access of ectotherms to floral resources and may accelerate ecological and evolutionary processes that drive the maintenance and origination of diversity. Not only species numbers, but also morphological traits like body size are expected to be shaped by both physiological and energetic constraints along elevational gradients. Paradoxically, Bergmann´s rule predicts increases of body sizes in cooler climates resulting from physiological constraints, while species-energy theory suggests declines in the mean body size of species caused by increased extinction probabilities for large-bodied species in low-energy habitats. In chapter III we confronted this ambiguity with field data by studying community-wide body size variation of wild bees on Mt. Kilimanjaro. We found that along a 3680 m elevational gradient bee individuals became on average larger within species, while large species were increasingly absent from high-elevational communities. This demonstrates, on the one hand, how well-established, but apparently contrasting ecological theories can be merged through the parallel consideration of different levels of biological organization. On the other hand it signals that the extinction risk in the course of environmental change is not equally distributed among species within a community. Land use intensification is known to threaten biodiversity, but the consequences for ecosystem services are still a matter of debate. In chapter IV, we experimentally tested the single and combined contributions of pest predators and pollinators to coffee production along a land use intensification gradient on Mount Kilimanjaro. We found that pest predation increased fruit set by on average 9\%, while pollination increased fruit weight of coffee by on average 7.4\%. Land use had no significant effect on both ecosystem services. However, we found that in coffee plantations with most intensified land use, pollination services were virtually exclusively provided by the honey bee (Apis mellifera). The reliance on a single pollinator species is risky, as possible declines of that species may directly lower pollination services, resulting in yield losses. In contrast, pollination services in structurally complex homegardens were found to be provided by a diverse pollinator community, increasing the stability of pollination services in a long term. We showed that on Mount Kilimanjaro pollinator communities changed along elevational gradients in terms of species richness (chapter II) and trait composition (chapter III). Temperature and the temperature-mediated accessibility of resources were identified as important predictors of these patterns, which contributes to our fundamental understanding about the factors that shape ectothermic insect communities along climatic gradients. The strong temperature-dependence of pollinators suggests that temperature shifts in the course of global change are likely to affect pollinator communities. Pollinators might either profit from rising temperatures, or shift to higher elevations, which could result in related biotic attrition in the lowland with consequences for the provision of ecosystem services in cropping systems. Up to now, land use intensification had no significant impact on the diversity of pollinator communities and their ecosystem services. Pollinators might profit from the strong landscape heterogeneity in the region and from the amount of flower resources in the understory of cropping systems. However,progressing homogenization of the landscape and the pronounced application of pesticides could result in reduced diversity and dominance of single species, as we already found in sun coffee plantations. Such shifts in community compositions could threaten the stability of ecosystem services within cropping and natural systems in a long term.},
  subject      = {Kilimandscharo},
  language  = {en}
}
@phdthesis{Kindeketa2014,
  author    = {Kindeketa, William Joseph},
  title     = {Pollination in wild plant communities along altitudinal and land use gradients Mount Kilimanjaro, Tanzania},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-100136},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {1. Pollination of sexually reproducing plants requires pollen transfer agents, which can be biotic, abiotic or a combination of biotic and abiotic agents. The dominance of one of pollination system in wild plant communities depends on climatic factors and/or degrees of anthropogenic influences, which have effects on pollinator diversity and pollination function. Anthropogenic activities and climate change are also considered as main causes of ongoing invasion of invasive species into wild and managed habitats which can bring up competition for pollinators with possible negative consequences for the reproduction of co-occurring native plant species. 2. The study aimed to determine pollination systems and pollination limitation of invasive and native plant communities in natural savannah between 870 - 1130 m and semi-natural (managed) grassland between 1300 - 1750 m above sea level; effects of flower density and pollinator abundance on seed production of cross-pollinated and self-pollinated plants; and relationships of bee abundance and the proportion of cross- pollinated plants at the southern slope of Mount Kilimanjaro, Tanzania. 3. Pollinator-exclusion, open pollination and supplemental hand-pollination treatments were applied to 27 plant species in savannah and grassland habitats. Flowers were counted in each clusters based upon their species. Pollinators were sampled by using pan traps. Information-theory-based multi-model averaging and generalized linear mixed effects models were used to identify and analyze the effects of flower density, pollinator abundance, pollination treatments and habitat types on seed production. Regression models were used to determine relationships of altitude with bee abundance, and with proportion of cross-pollinated plants. 4. My results show that mean seed numbers of native plants were significantly lower in pollinator-exclusion treatments than in open-pollination treatments, indicating their reliance on pollinators for reproductive success. In contrast, seed numbers of invasive plants were similar in pollinator-exclusion and open-pollination treatments, demonstrating an ability of reproduction without pollinators. Despite of higher levels of self-pollination in invasive plants, supplemental hand-pollination treatments revealed pollen limitation in grassland and marginally in savannah habitats. There were no significant difference in seed numbers between supplemental hand pollination and open pollination treatments of native plant communities in savannah and grassland, which indicates no pollination limitation in the studied ecological system for native communities. Besides, grassland plants produced comparatively more seeds than savannah plants, however seeds in grasslands were lighter than those of the savannah which may be due to nutrient limitation in grassland. 5. I found 12 cross-pollinated and 15 self-pollinated plants along altitudinal gradient after comparing seeds from pollinator-excluded and open-pollinated experiments. I also found that proportions of cross-pollinated plants and bee abundance simultaneously decreased with increasing altitude. All cross-pollinated plants were native and grew in savannah habitats, with an exception of one species. 6. Neither effects of focal flower density nor a significant interaction between focal flower densities and bee abundance for self-pollinated plants were observed. However, there were effects of focal flower densities and interactions of flower density with bee abundance for cross-pollinated plants. Non-focal flower density has no significant effects on seed production of cross-pollinated and self-pollinated plants. 7. The results show that native plants depend more on cross-pollination than invasive plants, despite of most native plants in managed habitat (grassland) rely on self-pollination for reproduction. The tendency of having more cross-pollinated plants in natural savannah which are in low altitude coincides with other finding that the cross-pollinated plants and bee abundance simultaneously decrease with increasing altitude. Therefore, our findings support the hypotheses that self-fertilization of flowering plants increases with increasing altitude, and pollinator limitation is most pronounced in managed or disturbed habitats. Despite of reduction of pollinators in grassland, only invasive plants experience pollen limitation, which may be due to poor integration with available pollinator networks. 8. I also found bee abundance and flower density are not the main pollination factors required by self-pollinated plants during reproduction. However, focal flower density, which influences pollinator diversity, is more applicable to cross-pollinated plants. Climate change and anthropogenic activities in natural habitats are factors that influence pollinator abundance and functioning, which lead to a shift of mating systems in plant communities so as to assure their reproduction.},
  subject      = {Best{\"a}ubungs{\"o}kologie},
  language  = {en}
}
@phdthesis{Fackler2014,
  author    = {Fackler, Marc},
  title     = {Biochemical characterization of GAS2L3, a target gene of the DREAM complex},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-103394},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {GAS2L3 was identified recently as a target gene of the DREAM complex (Reichert et al., 2010; Wolter et al., 2012). It was shown that GAS2L3 is expressed in a cell cycle specific manner and that depletion of the protein leads to defects in cytokinesis and genomic instability (Wolter et al., 2012). Major aim of this thesis was, to further characterize the biochemical properties and physiological function of GAS2L3. By in vitro co-sedimentation and bundling assays, GAS2L3 was identified as a cytoskeleton associated protein which bundles, binds and crosslinks F-actin and MTs. GST pulldown assays and co-immunoprecipitation experiments revealed that GAS2L3 interacts in vitro and in vivo with the chromosomal passenger complex (CPC), a very important regulator of mitosis and cytokinesis, and that the interaction is mediated by the GAR domain of GAS2L3 and the C-terminal part of Borealin and the N-terminal part of Survivin. Kinase assays showed that GAS2L3 is not a substrate of the CPC but is strongly phosphorylated by CDK1 in vitro. Depletion of GAS2L3 by shRNA influenced protein stability and activity of the CPC. However pharmacological studies showed that the decreased CPC activity is not responsible for the observed cytokinesis defects upon GAS2L3 depletion. Immunofluorescence experiments revealed that GAS2L3 is localized to the constriction zone by the CPC in a GAR dependent manner and that the GAR domain is important for proper protein function. New interacting proteins of GAS2L3 were identified by stable isotope labelling by amino acids in cell culture (SILAC) in combination with tandem affinity purification and subsequent mass spectrometrical analysis. Co-immunoprecipitation experiments further confirmed the obtained mass spectrometrical data. To address the physiological function of GAS2L3 in vivo, a conditional and a non-conditional knockout mouse strain was established. The non-conditional mouse strain showed a highly increased mortality rate before weaning age probably due to heart failure. The physiological function of GAS2L3 in vivo as well as the exact reason for the observed heart phenotype is not known at the moment.},
  subject      = {Zellzyklus},
  language  = {en}
}
@phdthesis{Andronic2014,
  author    = {Andronic, Joseph},
  title     = {Volumenregulatorische Transportwege von anorganischen und organischen Osmolyten in S{\"a}ugetierzellen},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-103255},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {Die Aufrechterhaltung des Zellvolumens unter variablen osmotischen Bedingungen stellt f{\"u}r nahezu alle tierischen Zellen eine essenzielle Aufgabe dar. Um regulatorische Volumenanpassungen vorzunehmen besitzen sie daher effektive Mechanismen, mit deren Hilfe der zellul{\"a}re Gehalt an organischen und anorganischen Osmolyten erh{\"o}ht (= regulatorische Volumenzunahme; RVI) oder gesenkt (= regulatorische Volumenabnahme; RVD) werden kann. Trotz langj{\"a}hriger Forschung auf diesem Gebiet konnten die hieran beteiligten Transportwege f{\"u}r Osmolyte bisher nur unvollst{\"a}ndig aufgekl{\"a}rt werden. Insbesondere bei T-Lymphozyten sind wichtige Zellfunktionen wie die Proliferation, Migration und die T-Zell-Aktivierung eng mit volumenregulatorischen Mechanismen verbunden. Bei all diesen Prozessen sind u. a. unterschiedliche Kaliumkan{\"a}le beteiligt, die insbesondere f{\"u}r die pharmakologische Manipulation von Immunsystemprozessen von wissenschaftlichem Interesse sind. Bisherige Modelle der hypotonen Volumenregulation von T-Lymphozyten ber{\"u}cksichtigen lediglich den spannungsabh{\"a}ngigen KV1.3 sowie den Ca2+-aktivierten IKCa1-Kanal, die zur Klasse der 6TM/P-K+-Kan{\"a}le geh{\"o}ren. Im ersten Teil der vorliegenden Arbeit wurde eine potentielle Rolle von k{\"u}rzlich entdeckten Zwei-Poren Dom{\"a}nen Kaliumkan{\"a}len (K2P) am RVD von murinen und humanen prim{\"a}ren CD4+-T-Lymphozyten untersucht. In einem kombinierten genetischen und pharmakologischen Ansatz mittels knockout-Tiermodellen und dem Einsatz kanalspezifischer Inhibitoren konnte mithilfe zellvolumetrischer Analysen gezeigt werden, dass die K2P-Vertreter TASK1, TASK2, TASK3 und TRESK maßgeblich am schwellungsaktivierten Efflux von K+ beteiligt sind. Beurteilt an den Ergebnissen dieser Untersuchung sind der spannungsabh{\"a}ngige TASK2- und der Ca2+-aktivierte TRESK-Kanal f{\"u}r die hypotone Volumenregulation in T-Zellen deutlich bedeutender als TASK1 und TASK3. Der Beitrag der Kan{\"a}le TASK2 und TRESK am RVD-Prozess war {\"u}ber dies vergleichbar mit dessen des bisher bekannten KV1.3-Kanals. In dieser Arbeit wurde damit erstmals eine Beteiligung der K2P-Kan{\"a}le am RVD muriner und humaner CD4+-Lymphozyten identifiziert. Aufgrund der engen Verbindung zwischen T-Zell-Funktion und der Volumenregulation k{\"o}nnen Zwei-Poren Dom{\"a}nen K+-Kan{\"a}le damit in den engeren Kreis potentieller immunmodulierende Angriffspunkte aufgefasst werden. Im zweiten und umfangreicheren Teil dieser Arbeit wurden dar{\"u}ber hinaus die schwellungsaktivierten Transportwege f{\"u}r organische Osmolyte (small organic osmolytes; SOOs) untersucht. SOOs stellen chemisch inerte Verbindungen dar, zu denen vor allem Polyole (Sorbitol, myo-Inositol), Methylamine (Betain, α-Glycerophosphocholin) sowie Aminos{\"a}uren (α- bzw. β-Alanin und Prolin) und deren Derivate (Taurin) z{\"a}hlen. Da SOOs weder die zellul{\"a}re Struktur noch die Funktion von Makromolek{\"u}len beeintr{\"a}chtigen, sind sie wichtige Instrumente der Volumenregulation, die sich in hohen Konzentrationen im Zytosol nahezu aller Zellen wiederfinden. Werden tierische Zellen mit hypotonen Bedingungen konfrontiert, dann ist bei nahezu allen Zellen die Freisetzung organischer Osmolyte zu beobachten, wodurch die zellul{\"a}re Osmolarit{\"a}t unabh{\"a}ngig von Elektrolyten angepasst werden kann. Trotz der wichtigen Funktion der SOOs in der Osmoregulation tierischer Zellen konnte die molekulare Identit{\"a}t beteiligter Effluxwege (Kan{\"a}le bzw. Transporter) bisher nicht aufgekl{\"a}rt werden. Ungeachtet der molekularen Identit{\"a}t der SOO-Effluxwege war es aus zahlreichen biotechnologischen Anwendungen zu Beginn dieser Arbeit bekannt, dass die schwellungsaktivierten Transportwege f{\"u}r organische Osmolyte eine gr{\"o}ßenselektive Permeabilit{\"a}t f{\"u}r eine Reihe monomerer Zucker und verwandter Verbindungen aufweisen. Um diese Gr{\"o}ßenselektivit{\"a}t n{\"a}her zu charakterisieren, wurde im ersten Schritt die schwellungsaktivierte Membranpermeabilit{\"a}t f{\"u}r eine Reihe strukturell homogener Polyethylenglykole unterschiedlicher Polymerl{\"a}nge (PEG200-1500; hydrodynamische Radien zwischen ~0,5-1,5 nm) unter iso- und hypotonen Bedingungen in Jurkat-Lymphozyten untersucht. Unter milden hypotonen Bedingungen (200 mOsm) war die Plasmamembran der untersuchten Lymphozyten f{\"u}r PEG300-1500 undurchl{\"a}ssig, was aus der F{\"a}higkeit der Zellen zur hypotonen Volumenregulation geschlossen werden konnte. Dar{\"u}ber hinaus wurde RVD in stark hypotonen L{\"o}sungen (100 mOsm) mit PEG600-1500 beobachtet, w{\"a}hrend PEG300-400 unter vergleichbaren osmotischen Bedingungen die Volumenregulation der Zellen inhibierten. Dieses Ergebnis deutet darauf hin, dass starkes hypotones Zellschwellen der Lymphozyten zur Permeabilisierung der Plasmamembran f{\"u}r PEG300-400, nicht jedoch f{\"u}r PEG600-1500, f{\"u}hrt. Anhand der hydrodynamischen Radien Rh der verwendeten PEGs konnte ein cutoff-Radius von ~0,74 nm f{\"u}r schwellungsaktivierte Transportwege organischer Osmolyte bestimmt werden. Da diese schwellungsaktivierten Transportwege vielf{\"a}ltig f{\"u}r Zellbeladungstechniken verwendet werden, k{\"o}nnte dieses Ergebnis f{\"u}r zahlreiche biotechnologische und biomedizinische Anwendungen von Interesse sein. Im zweiten Schritt wurde der Versuch unternommen, potentielle Transportwege f{\"u}r organische Osmolyte im RVD-Prozess molekular zu identifizieren. Da es grundlegend ungekl{\"a}rt war, wie viele unterschiedliche Transporter bzw. Kan{\"a}le am Efflux der zahlreichen organischen Osmolyte beteiligt sind, erfolgte zun{\"a}chst die vergleichende Analyse des schwellungsaktivierten Membrantransports strukturell verschiedener SOOs einschließlich der Aminosulfons{\"a}ure Taurin und des Polyols myo-Inositol. Hierbei wurde erstmals gezeigt, dass die schwellungsaktivierten Transportwege f{\"u}r Taurin und myo-Inositol deutlich unterschiedliche Aktivit{\"a}tsprofile aufweisen. W{\"a}hrend der Taurintransport bereits unter milden hypotonen Bedingungen, d.h. nach einer geringen Absenkung der Osmolalit{\"a}t von 300 auf ~230 mOsm, aktiviert wurde, erfolgte die Aktivierung der Membranpermeabilit{\"a}t f{\"u}r myo-Inositol bei einer viel niedrigeren Osmolalit{\"a}t von ~150 mOsm. Dar{\"u}ber hinaus wiesen die beiden Transportwege unter vergleichbarem hypotonen Stress von 100 mOsm deutlich unterschiedliche Aktivit{\"a}tsdauern auf (Transport von Taurin ~95 min und myo-Inositol ~40 min). Somit deuteten diese Ergebnisse erstmals auf substrat-spezifische Transportwege f{\"u}r SOOs hin, die voneinander stark abweichende osmotische Aktivierungsprofile besitzen. Als aussichtsreiche Kandidaten f{\"u}r diese Transportwege wurden zwei Mitglieder der Gruppe der Solute Carrier (SLC) untersucht, die klare {\"U}bereinstimmungen mit den gesuchten Transportern f{\"u}r SOOs aufweisen. Daher wurde im Weiteren eine RVD-Beteiligung dieser Transportergruppe mit einer Kombination aus molekularbiologischer und konventioneller bzw. hochaufgel{\"o}ster mikroskopischen Techniken {\"u}berpr{\"u}ft. Die semiqantitativen RT-PCR-Ergebnisse dieser Arbeit zeigen dabei, dass die Gentranskription der potentiellen SOO-Transporter SLC5A3 und SLC6A6 in den untersuchten Zelllinien Jurkat, HEK wie auch HepG2-Zellen durch hypotone Bedingungen deutlich verst{\"a}rkt wird. Hierbei nimmt der zellul{\"a}re mRNA-Gehalt der Gene SLC5A3 zwischen 20-60\% und SLC6A6 um 30-100\% innerhalb von 10-20 min zu, was auf eine potentielle RVD-Beteiligung von SLC-Transportern hindeutet. Ausgehend von diesem Ergebnis wurde daraufhin die zellul{\"a}re Lokalisation des SLC5A3-Transporters unter isotonen und hypotonen Bedingungen mikroskopisch untersucht. Wie anhand der konfokalen lasermikroskopischen Untersuchung zu erkennen ist, findet unter hypotoner Stimulation eine zellul{\"a}re Umverteilung des mit EGFP fluoreszenzmarkierten Proteins SLC5A3 statt. Innerhalb von 10 min wird der Transporter dabei von intrazellul{\"a}ren Regionen in Richtung Plasmamembran verlagert. Dar{\"u}ber hinaus konnte mit Hilfe der hochaufl{\"o}senden Mikroskopie-Technik dSTORM gezeigt werden, dass der Transporter SLC5A3 unter hypotoner Stimulation verst{\"a}rkt mit der Plasmamembran assoziiert vorliegt. Diese verst{\"a}rkte Membranassoziation des SLC5A3-Proteins deutet damit auf einen schwellungsinduzierten exozytotischen Einbau des Transporters hin. Die Ergebnisse dieser Arbeit zeigen damit erstmals, dass SLC-Transporter wie SLC5A3, SLC6A6 und vermutlich andere Vertreter der SLC-Superfamilie potentiell am Mechanismus der hypotonen Volumenregulation beteiligt sind. Da SLC-Transporter als wichtige Transportsysteme f{\"u}r Therapeutika angesehen werden und die Mechanismen der Volumenregulation bereits in zahlreichen biotechnologischen Anwendungen implementiert sind, k{\"o}nnte der hier aufgedeckte Zusammenhang einen Erkenntnisgewinn f{\"u}r zahlreiche biomedizinische Forschungsgebiete darstellen.},
  subject      = {S{\"a}ugetiere},
  language  = {de}
}
@phdthesis{Loeschberger2014,
  author    = {L{\"o}schberger, Anna},
  title     = {Biologische Referenzstrukturen und Protokolloptimierung in der hochaufl{\"o}senden Fluoreszenzmikroskopie mit dSTORM},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-102630},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {Die Lokalisationsmikroskopie ist eine neue, vielversprechende Methode der hochaufl{\"o}senden Fluoreszenzmikroskopie. Sie erm{\"o}glicht detaillierte Einblicke in die Organisation und den strukturellen Aufbau von Zellen. Da die Vorbereitung der Proben und das Aufnehmen der Bilder im Vergleich zu herk{\"o}mmlichen Methoden h{\"o}here Anforderungen stellt, mussten ihr Potential und ihre Zuverl{\"a}ssigkeit erst noch {\"u}berzeugend gezeigt werden. Bis vor kurzem wurde das Aufl{\"o}sungsverm{\"o}gen vor allem an Mikrotubuli gezeigt, deren filament{\"o}se Struktur allerdings schon in konfokalen Bildern zu erkennen ist. Deswegen wurde in dieser Dissertation der Kernporenkomplex (NPC), dessen Struktur in der konventionellen Fluoreszenzmikroskopie nicht aufl{\"o}sbar ist, als Modellstruktur f{\"u}r die hochaufl{\"o}sende Fluoreszenzmikroskopie eingef{\"u}hrt. Dazu wurden Kernporenkomplexe aus Kernh{\"u}llen von Xenopus laevis Oocyten mit dSTORM (direct stochastic optical reconstruction microscopy), einer Methode der Lokalisationsmikroskopie, hochaufgel{\"o}st. Damit konnte nun erstmals die Achtfachsymmetrie dieses Proteinkomplexes lichtmikroskopisch dargestellt werden. Desweiteren konnte der Zentralkanal mit einem Durchmesser von ca. 40 nm aufgel{\"o}st werden. Die Daten eigneten sich außerdem f{\"u}r eine automatisierte Bildanalyse nach dem sogenannten "particle averaging" - einer aus der Elektronenmikroskopie bekannten Methode, um eine Durchschnittsstruktur zu ermitteln. Dar{\"u}ber hinaus wurden Zweifach-F{\"a}rbungen von NPCs benutzt, um verschiedene Ans{\"a}tze f{\"u}r Zweifarben-Aufnahmen mit dSTORM zu testen. Neben dem mittlerweile standardm{\"a}ßig benutzten, sequentiellen Ansatz mit zwei spektral getrennten Farbstoffen, wurde auch ein simultaner Ansatz mit zwei spektral {\"u}berlappenden Farbstoffen erfolgreich angewandt. Auch f{\"u}r 3D-Messungen mit den Ans{\"a}tzen Biplane und Astigmatismus eignete sich die Markierung der Kernh{\"u}lle. Hier wurden jedoch A6-Zellen benutzt und die Kr{\"u}mmung des Zellkerns {\"u}ber die gef{\"a}rbten Kernporen dargestellt. dSTORM-Messungen k{\"o}nnen nicht nur an fixierten, sondern auch in lebenden Zellen durchgef{\"u}hrt werden. Hierzu eignen sich vor allem sehr immobile Proteine, wie H2B oder Lamin C. Anhand von SNAP-Tag- und Halo-Tag-Konstrukten konnte gezeigt werden, dass sich kommerziell erh{\"a}ltliche, organische Farbstoffe auch in endogener zellul{\"a}rer Umgebung schalten lassen, wodurch Lebendzell-Aufnahmen mit dSTORM m{\"o}glich sind. Ein weiterer Teil dieser Arbeit befasst sich mit korrelativen Aufnahmen aus dSTORM und Rasterelektronenmikroskopie (SEM). Hierzu wurden Xenopus laevis Kernh{\"u}llen zuerst mit dSTORM hochaufgel{\"o}st und danach f{\"u}r die EM pr{\"a}pariert. Anschließend wurden zugeh{\"o}rige Bereiche am Rasterelektronenmikroskop aufgenommen. Mit den erhaltenen korrelativen Bildern konnte gezeigt werden, dass sich dSTORM und SEM bei geeigneten Proben durchaus kombinieren lassen. Proteine k{\"o}nnen somit spezifisch markiert und im Rahmen ihrer strukturellen Umgebung mit nahezu molekularer Aufl{\"o}sung dargestellt werden. Da hochwertige Aufnahmen eine ausgereifte Probenpr{\"a}paration voraussetzen, darf deren Etablierung nicht zu kurz kommen. Unter dieser Pr{\"a}misse wurde ein optimiertes Markierungsprotokoll mit dem Namen ClickOx entwickelt. Mit ClickOx bleibt bei der kupferkatalysierten Azid-Alkin-Cycloaddition die Feinstruktur von Aktinfilamenten, sowie die Fluoreszenz fluoreszierender Proteine, deutlich sichtbar erhalten. W{\"a}hrend bei den klassischen Click-Protokollen auf Grund der Entstehung von reaktiven Sauerstoff-Spezies (ROS) feine zellul{\"a}re Strukturen, wie Aktinfilamente, angegriffen oder zerst{\"o}rt werden, sch{\"u}tzt das neue Protokoll mit enzymatischem Sauerstoffentzug Proteine und somit Strukturen vor Reaktionen mit ROS. Das unterstreicht, wie wichtig es ist auch sogenannte "etablierte" Protokolle weiterzuentwickeln, denn bestimmte Nebeneffekte in Pr{\"a}parationen werden unter Umst{\"a}nden erstmals in der Hochaufl{\"o}sung sichtbar. Ein weiterer Aspekt war die Untersuchung des Einflusses von D1 auf die Chromatinorganisation. Mit verschiedenen mikroskopischen Methoden konnten Hinweise auf eine m{\"o}gliche DNA-Cross-Linking-F{\"a}higkeit dieses Proteins gesammelt werden. Hier wurde die Einzelmolek{\"u}linformation der dSTORM-Filme genutzt, um unterschiedliche Grade von DNA- bzw. Chromatin-Akkumulation zu vergleichen. Die Ergebnisse deuten darauf hin, dass wildtypisches D1 DNA vernetzen kann. Dies erfolgt {\"u}ber die sogenannten AT-Haken-Motive. Sobald diese alle durch Mutation funktionsunf{\"a}hig gemacht werden - wie bei der verwendeten R10xG-Mutante - l{\"a}sst sich keine Akkumulation der DNA mehr beobachten. Neben der Chromatinaggregation durch D1-Expression konnte in FRAP-Experimenten gezeigt werden, dass nur die "echten" AT-Haken eine hohe Affinit{\"a}t zum Chromatin aufweisen, die sogenannten "potentiellen" hingegen nicht.},
  subject      = {Fluoreszenzmikroskopie},
  language  = {de}
}
@phdthesis{Ullrich2014,
  author    = {Ullrich, Melanie},
  title     = {Identification of SPRED2 as a Novel Regulator of Hypothalamic-Pituitary-Adrenal Axis Activity and of Body Homeostasis},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-107355},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {SPRED proteins are inhibitors of the Ras/ERK/MAPK signaling pathway, an evolutionary highly conserved and very widespread signaling cascade regulating cell proliferation, differentiation, and growth. To elucidate physiological consequences of SPRED2 deficiency, SPRED2 KO mice were generated by a gene trap approach. An initial phenotypical characterization of KO mice aged up to five months identified SPRED2 as a regulator of chondrocyte differentiation and bone growth. Here, the loss of SPRED2 leads to an augmented FGFR-dependent ERK activity, which in turn causes hypochondroplasia-like dwarfism. However, long term observations of older KO mice revealed a generally bad state of health and manifold further symptoms, including excessive grooming associated with severe self-inflicted wounds, an abnormally high water uptake, clear morphological signs of kidney deterioration, and a reduced survival due to sudden death. Based on these observations, the aim of this study was to discover an elicitor of this complex and versatile phenotype. The observed kidney degeneration in our SPRED2 KO mice was ascribed to hydronephrosis characterized by severe kidney atrophy and apoptosis of renal tubular cells. Kidney damage prompted us to analyze drinking behavior and routine serum parameters. Despite polydipsia, which was characterized by a nearly doubled daily water uptake, the significantly elevated Na+ and Cl- levels and the resulting serum hyperosmolality could not be compensated in SPRED2 KOs. Since salt and water balance is primarily under hormonal control of aldosterone and AVP, we analyzed both hormone levels. While serum AVP was similar in WTs and KOs, even after experimental water deprivation and an extreme loss of body fluid, serum aldosterone was doubled in SPRED2 KO mice. Systematic investigation of contributing upstream hormone axes demonstrated that hyperaldosteronism developed independently of an overactivated Renin-Angiotensin system as indicated by halved serum Ang II levels in KO mice. However, aldosterone synthase expression in the adrenal gland was substantially augmented. Serum corticosterone, which is like aldosterone released from the adrenal cortex, was more than doubled in SPRED2 KOs, too. Similar to corticosterone, the production of aldosterone is at least in part under control of pituitary ACTH, which is further regulated by upstream hypothalamic CRH release. In fact, stress hormone secretion from this complete hypothalamic-pituitary-adrenal axis was upregulated because serum ACTH, the mid acting pituitary hormone, and hypothalamic CRH, the upstream hormonal inductor of HPA axis activity, were also elevated by 30\% in SPRED2 KO mice. This was accompanied by an upregulated ERK activity in paraventricular nucleus-containing hypothalamic brain regions and by augmented hypothalamic CRH mRNA levels in our SPRED2 KO mice. In vitro studies using the hypothalamic cell line mHypoE-44 further demonstrated that both SPRED1 and SPRED2 were able to downregulate CRH promoter activity, CRH secretion, and Ets factor-dependent CRH transcription. This was in line with the presence of various Ets factor binding sites in the CRH promoter region, especially for Ets1. Thus, this study shows for the first time that SPRED2-dependent inhibition of Ras/ERK/MAPK signaling by suppression of ERK activity leads to a downregulation of Ets1 factor-dependent transcription, which further results in inhibition of CRH promoter activity, CRH transcription, and CRH release from the hypothalamus. The consecutive hyperactivity of the complete HPA axis in our SPRED2 KO mice reflects an elevated endogenous stress response becoming manifest by excessive grooming behavior and self-inflicted skin lesions on the one hand; on the other hand, in combination with elevated aldosterone synthase expression, this upregulated HPA hormone release explains hyperaldosteronism and the associated salt and water imbalances. Both hyperaldosteronism and polydipsia very likely contribute further to the observed kidney damage. Taken together, this study initially demonstrates that SPRED2 is essential for the appropriate regulation of HPA axis activity and of body homeostasis. To further enlighten and compare consequences of SPRED2 deficiency in mice and particularly in humans, two follow-up studies investigating SPRED2 function especially in heart and brain, and a genetic screen to identify human SPRED2 loss-of-function mutations are already in progress.},
  subject      = {Renin-Angiotensin-System},
  language  = {en}
}
@phdthesis{Riedinger2014,
  author    = {Riedinger, Verena},
  title     = {Landscape-scale spillover of pollinators from oil-seed rape to crop and semi-natural habitats on different temporal scales},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-96844},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {Organisms use different resources in different habitat types during their life cycle. Thereby, they connect habitats and provide ecosystem services or disservices in several habitat types. In agricultural landscapes, the spillover of organisms, i.e. movement of an organism and its function from one habitat to another, especially from semi-natural to managed habitats, is one of the most important processes that influence population dynamics and community composition. Importantly, spillover connects habitats not only spatially, but also on different temporal scales, because availability of resources changes over time in agricultural landscapes, e.g. by mass-flowering events of crops, harvesting or crop rotation. Most often, semi-natural habitats are seen as beneficial source of organisms, but also managed habitats can provide valuable resources, and thereby initiate spillover to other habitats. Mass-flowering crops, like oil-seed rape, are such valuable feeding resources for pollinators, and pollinators might spillover from oil-seed rape to other habitats which provide alternative foraging resources. The focus of this dissertation was to evaluate the influence of oil-seed rape on pollinators in agricultural landscapes by studying effects (1) on different temporal scales (from effects during the flowering period of oil-seed rape, Chapter II \& IV, to intermediate effects on a second mass-flowering crop, Chapter III, to spillover effects to the flowering period in the next year, Chapter IV), (2) semi-natural (Chapter II) and crop (Chapter III, IV) habitats, and (3) on various pollinator groups which differ in their life cycle (Chapter II, III, IV). In this dissertation effects from oil-seed rape on all temporal scales - in the short term during mass-flowering and in the long term on a late-flowering crop and even in the next year on oil-seed rape fields ─ were found. These effects might be important for crop and wild plant pollination, and pollinator conservation. Importantly, the effects on different temporal scales depend on the considered habitat (managed or different semi-natural habitats) and on the investigated pollinator group. The more pollinators match the flowering period of oil-seed rape in their activity period and the more dependent they are on flowering resources in their life cycle, the more pronounced are their responses. Effects were found for wild bees, but not for hoverflies and honey bees. Moreover, the availability of semi-natural habitats in the landscape is important and may modulate effects from oil-seed rape. The longevity of effects of oil-seed rape shows the importance of including several temporal scales into ecosystem-service studies, not only for pollinators, but also for other ecosystem-service providing species groups.},
  subject      = {Raps},
  language  = {en}
}
@phdthesis{Wende2014,
  author    = {Wende, Beate},
  title     = {Diversity of saproxylic beetles and host tree specialisation in differently managed forests across Germany},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-107049},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {Chapter I The gradual turnover of dead organic material into mineral nutrients is a key ecological function, linking decomposition and primary production, the essential parts of the nutrient-energy cycle. However, disturbances in terms of species or resource losses might impair the equilibrium between production and decomposition. Humanity has converted large proportions of natural landscapes and intensified land-use activity for food production. Globally, only very few areas are totally unaffected by human activity today. To ensure the maintenance of both essential ecosystem services, knowledge about the interplay of biodiversity and ecosystem functioning as well as effects of intensified management on both is crucial. The vast majority of terrestrial biomass production as well as decomposition take place in forest ecosystems. Though forestry has a long sustainable history in Europe, its intensification during the last century has caused severe impacts on forest features and, consequently, on the associated biota, especially deadwood dependent organisms. Among these, saproxylic beetles are the most diverse group in terms of species numbers and functional diversity, but also most endangered due to habitat loss. These features classify them as ideal research organisms to study effects of intensified forestry on ecosystem services. The BELONGDEAD project located in Germany aimed to investigate deadwood decay and functional consequences of diversity changes in the associated fauna on the decomposition process from the initialisation of deadwood decay to complete degradation. As part of the BeLongDead project, this dissertation focussed on saproxylic beetle species, thereby evaluating (1) regionally effects of tree species identity of fresh deadwood and (2) forest management of varying intensities on the diversity, abundance and community composition of saproxylic beetles (chapter II); (3) the specialisation degree of different trophic guilds of saproxylic beetles, and thus the stability and robustness of their interaction networks against disturbances (chapter III); (4) the impact of environmental features of local to regional spatial scales on species richness of saproxylic beetles differing in their habitat niche in terms of deadwood decay stages (chapter IV). Chapter II The vast majority of European forest ecosystems have been anthropogenically affected, leaving less than 1\% of the about 1 milliard hectare as natural forests. A long history of forestry and especially the technological progress during the last century have caused massive habitat fragmentation as well as substantial loss of essential resources in European forest ecosystems. Due to this, the substrate-dependent group of saproxylic beetles has experienced severe species losses. Thus, investigations concerning saproxylic diversity and deadwood volume were badly needed. However, the importance of different deadwood in terms of tree species identity for the colonization by saproxylic beetles under different local and regional management regimes is poorly understood. Therefore, we studied possible regional differences in colonization patterns of saproxylic beetle species in a total of 688 fresh deadwood logs of 13 tree species in 9 sites of managed conifer and beech forests, and unmanaged beech forests, respectively. We found that tree species identity was an important driver in determining saproxylic species composition and abundance within fresh deadwood. However, saproxylic species showed different colonization patterns of deadwood items of the same tree species among the study regions. Regionally consistent, conifer forests were most diverse. We attribute the latter result to the historically adaption of saproxylic beetle species to semi-open forests, which conditions are actually best reflected by conifer forests. To preserve a diverse local species pool of early successional saproxylic beetles, we suggest an equal high degree of deadwood diversity in a tree species context in due consideration of regional differences. Chapter III The extinction risk of a particular species corresponds with its species-specific requirements on resources and habitat conditions, in other words with the width of the species` ecological niche. Species with a narrow ecological niche are defined as specialists. Members of this group experience higher extinction risk by resource limitation than generalists, which are able to utilize a variety of resources. For the classification of species as specialists or generalists, thus evaluating possible extinction risks, ecologists use the concept of interaction networks. This method has often been applied for mutualistic or antagonistic plant-animal interactions, but information for networks of detritivores is scarce. Therefore, saproxylic beetle species sampled as described in chapter II were categorised according to their larval diet; additionally their interaction networks (N=108) with 13 dead host tree species were analysed. Specialisation degree was highest for wood-digesting beetles and decreased with increasing trophic level. Also the network indices evaluating robustness and generality indicated a higher susceptibility to species extinctions for xylophagous than for mycetophagous and predatory beetles. The specialisation of xylophagous species on specific tree species might be an adaption to tree species specific ingredients stored for defence against pathogens and pests. However, we conclude that the high specialisation degree of xylophages and thus their higher extinction risk by resource loss harbours certain dangers for ecosystem function and stability as species diversity is positively linked to both. Chapter IV Populations depend on individual emigration and immigration events to ensure genetic exchange. For successful migration it is of utmost importance that spatially separated populations are obtainable by specimen. Migratory success depends on the one hand on the species dispersal abilities and on the other on the availability of suitable habitats in the surrounding landscape in which the distinct host populations exist. However, consequences of intensive forest management correspond not only to severe reduction of local deadwood amount, but, among others, also a change in tree species composition and high levels of fragmentation in the surrounding forest area. Saproxylic beetle species differ in their dispersal behaviour according to the temporal availability of their preferred habitat. Generally, early successional saproxylic beetles are able to disperse over large distances, whereas beetles inhabiting advanced decayed wood often remain close to their larval habitat. Due to this, environmental factors might affect saproxylic beetle guilds differently. We classified the saproxylic beetles sampled as described in chapter II according to their calculated habitat niche as early, intermediate or late successional saproxylic beetles. For the different guilds the effects of 14 environmental factors on different spatial scales (stand factors at 0.1 km radius, landscape composition at 2 km radius, and regionally differing abiotic factors in 400 km to 700 km distance) were investigated. Consistently for all guilds, species richness decreased with fragmentation at local and landscape scale, and increased in warmer climate. However, we found contradictory results between the guilds to some extent. We relate this to guild specific habitat requirements of the saproxylic beetles. Therefore, for the development of appropriate conservation practices guild-specific requirements saproxylic beetles have to be considered not only locally but on larger spatial scales. Chapter V In conclusion, this dissertation identified main drivers of early successional saproxylic beetle species richness on various spatial scales. Our results emphasize the importance to develop management schemes meeting species-specific and guild-specific habitat requirements of the saproxylic beetle fauna at relevant spatial and temporal scales. Therefore, short-term actions suggested for sustainable forest management should be the focus on a diverse tree species composition consisting of indigenous tree species with respect to regional differences. Moreover, senescent trees, fallen and standing deadwood should remain in the forests, and some tree individuals should be allowed to grow old. Long-term actions should involve the reduction of forest fragmentation and the connection of spatial widely separated forest fragments. Furthermore, to fully understand the effects of forest management long-term research should be conducted to compare habitat requirements of intermediate and late successional beetles with the results presented in this dissertation.},
  subject      = {Saproxylophage},
  language  = {en}
}
@phdthesis{Kirscher2014,
  author    = {Kirscher, Lorenz},
  title     = {Melanogene rekombinante Vaccinia-Viren als diagnostisches und therapeutisches Agenz zur Tumorbehandlung},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112074},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {Die g{\"a}ngigen therapeutischen Behandlungsmethoden f{\"u}r die verschiedensten Krebserkrankungen zeigen nach wie vor M{\"a}ngel bez{\"u}glich der Effizienz sowie zahlreiche Nebenwirkungen w{\"a}hrend und nach der Behandlung. Maßgeblich f{\"u}r diese Defizite ist die teilweise geringe Sensitivit{\"a}t der meisten konventionellen diagnostischen Systeme und damit einhergehend die oftmals zu sp{\"a}te Identifikation entarteter Gewebsbereiche. Zur L{\"o}sung dieser Problematik bieten onkolytische Vaccinia-Viren einen Ansatz, sowohl die Effizienz der Therapie wie auch die Diagnostik zu verbessern. In beiden F{\"a}llen sind die Tumorzell-spezifische Vermehrung der Viren und die M{\"o}glichkeit entscheidend, die Viren als Vektorsystem zur Expression therapeutischer oder diagnostischer Fremdgenkassetten zu nutzen. Um ein auf Vaccinia-Virus-basierendes Reportersystem zum diagnostischen Nachweis von Krebszellen mittels Tiefengewebs-Tomographie bereit zu stellen, wurden die f{\"u}r die murine Tyrosinase (mTyr) und das Tyrosinase-Helferprotein 1 (Tyrp1) kodierenden Gene in das Genom eines onkolytischen Vaccinia-Virus inseriert. Die Tyrosinase ist das Schl{\"u}sselenzym der Melaninsynthese. Bereits die solit{\"a}re Expression der Tyrosinase f{\"u}hrt in der transformierten Zelle zur Melaninproduktion. Das Tyrosinase-Helferprotein 1 ist an der Prozessierung und Stabilisierung der Tyrosinase beteiligt. Bereits in verschiedenen Studien konnte gezeigt werden, dass Melanin als Reportermolek{\"u}l f{\"u}r die Magnetresonanz sowie f{\"u}r die multispektrale optoakustische Tomographie einsetzbar ist. Es wurde deswegen angestrebt, die Kombination aus dem therapeutischen Potential des onkolytischen Vaccinia-Virus und der diagnostischen Anwendung des Melanins als Reporter auszunutzen. S{\"a}mtliche in dieser Arbeit aufgef{\"u}hrten rekombinanten Vaccinia-Viren (rVACV) wurden von der Firma Genelux Corporation zur Verf{\"u}gung gestellt und in dieser Arbeit hinsichtlich der therapeutischen Effizienz und des diagnostischen Potentials untersucht. In ersten Zellkultur-Versuchen wurde anhand verschiedener konstitutiv melanogener rVACV-Konstrukte festgestellt, dass die Kombination aus dem Vaccinia-Virus-spezifischen synthetic early/late Promotor und dem Enzym Tyrosinase (GLV-1h327) bzw. den Enzymen Tyrosinase und Tyrosinase-Helferprotein 1 (GLV-1h324) die h{\"o}chste Melaninsynthese-Rate zeigte. Anschließend wurde mittels der Bestimmung der spektralen Absorption und der Enzymaktivit{\"a}t der viral kodierten Melanin synthetisierenden Enzyme sowie mikroskopischer Analysen gezeigt, dass es mit diesen auf 8 Vaccinia-Virus-basierenden melanogenen Reportersystemen m{\"o}glich ist, die Melaninsynthese in nicht-melanogenen Zellen zu induzieren. Anhand elektronenmikroskopischer Untersuchungen in Zellkultur und ex vivo konnte gezeigt werden, dass die nach rVACV-Infektion stattfindende Melaninsynthese in den Lysosomen der Wirtszelle abl{\"a}uft. Eine Analyse der atomaren Zusammensetzung des viral vermittelten Melanins ergab, dass es sich um eine Mischform aus Eu- und Ph{\"a}omelanin handelt. Dieser Melanin-Mix {\"a}hnelte dem Melanin aus Haut und Augen, jedoch lagen an Melanin-gebundene Metallionen in erh{\"o}htem Maß vor...},
  subject      = {Melanin},
  language  = {de}
}
@phdthesis{LuiblneeHermann2014,
  author    = {Luibl [n{\´e}e Hermann], Christiane},
  title     = {The role of the neuropeptides NPF, sNPF, ITP and PDF in the circadian clock of Drosophila melanogaster},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-93796},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {Organisms have evolved endogenous clocks which allow them to organize their behavior, metabolism and physiology according to the periodically changing environmental conditions on earth. Biological rhythms that are synchronized to daily changes in environment are governed by the so-called circadian clock. Since decades, chronobiologists have been investigating circadian clocks in various model organisms including the fruitfly Drosophila melanogaster, which was used in the present thesis. Anatomically, the circadian clock of the fruitfly consists of about 150 neurons in the lateral and dorsal protocerebrum, which are characterized by their position, morphology and neurochemistry. Some of these neurons had been previously shown to contain either one or several neuropeptides, which are thought to be the main signaling molecules used by the clock. The best investigated of these neuropeptides is the Pigment Dispersing Factor (PDF), which had been shown to constitute a synchronizing signal between clock neurons as well as an output factor of the clock. In collaboration with various coworkers, I investigated the roles of three other clock expressed neuropeptides for the generation of behavioral rhythms and the partly published, partly unpublished data are presented in this thesis. Thereby, I focused on the Neuropeptide F (NPF), short Neuropeptide F (sNPF) and the Ion Transport Peptide (ITP). We show that part of the neuropeptide composition within the clock network seems to be conserved among different Drosophila species. However, the PDF expression pattern in certain neurons varied in species deriving from lower latitudes compared to higher latitudes. Together with findings on the behavioral level provided by other people, these data suggest that different species may have altered certain properties of their clocks - like the neuropeptide expression in certain neurons - in order to adapt their behavior to different habitats. We then investigated locomotor rhythms in Drosophila melanogaster flies, in which neuropeptide circuits were genetically manipulated either by cell ablation or RNA interference (RNAi). We found that none of the investigated neuropeptides seems to be of equal importance for circadian locomotor rhythms as PDF. PDF had been previously shown to be necessary for rhythm maintenance in constant darkness (DD) as well as for the generation of morning (M) activity and for the right phasing of the evening (E) activity in entrained conditions. We now demonstrate that NPF and ITP seem to promote E activity in entrained conditions, but are clearly not the only factors doing so. In addition, ITP seems to reduce nighttime activity. Further, ITP and possibly also sNPF constitute weak period shortening components in DD, thereby opposing the effect of PDF. However, neither NPF or ITP, nor sNPF seem to be necessary in the clock neurons for maintaining rhythmicity in DD. It had been previously suggested that PDF is released rhythmically from the dorsal projection terminals. Now we discovered a rhythm in ITP immunostaining in the dorsal projection terminals of the ITP+ clock neurons in LD, suggesting a rhythm in peptide release also in the case of ITP. Rhythmic release of both ITP and PDF seems to be important to maintain rhythmic behavior in DD, since constantly high levels of PDF and ITP in the dorsal protocerebrum lead to behavioral arrhythmicity. Applying live-imaging techniques we further demonstrate that sNPF acts in an inhibitory way on few clock neurons, including some that are also activated by PDF, suggesting that it acts as signaling molecule within the clock network and has opposing effects to PDF. NPF did only evoke very little inhibitory responses in very few clock neurons, suggesting that it might rather be used as a clock output factor. We were not able to apply the same live-imaging approach for the investigation of the clock neuron responsiveness to ITP, but overexpression of ITP with various driver lines showed that the peptide most likely acts mainly in clock output pathways rather than inter-clock neuron communication. Taking together, I conclude that all investigated peptides contribute to the control of locomotor rhythms in the fruitfly Drosophila melanogaster. However, this control is in most aspects dominated by the actions of PDF and rather only fine-tuned or complemented by the other peptides. I assume that there is a high complexity in spatial and temporal action of the different neuropeptides in order to ensure correct signal processing within the clock network as well as clock output.},
  subject      = {Taufliege},
  language  = {en}
}
@article{ChenGerber2014,
  author    = {Chen, Yi-chun and Gerber, Bertram},
  title     = {Generalization and discrimination tasks yield concordant measures of perceived distance between odours and their binary mixtures in larval Drosophila},
  series = {The Journal of Experimental Biology},
  volume    = {217},
  journal   = {The Journal of Experimental Biology},
  number    = {12},
  doi       = {10.1242/jeb.100966},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-121625},
  pages     = {2071-7},
  year      = {2014},
  abstract  = {Similarity between odours is notoriously difficult to measure. Widely used behavioural approaches in insect olfaction research are cross-adaptation, masking, as well as associative tasks based on olfactory learning and the subsequent testing for how specific the established memory is. A concern with such memory-based approaches is that the learning process required to establish an odour memory may alter the way the odour is processed, such that measures of perception taken at the test are distorted. The present study was therefore designed to see whether behavioural judgements of perceptual distance are different for two different memory-based tasks, namely generalization and discrimination. We used odour-reward learning in larval Drosophila as a study case. In order to challenge the larvae's olfactory system, we chose to work with binary mixtures and their elements (1-octanol, n-amyl acetate, 3-octanol, benzaldehyde and hexyl acetate). We determined the perceptual distance between each mixture and its elements, first in a generalization task, and then in a discrimination task. It turns out that scores of perceptual distance are correlated between both tasks. A re-analysis of published studies looking at element-to-element perceptual distances in larval reward learning and in adult punishment learning confirms this result. We therefore suggest that across a given set of olfactory stimuli, associative training does not grossly alter the pattern of perceptual distances.},
  language  = {en}
}
@article{StefanovicBarnettvanDuijvenbodenetal.2014,
  author    = {Stefanovic, Sonia and Barnett, Phil and van Duijvenboden, Karel and Weber, David and Gessler, Manfred and Christoffels, Vincent M.},
  title     = {GATA-dependent regulatory switches establish atrioventricular canal specificity during heart development},
  series = {Nature Communications},
  volume    = {5},
  journal   = {Nature Communications},
  number    = {3680},
  issn      = {2041-1723},
  doi       = {10.1038/ncomms4680},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-121437},
  year      = {2014},
  abstract  = {The embryonic vertebrate heart tube develops an atrioventricular canal that divides the atrial and ventricular chambers, forms atrioventricular conduction tissue and organizes valve development. Here we assess the transcriptional mechanism underlying this localized differentiation process. We show that atrioventricular canal-specific enhancers are GATA-binding site-dependent and act as switches that repress gene activity in the chambers. We find that atrioventricular canal-specific gene loci are enriched in H3K27ac, a marker of active enhancers, in atrioventricular canal tissue and depleted in H3K27ac in chamber tissue. In the atrioventricular canal, Gata4 activates the enhancers in synergy with Bmp2/Smad signalling, leading to H3K27 acetylation. In contrast, in chambers, Gata4 cooperates with pan-cardiac Hdac1 and Hdac2 and chamber-specific Hey1 and Hey2, leading to H3K27 deacetylation and repression. We conclude that atrioventricular canal-specific enhancers are platforms integrating cardiac transcription factors, broadly active histone modification enzymes and localized co-factors to drive atrioventricular canal-specific gene activity.},
  language  = {en}
}
@article{McCarthyMooreKraussetal.2014,
  author    = {McCarthy, Michael A. and Moore, Alana L. and Krauss, Jochen and Morgan, John W. and Clements, Christopher F.},
  title     = {Linking Indices for Biodiversity Monitoring to Extinction Risk Theory},
  series = {Conservation Biology},
  volume    = {28},
  journal   = {Conservation Biology},
  number    = {6},
  doi       = {10.1111/cobi.12308},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-121218},
  pages     = {1575-83},
  year      = {2014},
  abstract  = {Biodiversity indices often combine data from different species when used in monitoring programs. Heuristic properties can suggest preferred indices, but we lack objective ways to discriminate between indices with similar heuristics. Biodiversity indices can be evaluated by determining how well they reflect management objectives that a monitoring program aims to support. For example, the Convention on Biological Diversity requires reporting about extinction rates, so simple indices that reflect extinction risk would be valuable. We developed 3 biodiversity indices that are based on simple models of population viability that relate extinction risk to abundance. We based the first index on the geometric mean abundance of species and the second on a more general power mean. In a third index, we integrated the geometric mean abundance and trend. These indices require the same data as previous indices, but they also relate directly to extinction risk. Field data for butterflies and woodland plants and experimental studies of protozoan communities show that the indices correlate with local extinction rates. Applying the index based on the geometric mean to global data on changes in avian abundance suggested that the average extinction probability of birds has increased approximately 1\% from 1970 to 2009.},
  language  = {en}
}
@article{ZhanStanciauskasStigloheretal.2014,
  author    = {Zhan, Hong and Stanciauskas, Ramunas and Stigloher, Christian and Dizon, Kevin K. and Jospin, Maelle and Bessereau, Jean-Luis and Pinaud, Fabien},
  title     = {In vivo single-molecule imaging identifies altered dynamics of calcium channels in dystrophin-mutant C. elegans},
  series = {Nature Communications},
  volume    = {5},
  journal   = {Nature Communications},
  number    = {4974},
  doi       = {10.1038/ncomms5974},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-121125},
  year      = {2014},
  abstract  = {Single-molecule (SM) fluorescence microscopy allows the imaging of biomolecules in cultured cells with a precision of a few nanometres but has yet to be implemented in living adult animals. Here we used split-GFP (green fluorescent protein) fusions and complementation-activated light microscopy (CALM) for subresolution imaging of individual membrane proteins in live Caenorhabditis elegans (C. elegans). In vivo tissue-specific SM tracking of transmembrane CD4 and voltage-dependent Ca(2+) channels (VDCC) was achieved with a precision of 30 nm within neuromuscular synapses and at the surface of muscle cells in normal and dystrophin-mutant worms. Through diffusion analyses, we reveal that dystrophin is involved in modulating the confinement of VDCC within sarcolemmal membrane nanodomains in response to varying tonus of C. elegans body-wall muscles. CALM expands the applications of SM imaging techniques beyond the petri dish and opens the possibility to explore the molecular basis of homeostatic and pathological cellular processes with subresolution precision, directly in live animals.},
  language  = {en}
}
@article{WirthGlushakovaScheuermayeretal.2014,
  author    = {Wirth, Christine C. and Glushakova, Svetlana and Scheuermayer, Matthias and Repnik, Urska and Garg, Swatl and Schaack, Dominik and Kachman, Marika M. and Weißbach, Tim and Zimmerberg, Joshua and Dandekar, Thomas and Griffiths, Gareth and Chitnis, Chetan E. and Singh, Shallja and Fischer, Rainer and Pradel, Gabriele},
  title     = {Perforin-like protein PPLP2 permeabilizes the red blood cell membrane during egress of Plasmodium falciparum gametocytes},
  series = {Cellular Microbiology},
  volume    = {16},
  journal   = {Cellular Microbiology},
  number    = {5},
  doi       = {10.1111/cmi.12288},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120895},
  pages     = {709-33},
  year      = {2014},
  abstract  = {Egress of malaria parasites from the host cell requires the concerted rupture of its enveloping membranes. Hence, we investigated the role of the plasmodial perforin-like protein PPLP2 in the egress of Plasmodium falciparum from erythrocytes. PPLP2 is expressed in blood stage schizonts and mature gametocytes. The protein localizes in vesicular structures, which in activated gametocytes discharge PPLP2 in a calcium-dependent manner. PPLP2 comprises a MACPF domain and recombinant PPLP2 has haemolytic activities towards erythrocytes. PPLP2-deficient [PPLP2(-)] merozoites show normal egress dynamics during the erythrocytic replication cycle, but activated PPLP2(-) gametocytes were unable to leave erythrocytes and stayed trapped within these cells. While the parasitophorous vacuole membrane ruptured normally, the activated PPLP2(-) gametocytes were unable to permeabilize the erythrocyte membrane and to release the erythrocyte cytoplasm. In consequence, transmission of PPLP2(-) parasites to the Anopheles vector was reduced. Pore-forming equinatoxin II rescued both PPLP2(-) gametocyte exflagellation and parasite transmission. The pore sealant Tetronic 90R4, on the other hand, caused trapping of activated wild-type gametocytes within the enveloping erythrocytes, thus mimicking the PPLP2(-) loss-of-function phenotype. We propose that the haemolytic activity of PPLP2 is essential for gametocyte egress due to permeabilization of the erythrocyte membrane and depletion of the erythrocyte cytoplasm.},
  language  = {en}
}
@article{KlattHolzschuhWestphaletal.2014,
  author    = {Klatt, Bj{\"o}rn K. and Holzschuh, Andrea and Westphal, Catrin and Clough, Yann and Smit, Inga and Pawelzik, Elke and Tscharntke, Teja},
  title     = {Bee pollination improves crop quality, shelf life and commercial value},
  series = {Proceedings of the Royal Society B: Biological Sciences},
  volume    = {281},
  journal   = {Proceedings of the Royal Society B: Biological Sciences},
  number    = {1775},
  doi       = {10.1098/rspb.2013.2440},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120797},
  year      = {2014},
  abstract  = {Pollination improves the yield of most crop species and contributes to one-third of global crop production, but comprehensive benefits including crop quality are still unknown. Hence, pollination is underestimated by international policies, which is particularly alarming in times of agricultural intensification and diminishing pollination services. In this study, exclusion experiments with strawberries showed bee pollination to improve fruit quality, quantity and market value compared with wind and self-pollination. Bee-pollinated fruits were heavier, had less malformations and reached higher commercial grades. They had increased redness and reduced sugar-acid-ratios and were firmer, thus improving the commercially important shelf life. Longer shelf life reduced fruit loss by at least 11\%. This is accounting for 0.32 billion US\$ of the 1.44 billion US\$ provided by bee pollination to the total value of 2.90 billion US\$ made with strawberry selling in the European Union 2009. The fruit quality and yield effects are driven by the pollination-mediated production of hormonal growth regulators, which occur in several pollination-dependent crops. Thus, our comprehensive findings should be transferable to a wide range of crops and demonstrate bee pollination to be a hitherto underestimated but vital and economically important determinant of fruit quality.},
  language  = {en}
}
@article{DandekarFieselmannFischeretal.2014,
  author    = {Dandekar, Thomas and Fieselmann, Astrid and Fischer, Eva and Popp, Jasmin and Hensel, Michael and Noster, Janina},
  title     = {Salmonella—how a metabolic generalist adopts an intracellular lifestyle during infection},
  series = {Frontiers in Cellular and Infection Microbiology},
  volume    = {4},
  journal   = {Frontiers in Cellular and Infection Microbiology},
  number    = {191},
  issn      = {2235-2988},
  doi       = {10.3389/fcimb.2014.00191},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120686},
  year      = {2014},
  abstract  = {The human-pathogenic bacterium Salmonella enterica adjusts and adapts to different environments while attempting colonization. In the course of infection nutrient availabilities change drastically. New techniques, "-omics" data and subsequent integration by systems biology improve our understanding of these changes. We review changes in metabolism focusing on amino acid and carbohydrate metabolism. Furthermore, the adaptation process is associated with the activation of genes of the Salmonella pathogenicity islands (SPIs). Anti-infective strategies have to take these insights into account and include metabolic and other strategies. Salmonella infections will remain a challenge for infection biology.},
  language  = {en}
}
@article{HaydnHufnagelGrimmetal.2014,
  author    = {Haydn, Johannes M. and Hufnagel, Anita and Grimm, Johannes and Maurus, Katja and Schartl, Manfred and Meierjohann, Svenja},
  title     = {The MAPK pathway as an apoptosis enhancer in melanoma},
  series = {Oncotarget},
  volume    = {5},
  journal   = {Oncotarget},
  number    = {13},
  issn      = {1949-2553},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120649},
  pages     = {5040-53},
  year      = {2014},
  abstract  = {Inhibition of RAF/MEK/ERK signaling is beneficial for many patients with BRAFV600E-mutated melanoma. However, primary and secondary resistances restrict long-lasting therapy success. Combination therapies are therefore urgently needed. Here, we evaluate the cellular effect of combining a MEK inhibitor with a genotoxic apoptosis inducer. Strikingly, we observed that an activated MAPK pathway promotes in several melanoma cell lines the pro-apoptotic response to genotoxic stress, and MEK inhibition reduces intrinsic apoptosis. This goes along with MEK inhibitor induced increased RAS and P-AKT levels. The protective effect of the MEK inhibitor depends on PI3K signaling, which prevents the induction of pro-apoptotic PUMA that mediates apoptosis after DNA damage. We could show that the MEK inhibitor dependent feedback loop is enabled by several factors, including EGF receptor and members of the SPRED family. The simultaneous knockdown of SPRED1 and SPRED2 mimicked the effects of MEK inhibitor such as PUMA repression and protection from apoptosis. Our data demonstrate that MEK inhibition of BRAFV600E-positive melanoma cells can protect from genotoxic stress, thereby achieving the opposite of the intended anti-tumorigenic effect of the combination of MEK inhibitor with inducers of intrinsic apoptosis.},
  language  = {en}
}
@article{NaseemKunzDandekar2014,
  author    = {Naseem, Muhammad and Kunz, Meik and Dandekar, Thomas},
  title     = {Probing the unknowns in cytokinin-mediated immune defense in Arabidopsis with systems biology approaches},
  series = {Bioinformatics and Biology Insights},
  volume    = {8},
  journal   = {Bioinformatics and Biology Insights},
  issn      = {1177-9322},
  doi       = {10.4137/bbi.s13462},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120199},
  pages     = {35-44},
  year      = {2014},
  abstract  = {Plant hormones involving salicylic acid (SA), jasmonic acid (JA), ethylene (Et), and auxin, gibberellins, and abscisic acid (ABA) are known to regulate host immune responses. However, plant hormone cytokinin has the potential to modulate defense signaling including SA and JA. It promotes plant pathogen and herbivore resistance; underlying mechanisms are still unknown. Using systems biology approaches, we unravel hub points of immune interaction mediated by cytokinin signaling in Arabidopsis. High-confidence Arabidopsis protein-protein interactions (PPI) are coupled to changes in cytokinin-mediated gene expression. Nodes of the cellular interactome that are enriched in immune functions also reconstitute sub-networks. Topological analyses and their specific immunological relevance lead to the identification of functional hubs in cellular interactome. We discuss our identified immune hubs in light of an emerging model of cytokinin-mediated immune defense against pathogen infection in plants.},
  language  = {en}
}
@phdthesis{Bettaga2014,
  author    = {Bettaga, Noomen},
  title     = {Bedeutung der NO-sensitiven Guanylyl Cyclase bei der Angiogenese und der Arteriogenese in der Maus},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111284},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {Stickstoffmonoxid (NO) spielt eine wichtige Rolle bei Gef{\"a}ßremodelling-Prozessen wie Angiogenese und Arteriogenese. Die NO-Synthese im Gef{\"a}ßsystem wird haupts{\"a}chlich durch die endotheliale NO-Synthase (eNOS) gew{\"a}hrleistet. Sie kann durch verschiedene Faktoren wie Scherkr{\"a}fte und Zytokine wie der vaskul{\"a}re endotheliale Wachstumsfaktor (VEGF) reguliert werden. VEGF ist ein wichtiger Stimulator der Angiogenese und wird w{\"a}hrend dieses Prozesses hochreguliert. Die meisten physiologischen Effekte von NO werden durch die NO-sensitive Guanylyl-Cyclase (NO-GC) vermittelt. Als Hauptrezeptor f{\"u}r NO produziert die NO-GC den sekund{\"a}ren Botenstoff cyklisches Guanosinmonophosphat (cGMP) und f{\"u}hrt dadurch zur Stimulation der verschiedenen Effektoren wie z.B. der PKG. Ob die Wirkung von NO in Angiogenese und Arteriogenese ebenfalls durch NO-GC vermittelt wird, war bis zum Beginn dieser Arbeit noch unklar. Die NO-GC besteht aus zwei Untereinheiten (α und ß). Die Deletion der ß1-Untereinheit in M{\"a}usen resultiert in einer vollst{\"a}ndigen Knockout Maus (GCKO). Mithilfe des Cre-LoxP-Systems wurden zus{\"a}tzlich zellspezifische Knockout-M{\"a}use f{\"u}r glatte Muskelzellen (SMC-GCKO) und Endothelzellen (EC-GCKO) generiert. Um die Rolle der NO-GC in der Angiogenese und Arteriogenese zu untersuchen, wurden drei gut etablierte Methoden benutzt. Im ersten Teil des Projekts sollte die Expression der NO-GC in Endothelzellen untersucht werden. Zu diesem Zweck wurde die reverse Transkriptase-Polymerase-Kettenreaktion (RT-PCR) benutzt. Die Ergebnisse zeigen, dass die NO-GC in Endothelzellen der Lunge nur {\"a}ußerst gering wenig exprimiert ist. Durch den Aortenring-Assay wurde eine Rolle der NO-GC bei der VEGF-vermittelten Angiogenese festgestellt. Dabei zeigte sich eine st{\"a}rkere Angiogeneserate bei globaler Abwesenheit der NO-GC. Bei Fehlen der NO-GC ausschließlich in Endothelzellen zeigte sich kein Unterschied in den aussprossenden Aorten im Vergleich zu den Kontroll-Tieren. Dies zeigt, dass die NO-GC in Endothelzellen sehr wahrscheinlich keine Rolle bei der VEGF-vermittelten Angiogenese spielt. Im zweiten Teil wurde die Rolle der NO-GC bei der Angiogenese in einem in vivo-Modell untersucht. In dem Modell der Sauerstoff-induzierten-Retinopathie zeigten die GCKO-M{\"a}use eine verringerte Vaso-Obliteration, eine verlangsamte Angiogenese und eine erh{\"o}hte Tuft-Bildung. {\"A}hnliche Ergebnisse wurden bei den SMC-GCKO-Tieren beobachtet. EC-GCKO-M{\"a}use zeigten eine gegen{\"u}ber den Kontroll-Tieren unver{\"a}nderte Vaso-Obliteration, Angiogeneserate und Tuft-Bildung. Diese Ergebnisse lassen darauf schließen, dass die NO-GC in Endothelzellen keine Rolle spielt. Immunfluoreszenz-Aufnahmen zeigten die Expression von NO-GC in Perizyten der Gef{\"a}ßkapillaren der Mausretina. Daher k{\"o}nnte die NO-GC in diesem Zelltyp letztendlich f{\"u}r die Effekte bei den GCKO- und SMC-GCKO-Tieren verantwortlich sein. Im letzten Teil dieser Arbeit wurde eine Versuchsreihe unter Anwendung des Hinterlauf-Isch{\"a}mie-Modells durchgef{\"u}hrt. Hierbei entwickelten die Pfoten aller GCKO- und teilweise der SMC-GCKO-Tiere nach der Ligation der Femoralarterie eine Nekrose. Die Regeneration der Hinterl{\"a}ufe der EC-GCKO-Tiere nach der Operation verlief normal. Diese Ergebnisse schließen eine bedeutende Rolle der NO-GC in Endothelzellen aus, zeigen allerdings, dass die NO-GC in den glatten Muskelzellen essentiell f{\"u}r den Arteriogenese-Prozess ist. Zusammengefasst f{\"u}hrt die Deletion der NO-GC in glatten Muskelzellen und wahrscheinlich auch in Perizyten zur einer verlangsamten Angiogenese und Inhibierung der Arteriogenese.},
  subject      = {Guanylylcyclase},
  language  = {de}
}
@phdthesis{Siegl2014,
  author    = {Siegl, Christine},
  title     = {Degradation of Tumour Suppressor p53 during Chlamydia trachomatis Infections},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-108679},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {The intracellular pathogen Chlamydia is the causative agent of millions of new infections per year transmitting diseases like trachoma, pelvic inflammatory disease or lymphogranuloma venereum. Undetected or recurrent infections caused by chlamydial persistence are especially likely to provoke severe pathologies. To ensure host cell survival and to facilitate long term infections Chlamydia induces anti-apoptotic pathways, mainly at the level of mitochondria, and restrains activity of pro-apoptotic proteins. Additionally, the pathogen seizes host energy, carbohydrates, amino acids, lipids and nucleotides to facilitate propagation of bacterial progeny and growth of the chlamydial inclusion. At the beginning of this study, Chlamydia-mediated apoptosis resistance to DNA damage induced by the topoisomerase inhibitor etoposide was investigated. In the course of this, a central cellular protein crucial for etoposide-mediated apoptosis, the tumour suppressor p53, was found to be downregulated during Chlamydia infections. Subsequently, different chlamydial strains and serovars were examined and p53 downregulation was ascertained to be a general feature during Chlamydia infections of human cells. Reduction of p53 protein level was established to be mediated by the PI3K-Akt signalling pathway, activation of the E3-ubiquitin ligase HDM2 and final degradation by the proteasome. Additionally, an intriguing discrepancy between infections of human and mouse cells was detected. Both activation of the PI3K-Akt pathway as well as degradation of p53 could not be observed in Chlamydia-infected mouse cells. Recently, production of reactive oxygen species (ROS) and damage to host cell DNA was reported to occur during Chlamydia infection. Thus, degradation of p53 strongly contributes to the anti-apoptotic environment crucial for chlamydial infection. To verify the importance of p53 degradation for chlamydial growth and development, p53 was stabilised and activated by the HDM2-inhibiting drug nutlin-3 and the DNA damage-inducing compound etoposide. Unexpectedly, chlamydial development was severely impaired and inclusion formation was defective. Completion of the chlamydial developmental cycle was prevented resulting in loss of infectivity. Intriguingly, removal of the p53 activating stimulus allowed formation of the bacterial inclusion and recovery of infectivity. A similar observation of growth recovery was made in infected cell lines deficient for p53. As bacterial growth and inclusion formation was strongly delayed in the presence of activated p53, p53-mediated inhibitory regulation of cellular metabolism was suspected to contribute to chlamydial growth defects. To verify this, glycolytic and pentose phosphate pathways were analysed revealing the importance of a functioning PPP for chlamydial growth. In addition, increased expression of glucose-6-phosphate dehydrogenase rescued chlamydial growth inhibition induced by activated p53. The rescuing effect was even more pronounced in p53-deficient cells treated with etoposide or nutlin-3 revealing additional p53-independent aspects of Chlamydia inhibition. Removal of ROS by anti-oxidant compounds was not sufficient to rescue chlamydial infectivity. Apparently, not only the anti-oxidant capacities of the PPP but also provision of precursors for nucleotide synthesis as well as contribution to DNA repair are important for successful chlamydial growth. Modulation of host cell signalling was previously reported for a number of pathogens. As formation of ROS and DNA damage are likely to occur during infections of intracellular bacteria, several strategies to manipulate the host and to inhibit induction of apoptosis were invented. Downregulation of the tumour suppressor p53 is a crucial point during development of Chlamydia, ensuring both host cell survival and metabolic support conducive to chlamydial growth.},
  subject      = {Chlamydia-trachomatis-Infektion},
  language  = {en}
}
@phdthesis{Proppert2014,
  author    = {Proppert, Sven Martin},
  title     = {Design, implementation and characterization of a microscope capable of three-dimensional two color super-resolution fluorescence imaging},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-107905},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {This thesis reviews the fundamentals of three-dimensional super-resolution localization imaging. In order to infer the axial coordinate of the emission of single fluorophores, the point spread function is engineered following a technique usually referred to as astigmatic imaging by the introduction of a cylindrical lens to the detection path of a microscope. After giving a short introduction to optics and localization microscopy, I outline sources of aberrations as frequently encountered in 3D-localization microscopy and will discuss their respective impact on the precision and accuracy of the localization process. With the knowledge from these considerations, experiments were designed and conducted to verify the validity of the conclusions and to demonstrate the abilities of the proposed microscope to resolve biological structures in the three spatial dimensions. Additionally, it is demonstrated that measurements of huge volumes with virtually no aberrations is in principle feasible. During the course of this thesis, a new method was introduced for inferring axial coordinates. This interpolation method based on cubic B-splines shows superior performance in the calibration of a microscope and the evaluation of subsequent measurement and will therefore be used and explained in this work. Finally, this work is also meant to give future students some guidance for entering the field of 3D localization microscopy and therefore, detailed protocols are provided covering the specific aspects of two color 3D localization imaging.},
  subject      = {Dimension 3},
  language  = {en}
}
@article{AhmedZeeshanHuberetal.2014,
  author    = {Ahmed, Zeeshan and Zeeshan, Saman and Huber, Claudia and Hensel, Michael and Schomburg, Dietmar and M{\"u}nch, Richard and Eylert, Eva and Eisenreich, Wolfgang and Dandekar, Thomas},
  title     = {'Isotopo' a database application for facile analysis and management of mass isotopomer data},
  series = {Database},
  volume    = {2014},
  journal   = {Database},
  number    = {bau077},
  doi       = {10.1093/database/bau077},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120102},
  year      = {2014},
  abstract  = {The composition of stable-isotope labelled isotopologues/isotopomers in metabolic products can be measured by mass spectrometry and supports the analysis of pathways and fluxes. As a prerequisite, the original mass spectra have to be processed, managed and stored to rapidly calculate, analyse and compare isotopomer enrichments to study, for instance, bacterial metabolism in infection. For such applications, we provide here the database application 'Isotopo'. This software package includes (i) a database to store and process isotopomer data, (ii) a parser to upload and translate different data formats for such data and (iii) an improved application to process and convert signal intensities from mass spectra of \(^{13}C\)-labelled metabolites such as tertbutyldimethylsilyl-derivatives of amino acids. Relative mass intensities and isotopomer distributions are calculated applying a partial least square method with iterative refinement for high precision data. The data output includes formats such as graphs for overall enrichments in amino acids. The package is user-friendly for easy and robust data management of multiple experiments.},
  language  = {en}
}
@article{Schartl2014,
  author    = {Schartl, Manfred},
  title     = {Beyond the zebrafish: diverse fish species for modeling human disease},
  series = {Disease Models \& Mechanisms},
  volume    = {7},
  journal   = {Disease Models \& Mechanisms},
  number    = {2},
  issn      = {1754-8411},
  doi       = {10.1242/dmm.012245},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119919},
  year      = {2014},
  abstract  = {In recent years, zebrafish, and to a lesser extent medaka, have become widely used small animal models for human diseases. These organisms have convincingly demonstrated the usefulness of fish for improving our understanding of the molecular and cellular mechanisms leading to pathological conditions, and for the development of new diagnostic and therapeutic tools. Despite the usefulness of zebrafish and medaka in the investigation of a wide spectrum of traits, there is evidence to suggest that other fish species could be better suited for more targeted questions. With the emergence of new, improved sequencing technologies that enable genomic resources to be generated with increasing efficiency and speed, the potential of non-mainstream fish species as disease models can now be explored. A key feature of these fish species is that the pathological condition that they model is often related to specific evolutionary adaptations. By exploring these adaptations, new disease-causing and disease-modifier genes might be identified; thus, diverse fish species could be exploited to better understand the complexity of disease processes. In addition, non-mainstream fish models could allow us to study the impact of environmental factors, as well as genetic variation, on complex disease phenotypes. This Review will discuss the opportunities that such fish models offer for current and future biomedical research.},
  language  = {en}
}
@article{AndreskaAufmkolkSaueretal.2014,
  author    = {Andreska, Thomas and Aufmkolk, Sarah and Sauer, Markus and Blum, Robert},
  title     = {High abundance of BDNF within glutamatergic presynapses of cultured hippocampal neurons},
  series = {Frontiers in Cellular Neuroscience},
  volume    = {8},
  journal   = {Frontiers in Cellular Neuroscience},
  number    = {107},
  issn      = {1662-5102},
  doi       = {10.3389/fncel.2014.00107},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119793},
  year      = {2014},
  abstract  = {In the mammalian brain, the neurotrophin brain-derived neurotrophic factor (BDNF) has emerged as a key factor for synaptic refinement, plasticity and learning. Although BDNF-induced signaling cascades are well known, the spatial aspects of the synaptic BDNF localization remained unclear. Recent data provide strong evidence for an exclusive presynaptic location and anterograde secretion of endogenous BDNF at synapses of the hippocampal circuit. In contrast, various studies using BDNF overexpression in cultured hippocampal neurons support the idea that postsynaptic elements and other dendritic structures are the preferential sites of BDNF localization and release. In this study we used rigorously tested anti-BDNF antibodies and achieved a dense labeling of endogenous BDNF close to synapses. Confocal microscopy showed natural BDNF close to many, but not all glutamatergic synapses, while neither GABAergic synapses nor postsynaptic structures carried a typical synaptic BDNF label. To visualize the BDNF distribution within the fine structure of synapses, we implemented super resolution fluorescence imaging by direct stochastic optical reconstruction microscopy (dSTORM). Two-color dSTORM images of neurites were acquired with a spatial resolution of ~20 nm. At this resolution, the synaptic scaffold proteins Bassoon and Homer exhibit hallmarks of mature synapses and form juxtaposed bars, separated by a synaptic cleft. BDNF imaging signals form granule-like clusters with a mean size of ~60 nm and are preferentially found within the fine structure of the glutamatergic presynapse. Individual glutamatergic presynapses carried up to 90\% of the synaptic BDNF immunoreactivity, and only a minor fraction of BDNF molecules was found close to the postsynaptic bars. Our data proof that hippocampal neurons are able to enrich and store high amounts of BDNF in small granules within the mature glutamatergic presynapse, at a principle site of synaptic plasticity.},
  language  = {en}
}
@article{ProppertWolterHolmetal.2014,
  author    = {Proppert, Sven and Wolter, Steve and Holm, Thorge and Klein, Theresa and van de Linde, Sebastian and Sauer, Markus},
  title     = {Cubic B-spline calibration for 3D super-resolution measurements using astigmatic imaging},
  series = {Optics Express},
  volume    = {22},
  journal   = {Optics Express},
  number    = {9},
  issn      = {1094-4087},
  doi       = {10.1364/OE.22.010304},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119730},
  pages     = {10304-16},
  year      = {2014},
  abstract  = {In recent years three-dimensional (3D) super-resolution fluorescence imaging by single-molecule localization (localization microscopy) has gained considerable interest because of its simple implementation and high optical resolution. Astigmatic and biplane imaging are experimentally simple methods to engineer a 3D-specific point spread function (PSF), but existing evaluation methods have proven problematic in practical application. Here we introduce the use of cubic B-splines to model the relationship of axial position and PSF width in the above mentioned approaches and compare the performance with existing methods. We show that cubic B-splines are the first method that can combine precision, accuracy and simplicity.},
  language  = {en}
}
@article{BatramJonesJanzenetal.2014,
  author    = {Batram, Christopher and Jones, Nivola G. and Janzen, Christian J. and Markert, Sebastian M. and Engstler, Markus},
  title     = {Expression site attenuation mechanistically links antigenic variation and development in Trypanosoma brucei},
  series = {eLife},
  volume    = {3},
  journal   = {eLife},
  number    = {e02324},
  issn      = {2050-084X},
  doi       = {10.7554/eLife.02324},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119727},
  year      = {2014},
  abstract  = {We have discovered a new mechanism of monoallelic gene expression that links antigenic variation, cell cycle, and development in the model parasite Trypanosoma brucei. African trypanosomes possess hundreds of variant surface glycoprotein (VSG) genes, but only one is expressed from a telomeric expression site (ES) at any given time. We found that the expression of a second VSG alone is sufficient to silence the active VSG gene and directionally attenuate the ES by disruptor of telomeric silencing-1B (DOT1B)-mediated histone methylation. Three conserved expression-site-associated genes (ESAGs) appear to serve as signal for ES attenuation. Their depletion causes G1-phase dormancy and reversible initiation of the slender-to-stumpy differentiation pathway. ES-attenuated slender bloodstream trypanosomes gain full developmental competence for transformation to the tsetse fly stage. This surprising connection between antigenic variation and developmental progression provides an unexpected point of attack against the deadly sleeping sickness.},
  language  = {en}
}
@article{YilmazAksoyCamlitepeetal.2014,
  author    = {Yilmaz, Ayse and Aksoy, Volkan and Camlitepe, Yilmaz and Giurfa, Martin},
  title     = {Eye structure, activity rhythms, and visually-driven behavior are tuned to visual niche in ants},
  series = {Frontiers in Behavioral Neuroscience},
  volume    = {8},
  journal   = {Frontiers in Behavioral Neuroscience},
  doi       = {10.3389/fnbeh.2014.00205},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119595},
  pages     = {205},
  year      = {2014},
  abstract  = {Insects have evolved physiological adaptations and behavioral strategies that allow them to cope with a broad spectrum of environmental challenges and contribute to their evolutionary success. Visual performance plays a key role in this success. Correlates between life style and eye organization have been reported in various insect species. Yet, if and how visual ecology translates effectively into different visual discrimination and learning capabilities has been less explored. Here we report results from optical and behavioral analyses performed in two sympatric ant species, Formica cunicularia and Camponotus aethiops. We show that the former are diurnal while the latter are cathemeral. Accordingly, F. cunicularia workers present compound eyes with higher resolution, while C. aethiops workers exhibit eyes with lower resolution but higher sensitivity. The discrimination and learning of visual stimuli differs significantly between these species in controlled dual-choice experiments: discrimination learning of small-field visual stimuli is achieved by F. cunicularia but not by C. aethiops, while both species master the discrimination of large-field visual stimuli. Our work thus provides a paradigmatic example about how timing of foraging activities and visual environment match the organization of compound eyes and visually-driven behavior. This correspondence underlines the relevance of an ecological/evolutionary framework for analyses in behavioral neuroscience.},
  language  = {en}
}
@article{DusikSenthilanMentzeletal.2014,
  author    = {Dusik, Verena and Senthilan, Pingkalai R. and Mentzel, Benjamin and Hartlieb, Heiko and W{\"u}lbeck, Corina and Yoshii, Taishi and Raabe, Thomas and Helfrich-F{\"o}rster, Charlotte},
  title     = {The MAP Kinase p38 Is Part of Drosophila melanogaster's Circadian Clock},
  series = {PLoS Genetics},
  volume    = {10},
  journal   = {PLoS Genetics},
  number    = {8},
  issn      = {1553-7404},
  doi       = {10.1371/journal.pgen.1004565},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119433},
  pages     = {e1004565},
  year      = {2014},
  abstract  = {All organisms have to adapt to acute as well as to regularly occurring changes in the environment. To deal with these major challenges organisms evolved two fundamental mechanisms: the p38 mitogen-activated protein kinase (MAPK) pathway, a major stress pathway for signaling stressful events, and circadian clocks to prepare for the daily environmental changes. Both systems respond sensitively to light. Recent studies in vertebrates and fungi indicate that p38 is involved in light-signaling to the circadian clock providing an interesting link between stress-induced and regularly rhythmic adaptations of animals to the environment, but the molecular and cellular mechanisms remained largely unknown. Here, we demonstrate by immunocytochemical means that p38 is expressed in Drosophila melanogaster's clock neurons and that it is activated in a clock-dependent manner. Surprisingly, we found that p38 is most active under darkness and, besides its circadian activation, additionally gets inactivated by light. Moreover, locomotor activity recordings revealed that p38 is essential for a wild-type timing of evening activity and for maintaining ∼ 24 h behavioral rhythms under constant darkness: flies with reduced p38 activity in clock neurons, delayed evening activity and lengthened the period of their free-running rhythms. Furthermore, nuclear translocation of the clock protein Period was significantly delayed on the expression of a dominant-negative form of p38b in Drosophila's most important clock neurons. Western Blots revealed that p38 affects the phosphorylation degree of Period, what is likely the reason for its effects on nuclear entry of Period. In vitro kinase assays confirmed our Western Blot results and point to p38 as a potential "clock kinase" phosphorylating Period. Taken together, our findings indicate that the p38 MAP Kinase is an integral component of the core circadian clock of Drosophila in addition to playing a role in stress-input pathways.},
  language  = {en}
}
@article{AdelfingerGentschevdeGuibertetal.2014,
  author    = {Adelfinger, Marion and Gentschev, Ivaylo and de Guibert, Julio Grimm and Weibel, Stephanie and Langbein-Laugwitz, Johanna and H{\"a}rtl, Barbara and Escobar, Hugo Murua and Nolte, Ingo and Chen, Nanhai G. and Aguilar, Richard J. and Yu, Yong A. and Zhang, Qian and Frentzen, Alexa and Szalay, Aladar A.},
  title     = {Evaluation of a New Recombinant Oncolytic Vaccinia Virus Strain GLV-5b451 for Feline Mammary Carcinoma Therapy},
  series = {PLoS ONE},
  volume    = {9},
  journal   = {PLoS ONE},
  number    = {8},
  doi       = {10.1371/journal.pone.0104337},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119387},
  pages     = {e104337},
  year      = {2014},
  abstract  = {Virotherapy on the basis of oncolytic vaccinia virus (VACV) infection is a promising approach for cancer therapy. In this study we describe the establishment of a new preclinical model of feline mammary carcinoma (FMC) using a recently established cancer cell line, DT09/06. In addition, we evaluated a recombinant vaccinia virus strain, GLV-5b451, expressing the anti-vascular endothelial growth factor (VEGF) single-chain antibody (scAb) GLAF-2 as an oncolytic agent against FMC. Cell culture data demonstrate that GLV-5b451 virus efficiently infected, replicated in and destroyed DT09/06 cancer cells. In the selected xenografts of FMC, a single systemic administration of GLV-5b451 led to significant inhibition of tumor growth in comparison to untreated tumor-bearing mice. Furthermore, tumor-specific virus infection led to overproduction of functional scAb GLAF-2, which caused drastic reduction of intratumoral VEGF levels and inhibition of angiogenesis. In summary, here we have shown, for the first time, that the vaccinia virus strains and especially GLV-5b451 have great potential for effective treatment of FMC in animal model.},
  language  = {en}
}
@article{LeonhardtKaltenpoth2014,
  author    = {Leonhardt, Sara D. and Kaltenpoth, Martin},
  title     = {Microbial Communities of Three Sympatric Australian Stingless Bee Species},
  series = {PLoS ONE},
  volume    = {9},
  journal   = {PLoS ONE},
  number    = {8},
  doi       = {10.1371/journal.pone.0105718},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119341},
  pages     = {e105718},
  year      = {2014},
  abstract  = {Bacterial symbionts of insects have received increasing attention due to their prominent role in nutrient acquisition and defense. In social bees, symbiotic bacteria can maintain colony homeostasis and fitness, and the loss or alteration of the bacterial community may be associated with the ongoing bee decline observed worldwide. However, analyses of microbiota associated with bees have been largely confined to the social honeybees (Apis mellifera) and bumblebees (Bombus spec.), revealing - among other taxa - host-specific lactic acid bacteria (LAB, genus Lactobacillus) that are not found in solitary bees. Here, we characterized the microbiota of three Australian stingless bee species (Apidae: Meliponini) of two phylogenetically distant genera (Tetragonula and Austroplebeia). Besides common plant bacteria, we find LAB in all three species, showing that LAB are shared by honeybees, bumblebees and stingless bees across geographical regions. However, while LAB of the honeybee-associated Firm4-5 clusters were present in Tetragonula, they were lacking in Austroplebeia. Instead, we found a novel clade of likely host-specific LAB in all three Australian stingless bee species which forms a sister clade to a large cluster of Halictidae-associated lactobacilli. Our findings indicate both a phylogenetic and geographical signal of host-specific LAB in stingless bees and highlight stingless bees as an interesting group to investigate the evolutionary history of the bee-LAB association.},
  language  = {en}
}
@article{NaseemSrivastavaDandekar2014,
  author    = {Naseem, Muhammad and Srivastava, Mugdha and Dandekar, Thomas},
  title     = {Stem-cell-triggered immunity safeguards cytokinin enriched plant shoot apexes from pathogen infection},
  series = {Frontiers in Plant Science},
  volume    = {5},
  journal   = {Frontiers in Plant Science},
  issn      = {1664-462X},
  doi       = {10.3389/fpls.2014.00588},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-118247},
  pages     = {588},
  year      = {2014},
  abstract  = {Intricate mechanisms discriminate between friends and foes in plants. Plant organs deploy overlapping and distinct protection strategies. Despite vulnerability to a plethora of pathogens, the growing tips of plants grow bacteria free. The shoot apical meristem (SAM) is among three stem cells niches, a self-renewable reservoir for the future organogenesis of leaf, stem, and flowers. How plants safeguard this high value growth target from infections was not known until now. Recent reports find the stem cell secreted 12-amino acid peptide CLV3p (CLAVATA3 peptide) is perceived by FLS2 (FLAGELLIN SENSING 2) receptor and activates the transcription of immunity and defense marker genes. No infection in the SAM of wild type plants and bacterial infection in clv3 and fls2 mutants illustrate this natural protection against infections. Cytokinins (CKs) are enriched in the SAM and regulate meristem activities by their involvement in stem cell signaling networks. Auxin mediates plant susceptibility to pathogen infections while CKs boost plant immunity. Here, in addition to the stem-cell-triggered immunity we also highlight a potential link between CK signaling and CLV3p mediated immune response in the SAM.},
  language  = {en}
}
@article{SchueleinVoelkWolfZhuetal.2014,
  author    = {Sch{\"u}lein-V{\"o}lk, Christina and Wolf, Elmar and Zhu, Jing and Xu, Wenshan and Taranets, Lyudmyla and Hellmann, Andreas and J{\"a}nicke, Laura A. and Diefenbacher, Markus E. and Behrens, Axel and Eilers, Martin and Popov, Nikita},
  title     = {Dual Regulation of Fbw7 Function and Oncogenic Transformation by Usp28},
  series = {CELL REPORTS},
  volume    = {9},
  journal   = {CELL REPORTS},
  number    = {3},
  issn      = {2211-1247},
  doi       = {10.1016/j.celrep.2014.09.057},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-118219},
  pages     = {1099-1109},
  year      = {2014},
  abstract  = {Fbw7, the substrate recognition subunit of SCF(Fbw7) ubiquitin ligase, mediates the turnover of multiple proto-oncoproteins and promotes its own degradation. Fbw7-dependent substrate ubiquitination is antagonized by the Usp28 deubiquitinase. Here, we show that Usp28 preferentially antagonizes autocatalytic ubiquitination and stabilizes Fbw7, resulting in dose-dependent effects in Usp28 knockout mice. Monoallelic deletion of Usp28 maintains stable Fbw7 but drives Fbw7 substrate degradation. In contrast, complete knockout triggers Fbw7 degradation and leads to the accumulation of Fbw7 substrates in several tissues and embryonic fibroblasts. On the other hand, overexpression of Usp28 stabilizes both Fbw7 and its substrates. Consequently, both complete loss and ectopic expression of Usp28 promote Ras-driven oncogenic transformation. We propose that dual regulation of Fbw7 activity by Usp28 is a safeguard mechanism for maintaining physiological levels of proto-oncogenic Fbw7 substrates, which is equivalently disrupted by loss or overexpression of Usp28.},
  language  = {en}
}
@phdthesis{Proft2014,
  author    = {Proft, Florian Lukas Patrick},
  title     = {Molekulare Wirkmechanismen des Antidepressivums Venlafaxin - genetische Untersuchungen in Maus und Mensch},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-109201},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {Depressive Erkrankungen verursachen sowohl das pers{\"o}nliche Leid der erkrankten Individuen als auch volkswirtschaftlichen Schaden durch krankheitsbedingten Arbeitsausfall und Belastung der Gesundheitsversorgungssysteme. Therapeutische Konzepte wie die Anwendung pharmakotherapeutischer Intervention sind in unterschiedlichem Maß von Erfolg gekr{\"o}nt. Zahlreiche somatische Faktoren wurden mit der {\"A}tiologie depressiver St{\"o}rungen in Verbindung gebracht. Die prim{\"a}r verfolgten pharmakologischen Ans{\"a}tze basieren nach wie vor auf Erkenntnissen aus der Mitte des vergangenen Jahrhunderts. In erster Linie setzt die Pharmakotherapie Substanzen ein, die die Wiederaufnahme monoaminerger Neurotransmitter (Serotonin, Noradrenalin, zum Teil auch Dopamin) aus dem synaptischen Spalt inhibieren und nach einer allerdings meist mehrw{\"o}chigen, regelm{\"a}ßigen Einnahme des Pr{\"a}parates zu einem R{\"u}ckgang der depressiven Symptomatik f{\"u}hren. Andererseits kann jedoch bei zahlreichen Erkrankten auch nach fortgesetzter Therapie mit verschiedenen Behandlungsans{\"a}tzen keine Remission verzeichnet werden und es stellt sich die Frage nach der Ursache dieser Diskrepanz. Im Fokus der vorliegenden Arbeit stand der als Antidepressivum eingesetzte selektive Serotonin- / Noradrenalin-Wiederaufnahme-Inhibitor Venlafaxin. Durch Blockade des pr{\"a}synaptischen Serotonin- und Noradrenalin-Transporters f{\"u}hrt Venlafaxin initial zu einer intensivierten Neurotransmission. Die Zielstrukturen von Venlafaxin sind der pr{\"a}synaptische Serotonin- und der Noradrenalin-Transporter, wobei aufgrund unterschiedlicher Affinit{\"a}t eine geringe Dosis beziehungsweise Konzentration als rein serotonerg betrachtet wird und bei einer hohen Dosis beziehungsweise Konzentration sowohl die Wiederaufnahme von Serotonin als auch Noradrenalin inhibiert wird. Es wurden in dieser Arbeit zwei Ziele verfolgt. Im ersten Teil wurde mittels Gen-expressionsuntersuchungen nach potentiellen Effektoren von Venlafaxin gesucht, um prinzipielle Mechanismen der antidepressiven Wirkung zu identifizieren und auf ihrer Basis die Entwicklung spezifischerer Intervention zu erm{\"o}glichen. Der zweite Teil beinhaltet eine pharmakogenetische Untersuchung am Menschen. Ziel war zu evaluieren, inwieweit die Expressionsaktivit{\"a}t von SLC6A2 und SLC6A4 und damit die pr{\"a}synaptische Transportkapazit{\"a}t in Kombination mit der Serumkonzentration aktiver Substanz als Pr{\"a}diktor des therapeutischen Effektes dienen kann. Die Kenntnis dieser Zusammenh{\"a}nge w{\"u}rde bei Vorliegen eines bestimmten Genotyps eine gezieltere Titration der individuell ben{\"o}tigten Konzentration erm{\"o}glichen und k{\"o}nnte die Effektivit{\"a}t der Therapie steigern. F{\"u}r die Genexpressionsuntersuchungen erhielten DBA/2-M{\"a}use {\"u}ber einen Zeitraum von 30 Tagen Venlafaxin in verschiedenen Dosierungen {\"u}ber das Trinkwasser. Anschließend wurden die Hippokampi der Tiere mittels genomweiter Microarray-Analyse hypothesenfrei auf zwischen den Dosisgruppen differentiell exprimierte Gene hin untersucht. Der Hippokampus wird als zentrales Element der Steuerung, Ausbildung und Ver{\"a}nderung von Verhaltensmustern gesehen. Signifikant differentiell exprimierte Gene, die in vorherigen Studien mit depressiver Erkrankung beziehungsweise einem Effekt psychiatrischer Medikation assoziiert worden waren, wurden mittels qRT-PCR-Analyse validiert. Im Anschluss an die Analyse im Tier wurden als differentiell exprimiert best{\"a}tigte Gene per qRT-PCR analog in humanen Leukozyten untersucht. Die Blutproben waren in einem klinisch-naturalistischen Design w{\"a}hrend der ersten und der f{\"u}nften Woche einer Venlafaxin-Pharmakotherapie von Patienten der Klinik f{\"u}r Psychiatrie, Psychosomatik und Psychotherapie des Universit{\"a}tsklinikums W{\"u}rzburg gewonnen worden, das heißt vor und nach potentiellem Eintreten der antidepressiven Wirkung. Trotz der unterschiedlichen Herkunft der analysierten Gewebe k{\"o}nnten auf diesem Weg Hinweise auf Vorg{\"a}nge im menschlichen Gehirn gefunden werden, wie in vergleichenden post mortem Untersuchungen zwischen peripherem und zentralem humanem Material erkannt worden war. Die in der Tierstudie identifizierten Gene kodieren f{\"u}r Transkriptionsfaktoren sowie Proteine die als Teil von second messenger-Kaskaden bekannt sind. Von statistischer Signifikanz erwies sich in der Analyse der humanen Leukozyten die Expressionsreduktion der mRNA der Transkriptionsfaktor-Untereinheit Fos. Befunde zu einer Funktion von Fos, die eine Interpretation im Bezug auf den antidepressiven Effekt von Venlafaxin erm{\"o}glichen, liegen lediglich aus Tierstudien vor. Fos-ko im Hippo-kampus von M{\"a}usen wurde mit reduziertem Angstverhalten und h{\"o}herer Exzitabilit{\"a}t von hippokampalen Neuronen assoziiert. Auch wurde eine Assoziation mit Vorg{\"a}ngen bei synaptischer Plastizit{\"a}t und damit potentiell bei Lernvorg{\"a}ngen gefunden. Auf der anderen Seite wurde depressions-{\"a}hnliches Verhalten bei Ratten mit niedriger hippokampaler Fos-Expression und dessen erfolgreiche pharmakologische "Therapie" mit einer Induktion der Fos-Expression assoziiert. Es scheinen also bereits zwischen nicht-menschlichen Spezies ausgepr{\"a}gte Unterschiede der Rolle von Fos beziehungsweise Fos zu bestehen. Aufgrund der unterschiedlichen Spezies und Gewebe in den hier durchgef{\"u}hrten Untersuchungen sowie den uneinheitlichen Befunden bez{\"u}glich der Rolle von Fos beziehungsweise Fos in vorangegangenen Studien kann abschließend lediglich konstatiert werden, dass Fos vermutlich an der Entstehung depressionsbeg{\"u}nstigender Physiologie beteiligt ist und auch, dass eine antidepressive Pharmakotherapie mit Venlafaxin ihre Wirkung vermutlich unter Beteiligung von Fos entfaltet. Die Entwicklung innovativer Antidepressiva die unter Umgehung der monoaminergen Transmissionssysteme durch gezielte Reduktion der Fos-Abundanz das therapeutische Ziel erreichen lassen, k{\"o}nnte auf Basis der vorliegenden Studie angedacht werden, scheint allerdings aufgrund der ubiquit{\"a}ren Mediatorent{\"a}tigkeit des Proteins und insbesondere aufgrund seiner nicht endg{\"u}ltig definierten Rolle bei der Entstehung von Krebs nicht praktikabel. Zuk{\"u}nftige Untersuchungen sollten daher auf andere im Microarray differentiell exprimiert gefundene Gene fokussieren. In die Untersuchung der Expressionsaktivit{\"a}t der f{\"u}r die prim{\"a}ren Zielstrukturen von Venlafaxin (Serotonin- beziehungsweise Noradrenalin-Transporter) kodierenden Gene (SLC6A4 beziehungsweise SLC6A2) und der Serumkonzentration an aktiver Substanz nach Venlafaxin-Applikation im Hinblick auf deren Pr{\"a}diktivit{\"a}t des therapeutischen Effektes, wurden in einem klinisch-naturalistischen Design Patienten der Klinik f{\"u}r Psychiatrie, Psychosomatik und Psychotherapie des Universit{\"a}tsklinikums W{\"u}rzburg eingeschlossen. Genotypisiert wurden f{\"u}r SLC6A2 der SNP rs28386840 und f{\"u}r SLC6A4 der Polymorphismus 5-HTTLPR. Die Genotypen wurden jeweils in niedrig- und hoch-exprimierend unterteilt und damit auf die ph{\"a}notypische Transportkapazit{\"a}t der pr{\"a}synaptischen Membran Bezug genommen. Der therapeutische Erfolg wurde anhand der CGI-I-Skala evaluiert und f{\"u}r die Analysen in "gutes Ansprechen" und "schlechtes Ansprechen" dichotomisiert. Der SLC6A2-Polymorphismus zeigte sich als nicht mit dem therapeutischen Effekt assoziiert. Der hochexprimierende SLC6A4-Genotyp wurde signifikant mit einem schlechteren Ansprechen assoziiert. Dies war in den nach Serumkonzentration aktiver Substanz stratifizierten Unterkollektiven insbesondere in dem Bereich zwischen 200 und 400 ng / ml zu erkennen, wohingegen unter- und oberhalb dieses Bereiches keine Assoziation zu finden war. Aus diesen Resultaten kann gefolgert werden, dass sich aus der Genotypisierung von rs28386840 keine therapeutischen Instruktionen ableiten lassen. Bei Kenntnis des 5-HTTLPR-Genotyps k{\"o}nnte f{\"u}r den klinischen Alltag die Empfehlung ergehen, falls Venlafaxin als sSNRI bei Patienten mit hochexprimierendem Genotyp eingesetzt werden soll, eine Serumsummenkonzentration jenseits des durch die AGNP empfohlenen Bereiches (100 - 400 ng / ml) anzustreben. Da hier jedoch lediglich eine Stichprobe von 56 Patienten untersucht und insbesondere, da zahlreiche potentielle Kofaktoren des therapeutischen Effektes nicht in die Analyse einbezogen werden konnten, ist die Assoziation vor Anwendung in der Therapiesteuerung anhand umfassenderer prospektiver kontrollierter Studien zu validieren.},
  subject      = {Wirkmechanismus},
  language  = {de}
}
@phdthesis{Xian2014,
  author    = {Xian, Yibo},
  title     = {Identification of essential genes and novel virulence factors of Neisseria gonorrhoeae by transposon mutagenesis},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-102659},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {Neisseria gonorrhoeae is a human-specific pathogen that causes gonorrhea. It is defined as a super bacterium by the WHO due to the emergence of gonococci that are resistant to a variety of antibiotics and a rapidly increasing infection incidence. Genome-wide investigation of neisserial gene essentiality and novel virulence factors is urgently required in order to identify new targets for anti-neisserial therapeutics. To identify essential genes and new virulence factors, a high-density mutant library in N. gonorrhoeae MS11 was generated by in vitro transposon mutagenesis. The transposon library harbors more than 100,000 individual mutants, a density that is unprecedented in gonococcal research. Essential genes in N. gonorrhoeae were determined by enumerating frequencies of transposon insertion sites (TIS) with Illumina deep sequencing (Tn-seq). Tn-seq indicated an average distance between adjacent TIS of 25 bp. Statistical analysis unequivocally demonstrated 781 genes that were significantly depleted in TIS and thus are essential for Neisseria survival. A subset of the genes was experimentally verified to comprise essential genes and thus support the outcome of the study. The hereby identified candidate essential genes thus may constitute excellent targets for the development of new antibiotics or vaccines. In a second study, the transposon mutant library was applied in a genome-scale "negative-selection strategy" to identify genes that are involved in low phosphate-dependent invasion (LPDI). LPDI is dependent on the Neisseria porin subtype PorBIA which acts as an epithelial cell invasin in absence of phosphate and is associated with severe pathogenicity in disseminated gonococcal infections (DGI). Tn-seq demonstrated 98 genes, which were involved in adherence to host cells and 43 genes involved in host cell invasion. E.g. the hypothetical protein NGFG_00506, an ABC transporter ATP-binding protein NGFG_01643, as well as NGFG_04218 encoding a homolog of mafI in N. gonorrhoeae FA1090 were experimentally verified as new invasive factors in LPDI. NGFG_01605, a predicted protease, was identified to be a common factor involved in PorBIA, Opa50 and Opa57-mediated neisserial engulfment by the epithelial cells. Thus, this first systematic Tn-seq application in N. gonorrhoeae identified a set of previously unknown N. gonorrhoeae invasive factors which demonstrate molecular mechanisms of DGI.},
  subject      = {Neisseria gonorrhoeae},
  language  = {en}
}
@article{SieglPrustyKarunakaranetal.2014,
  author    = {Siegl, Christine and Prusty, Bhupesh K. and Karunakaran, Karthika and Wischhusen, J{\"o}rg and Rudel, Thomas},
  title     = {Tumor Suppressor p53 Alters Host Cell Metabolism to Limit Chlamydia trachomatis Infection},
  series = {Cell Reports},
  volume    = {9},
  journal   = {Cell Reports},
  number    = {3},
  issn      = {2211-1247},
  doi       = {10.1016/j.celrep.2014.10.004},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-118200},
  pages     = {918-929},
  year      = {2014},
  abstract  = {Obligate intracellular bacteria depend entirely on nutrients from the host cell for their reproduction. Here, we show that obligate intracellular Chlamydia downregulate the central tumor suppressor p53 in human cells. This reduction of p53 levels is mediated by the PI3K-Akt signaling pathway, activation of HDM2, and subsequent proteasomal degradation of p53. The stabilization of p53 in human cells severely impaired chlamydial development and caused the loss of infectious particle formation. DNA-damage-induced p53 interfered with chlamydial development through downregulation of the pentose phosphate pathway (PPP). Increased expression of the PPP key enzyme glucose-6-phosphate dehydrogenase rescued the inhibition of chlamydial growth induced by DNA damage or stabilized p53. Thus, downregulation of p53 is a key event in the chlamydial life cycle that reprograms the host cell to create a metabolic environment supportive of chlamydial growth.},
  language  = {en}
}
@article{PeterBultinckMyantetal.2014,
  author    = {Peter, Stefanie and Bultinck, Jennyfer and Myant, Kevin and Jaenicke, Laura A. and Walz, Susanne and M{\"u}ller, Judith and Gmachl, Michael and Treu, Matthias and Boehmelt, Guido and Ade, Casten P. and Schmitz, Werner and Wiegering, Armin and Otto, Christoph and Popov, Nikita and Sansom, Owen and Kraut, Norbert and Eilers, Martin},
  title     = {H Tumor cell-specific inhibition of MYC function using small molecule inhibitors of the HUWE1 ubiquitin ligase},
  series = {EMBO Molecular Medicine},
  volume    = {6},
  journal   = {EMBO Molecular Medicine},
  number    = {12},
  issn      = {1757-4684},
  doi       = {10.15252/emmm.201403927},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-118132},
  pages     = {1525-41},
  year      = {2014},
  abstract  = {Deregulated expression of MYC is a driver of colorectal carcinogenesis, necessitating novel strategies to inhibit MYC function. The ubiquitin ligase HUWE1 (HECTH9, ARF-BP1, MULE) associates with both MYC and the MYC-associated protein MIZ1. We show here that HUWE1 is required for growth of colorectal cancer cells in culture and in orthotopic xenograft models. Using high-throughput screening, we identify small molecule inhibitors of HUWE1, which inhibit MYC-dependent transactivation in colorectal cancer cells, but not in stem and normal colon epithelial cells. Inhibition of HUWE1 stabilizes MIZ1. MIZ1 globally accumulates on MYC target genes and contributes to repression of MYC-activated target genes upon HUWE1 inhibition. Our data show that transcriptional activation by MYC in colon cancer cells requires the continuous degradation of MIZ1 and identify a novel principle that allows for inhibition of MYC function in tumor cells.},
  language  = {en}
}
@article{SommerlandtHuberSpaethe2014,
  author    = {Sommerlandt, F. M. J. and Huber, W. and Spaethe, J.},
  title     = {Social Information in the Stingless Bee, Trigona corvina Cockerell (Hymenoptera: Apidae): The Use of Visual and Olfactory Cues at the Food Site},
  series = {Sociobiology},
  volume    = {61},
  journal   = {Sociobiology},
  number    = {4},
  doi       = {10.13102/sociobiology.v61i4.401-406},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-118120},
  year      = {2014},
  abstract  = {For social insects, colony performance is largely dependent on the quantity and quality of food intake and thus on the efficiency of its foragers. In addition to innate preferences and previous experience, foragers can use social information to decide when and where to forage. In some stingless bee (Meliponini) species, individual foraging decisions are shown to be influenced by the presence of social information at resource sites. In dual choice tests, we studied whether visual and/or olfactory cues affect individual decision-making in rigona corvina Cockerell and if this information is species-specific. We found that T. corvina foragers possess local enhancement: they are attracted by olfactory and visual cues released by conspecifics but avoid feeders associated with heterospecific individuals of the species Tetragona ziegleri (Friese). Overall, olfactory cues seem to be more important than visual cues, but information by visual cues alone is sufficient for discrimination.},
  language  = {en}
}
@article{BenzMaierBaueretal.2014,
  author    = {Benz, Roland and Maier, Elke and Bauer, Susanne and Ludwig, Albrecht},
  title     = {The Deletion of Several Amino Acid Stretches of Escherichia coli Alpha-Hemolysin (HlyA) Suggests That the Channel-Forming Domain Contains Beta-Strands},
  series = {PLOS ONE},
  volume    = {9},
  journal   = {PLOS ONE},
  number    = {12},
  issn      = {1932-6203},
  doi       = {10.1371/journal.pone.0112248},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-118115},
  pages     = {e112248},
  year      = {2014},
  abstract  = {Escherichia coli α-hemolysin (HlyA) is a pore-forming protein of 110 kDa belonging to the family of RTX toxins. A hydrophobic region between the amino acid residues 238 and 410 in the N-terminal half of HlyA has previously been suggested to form hydrophobic and/or amphipathic α-helices and has been shown to be important for hemolytic activity and pore formation in biological and artificial membranes. The structure of the HlyA transmembrane channel is, however, largely unknown. For further investigation of the channel structure, we deleted in HlyA different stretches of amino acids that could form amphipathic β-strands according to secondary structure predictions (residues 71-110, 158-167, 180-203, and 264-286). These deletions resulted in HlyA mutants with strongly reduced hemolytic activity. Lipid bilayer measurements demonstrated that HlyAΔ71-110 and HlyAΔ264-286 formed channels with much smaller single-channel conductance than wildtype HlyA, whereas their channel-forming activity was virtually as high as that of the wildtype toxin. HlyAΔ158-167 and HlyAΔ180-203 were unable to form defined channels in lipid bilayers. Calculations based on the single-channel data indicated that the channels generated by HlyAΔ71-110 and HlyAΔ264-286 had a smaller size (diameter about 1.4 to 1.8 nm) than wildtype HlyA channels (diameter about 2.0 to 2.6 nm), suggesting that in these mutants part of the channel-forming domain was removed. Osmotic protection experiments with erythrocytes confirmed that HlyA, HlyAΔ71-110, and HlyAΔ264-286 form defined transmembrane pores and suggested channel diameters that largely agreed with those estimated from the single-channel data. Taken together, these results suggest that the channel-forming domain of HlyA might contain β-strands, possibly in addition to α-helical structures.},
  language  = {en}
}
@article{OervoessyKoroesiBataryetal.2014,
  author    = {Oervoessy, Noemi and Koroesi, Adam and Batary, Peter and Vozar, Agnes and Peregovits, Laszlo},
  title     = {Habitat Requirements of the Protected Southern Festoon (Zerynthia Polysena); Adult, Egg and Larval Distribution in a Highly Degraded Habitat Complex},
  series = {Acta Zoologica Academiae Scientiarum Hungaricae},
  volume    = {60},
  journal   = {Acta Zoologica Academiae Scientiarum Hungaricae},
  number    = {4},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117810},
  pages     = {371-387},
  year      = {2014},
  abstract  = {Habitat quality affects the presence and size of butterfly populations. Resources for all life stages must be found in a given or few habitat patches. Southern festoon (Zerynthia polyxena) is a vulnerable, but locally abundant species in Hungary. The larva requires birthwort (Aristolochia clematitis) as food plant. We examined the small scale habitat use of adults and distribution of eggs and larvae among different vegetation types to reveal the requirements of the species in all life stages. Transect counts were conducted in a tree plantation complex comprising four types of vegetation. Number (+/- SE) of adults, eggs and larvae were lowest in poplar plantation (adult 0.3 +/- 0.2, egg 1.1 +/- 1.1, larva 0.6 +/- 0.3). Medium amount of butterflies were observed in open (adult 8.3 +/- 2.9, egg 3.1 +/- 2.6, larva 3.1 +/- 1.9) and black-locust (adult 9.4 +/- 4.2, egg 12.7 +/- 4.9, larva 4.1 +/- 1.1) habitat. Number of butterflies was highest in hummocks (adult 13.5 +/- 1.5, egg 12.9 +/- 5.7, larva 8.4 +/- 2.1). Adults avoided bare ground. We encountered most eggs in dense food plant patches with high plants. Food plant height also positively influenced the occurrence of the larvae. Although distribution of adults and juvenile forms showed quite similar patterns, we could also reveal some differences that caused by different environmental conditions in distinct vegetation types. Our study stresses the importance of habitat quality, which affects population size of butterflies even in a highly degraded habitat complex.},
  language  = {en}
}
@article{BreezeVaissiereBommarcoetal.2014,
  author    = {Breeze, Tom D. and Vaissiere, Bernhard E. and Bommarco, Riccardo and Petanidou, Theodora and Seraphides, Nicos and Kozak, Lajos and Scheper, Jeroen and Biesmeijer, Jacobus C. and Kleijn, David and Gyldenk{\ae}rne, Steen and Moretti, Marco and Holzschuh, Andrea and Steffan-Dewenter, Ingolf and Stout, Jane C. and P{\"a}rtel, Meelis and Zobel, Martin and Potts, Simon G.},
  title     = {Agricultural Policies Exacerbate Honeybee Pollination Service Supply-Demand Mismatches Across Europe},
  series = {PLOS ONE},
  volume    = {9},
  journal   = {PLOS ONE},
  number    = {1},
  issn      = {1932-6203},
  doi       = {10.1371/journal.pone.0082996},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117692},
  pages     = {e82996},
  year      = {2014},
  abstract  = {Declines in insect pollinators across Europe have raised concerns about the supply of pollination services to agriculture. Simultaneously, EU agricultural and biofuel policies have encouraged substantial growth in the cultivated area of insect pollinated crops across the continent. Using data from 41 European countries, this study demonstrates that the recommended number of honeybees required to provide crop pollination across Europe has risen 4.9 times as fast as honeybee stocks between 2005 and 2010. Consequently, honeybee stocks were insufficient to supply >90\% of demands in 22 countries studied. These findings raise concerns about the capacity of many countries to cope with major losses of wild pollinators and highlight numerous critical gaps in current understanding of pollination service supplies and demands, pointing to a pressing need for further research into this issue.},
  language  = {en}
}
@article{WaeschkeHardgeHancocketal.2014,
  author    = {W{\"a}schke, Nicole and Hardge, Kerstin and Hancock, Christine and Hilker, Monika and Obermaier, Elisabeth and Meiners, Torsten},
  title     = {Odour Environments: How Does Plant Diversity Affect Herbivore and Parasitoid Orientation?},
  series = {PlOS ONE},
  volume    = {9},
  journal   = {PlOS ONE},
  number    = {1},
  issn      = {1932-6203},
  doi       = {10.1371/journal.pone.0085152},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117687},
  pages     = {e85152},
  year      = {2014},
  abstract  = {Plant diversity is known to affect success of host location by pest insects, but its effect on olfactory orientation of non-pest insect species has hardly been addressed. First, we tested in laboratory experiments the hypothesis that non-host plants, which increase odour complexity in habitats, affect the host location ability of herbivores and parasitoids. Furthermore, we recorded field data of plant diversity in addition to herbivore and parasitoid abundance at 77 grassland sites in three different regions in Germany in order to elucidate whether our laboratory results reflect the field situation. As a model system we used the herb Plantago lanceolata, the herbivorous weevil Mecinus pascuorum, and its larval parasitoid Mesopolobus incultus. The laboratory bioassays revealed that both the herbivorous weevil and its larval parasitoid can locate their host plant and host via olfactory cues even in the presence of non-host odour. In a newly established two-circle olfactometer, the weevils capability to detect host plant odour was not affected by odours from non-host plants. However, addition of non-host plant odours to host plant odour enhanced the weevils foraging activity. The parasitoid was attracted by a combination of host plant and host volatiles in both the absence and presence of non-host plant volatiles in a Y-tube olfactometer. In dual choice tests the parasitoid preferred the blend of host plant and host volatiles over its combination with non-host plant volatiles. In the field, no indication was found that high plant diversity disturbs host (plant) location by the weevil and its parasitoid. In contrast, plant diversity was positively correlated with weevil abundance, whereas parasitoid abundance was independent of plant diversity. Therefore, we conclude that weevils and parasitoids showed the sensory capacity to successfully cope with complex vegetation odours when searching for hosts.},
  language  = {en}
}
@article{SanzMorenoFuhrmannWolfetal.2014,
  author    = {Sanz-Moreno, Adrian and Fuhrmann, David and Wolf, Elmar and von Eyss, Bj{\"o}rn and Eilers, Martin and Els{\"a}sser, Hans-Peter},
  title     = {Miz1 Deficiency in the Mammary Gland Causes a Lactation Defect by Attenuated Stat5 Expression and Phosphorylation},
  series = {PLOS ONE},
  volume    = {9},
  journal   = {PLOS ONE},
  number    = {2},
  doi       = {10.1371/journal.pone.0089187},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117286},
  pages     = {e89187},
  year      = {2014},
  abstract  = {Miz1 is a zinc finger transcription factor with an N-terminal POZ domain. Complexes with Myc, Bcl-6 or Gfi-1 repress expression of genes like Cdkn2b (p15(Ink4)) or Cd-kn1a (p21(Cip1)). The role of Miz1 in normal mammary gland development has not been addressed so far. Conditional knockout of the Miz1 POZ domain in luminal cells during pregnancy caused a lactation defect with a transient reduction of glandular tissue, reduced proliferation and attenuated differentiation. This was recapitulated in vitro using mouse mammary gland derived HC11 cells. Further analysis revealed decreased Stat5 activity in Miz1 Delta POZ mammary glands and an attenuated expression of Stat5 targets. Gene expression of the Prolactin receptor (PrlR) and ErbB4, both critical for Stat5 phosphorylation (pStat5) or pStat5 nuclear translocation, was decreased in Miz1 Delta POZ females. Microarray, ChIP-Seq and gene set enrichment analysis revealed a down-regulation of Miz1 target genes being involved in vesicular transport processes. Our data suggest that deranged intracellular transport and localization of PrlR and ErbB4 disrupt the Stat5 signalling pathway in mutant glands and cause the observed lactation phenotype.},
  language  = {en}
}
@article{PascoalinoDindarVieiradaRochaetal.2014,
  author    = {Pascoalino, Bruno and Dindar, G{\"u}lcin and Vieira-da-Rocha, Jo{\~a}o P. and Machado, Carlos Renato and Janzen, Christian J. and Schenkman, Sergio},
  title     = {Characterization of two different Asf1 histone chaperones with distinct cellular localizations and functions in Trypanosoma brucei},
  series = {Nucleic Acids Research},
  volume    = {42},
  journal   = {Nucleic Acids Research},
  number    = {5},
  issn      = {1362-4962},
  doi       = {10.1093/nar/gkt1267},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117220},
  pages     = {2906-2918},
  year      = {2014},
  abstract  = {The anti-silencing function protein 1 (Asf1) is a chaperone that forms a complex with histones H3 and H4 facilitating dimer deposition and removal from chromatin. Most eukaryotes possess two different Asf1 chaperones but their specific functions are still unknown. Trypanosomes, a group of early-diverged eukaryotes, also have two, but more divergent Asf1 paralogs than Asf1 of higher eukaryotes. To unravel possible different functions, we characterized the two Asf1 proteins in Trypanosoma brucei. Asf1A is mainly localized in the cytosol but translocates to the nucleus in S phase. In contrast, Asf1B is predominantly localized in the nucleus, as described for other organisms. Cytosolic Asf1 knockdown results in accumulation of cells in early S phase of the cell cycle, whereas nuclear Asf1 knockdown arrests cells in S/G2 phase. Overexpression of cytosolic Asf1 increases the levels of histone H3 and H4 acetylation. In contrast to cytosolic Asf1, overexpression of nuclear Asf1 causes less pronounced growth defects in parasites exposed to genotoxic agents, prompting a function in chromatin remodeling in response to DNA damage. Only the cytosolic Asf1 interacts with recombinant H3/H4 dimers in vitro. These findings denote the early appearance in evolution of distinguishable functions for the two Asf1 chaperons in trypanosomes.},
  language  = {en}
}
@article{GroezingerTheinFeldhaaretal.2014,
  author    = {Gr{\"o}zinger, Franziska and Thein, J{\"u}rgen and Feldhaar, Heike and R{\"o}del, Mark-Oliver},
  title     = {Giants, Dwarfs and the Environment - Metamorphic Trait Plasticity in the Common Frog},
  series = {PLOS ONE},
  volume    = {9},
  journal   = {PLOS ONE},
  number    = {3},
  issn      = {1932-6203},
  doi       = {10.1371/journal.pone.0089982},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117203},
  pages     = {e89982},
  year      = {2014},
  abstract  = {In order to understand adaptation processes and population dynamics, it is central to know how environmental parameters influence performance of organisms within populations, including their phenotypes. The impact of single or few particular parameters in concert was often assessed in laboratory and mesocosm experiments. However, under natural conditions, with many biotic and abiotic factors potentially interacting, outcomes on phenotypic changes may be different. To study the potential environmental impact on realized phenotypic plasticity within a natural population, we assessed metamorphic traits (developmental time, size and body mass) in an amphibian species, the European common frog Rana temporaria, since a) larval amphibians are known to exhibit high levels of phenotypic plasticity of these traits in response to habitat parameters and, b) the traits' features may strongly influence individuals' future performance and fitness. In 2007 we studied these metamorphic traits in 18 ponds spread over an area of 28 km 2. A subset of six ponds was reinvestigated in 2009 and 2010. This study revealed locally high variances in metamorphic traits in this presumed generalist species. We detected profound differences between metamorphing froglets (up to factor ten); both between and within ponds, on a very small geographic scale. Parameters such as predation and competition as well as many other pond characteristics, generally expected to have high impact on development, could not be related to the trait differences. We observed high divergence of patterns of mass at metamorphosis between ponds, but no detectable pattern when metamorphic traits were compared between ponds and years. Our results indicate that environment alone, i.e. as experienced by tadpoles sharing the same breeding pond, can only partly explain the variability of metamorphic traits observed. This emphasizes the importance to assess variability of reaction norms on the individual level to explain within-population variability.},
  language  = {en}
}
@article{GroenewegvanRoyenFenzetal.2014,
  author    = {Groeneweg, Femke L. and van Royen, Martin E. and Fenz, Susanne and Keizer, Veer I. P. and Geverts, Bart and Prins, Jurrien and de Kloet, E. Ron and Houtsmuller, Adriaan B. and Schmidt, Thomas S. and Schaaf, Marcel J. M.},
  title     = {Quantitation of Glucocorticoid Receptor DNA-Binding Dynamics by Single-Molecule Microscopy and FRAP},
  series = {PLOS ONE},
  volume    = {9},
  journal   = {PLOS ONE},
  number    = {3},
  doi       = {10.1371/journal.pone.0090532},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117085},
  pages     = {e90532},
  year      = {2014},
  abstract  = {Recent advances in live cell imaging have provided a wealth of data on the dynamics of transcription factors. However, a consistent quantitative description of these dynamics, explaining how transcription factors find their target sequences in the vast amount of DNA inside the nucleus, is still lacking. In the present study, we have combined two quantitative imaging methods, single-molecule microscopy and fluorescence recovery after photobleaching, to determine the mobility pattern of the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), two ligand-activated transcription factors. For dexamethasone-activated GR, both techniques showed that approximately half of the population is freely diffusing, while the remaining population is bound to DNA. Of this DNA-bound population about half the GRs appeared to be bound for short periods of time (similar to 0.7 s) and the other half for longer time periods (similar to 2.3 s). A similar pattern of mobility was seen for the MR activated by aldosterone. Inactive receptors (mutant or antagonist-bound receptors) show a decreased DNA binding frequency and duration, but also a higher mobility for the diffusing population. Likely, very brief (<= 1 ms) interactions with DNA induced by the agonists underlie this difference in diffusion behavior. Surprisingly, different agonists also induce different mobilities of both receptors, presumably due to differences in ligand-induced conformational changes and receptor complex formation. In summary, our data provide a consistent quantitative model of the dynamics of GR and MR, indicating three types of interactions with DNA, which fit into a model in which frequent low-affinity DNA binding facilitates the search for high-affinity target sequences.},
  language  = {en}
}
@article{HellerHemp2014,
  author    = {Heller, Klaus-Gerhard and Hemp, Claudia},
  title     = {Fiddler on the Tree - A Bush-Cricket Species with Unusual Stridulatory Organs and Song},
  series = {PLOS ONE},
  volume    = {9},
  journal   = {PLOS ONE},
  number    = {3},
  doi       = {10.1371/journal.pone.0092366},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117068},
  pages     = {e92366},
  year      = {2014},
  abstract  = {Insects of the order Orthoptera are well-known for their acoustic communication. The structures used for this purpose show a high diversity which obviously relates to differences in song parameters and to the physics of sound production. Here we describe song and morphology of the sound producing organs of a tropical bush-cricket, Ectomoptera nepicauda, from East Africa. It has a very unusual calling song consisting of frequency-modulated, pure-tone sounds in the high ultrasonic range of 80 to 120 kHz and produced by extremely fast wing movements. Concerning morphology, it represents the most extreme state in the degree of left-right fore-wing differentiation found among Orthoptera: the acoustic parts of the left fore-wing consist exclusively of the stridulatory file, comparable in function to the bow of a violin, while the right wing carries only the plectrum (= string) and mirror (= soundbox).},
  language  = {en}
}
@article{KoetschanKittelmannLuetal.2014,
  author    = {Koetschan, Christian and Kittelmann, Sandra and Lu, Jingli and Al-Halbouni, Djamila and Jarvis, Graeme N. and M{\"u}ller, Tobias and Wolf, Matthias and Janssen, Peter H.},
  title     = {Internal Transcribed Spacer 1 Secondary Structure Analysis Reveals a Common Core throughout the Anaerobic Fungi (Neocallimastigomycota)},
  series = {PLOS ONE},
  volume    = {9},
  journal   = {PLOS ONE},
  number    = {3},
  doi       = {10.1371/journal.pone.0091928},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117058},
  pages     = {e91928},
  year      = {2014},
  abstract  = {The internal transcribed spacer (ITS) is a popular barcode marker for fungi and in particular the ITS1 has been widely used for the anaerobic fungi (phylum Neocallimastigomycota). A good number of validated reference sequences of isolates as well as a large number of environmental sequences are available in public databases. Its highly variable nature predisposes the ITS1 for low level phylogenetics; however, it complicates the establishment of reproducible alignments and the reconstruction of stable phylogenetic trees at higher taxonomic levels (genus and above). Here, we overcame these problems by proposing a common core secondary structure of the ITS1 of the anaerobic fungi employing a Hidden Markov Model-based ITS1 sequence annotation and a helix-wise folding approach. We integrated the additional structural information into phylogenetic analyses and present for the first time an automated sequence-structure-based taxonomy of the ITS1 of the anaerobic fungi. The methodology developed is transferable to the ITS1 of other fungal groups, and the robust taxonomy will facilitate and improve high-throughput anaerobic fungal community structure analysis of samples from various environments.},
  language  = {en}
}
@article{BartomeusPottsSteffanDewenteretal.2014,
  author    = {Bartomeus, Ignasi and Potts, Simon G. and Steffan-Dewenter, Ingolf and Vaissiere, Bernard E. and Woyciechowski, Michal and Krewenka, Kristin M. and Tscheulin, Thomas and Roberts, Stuart P. M. and Szentgyoergyi, Hajnalka and Westphal, Catrin and Bommarco, Riccardo},
  title     = {Contribution of insect pollinators to crop yield and quality varies with agricultural intensification},
  series = {PEERJ},
  volume    = {2},
  journal   = {PEERJ},
  number    = {e328},
  issn      = {2167-9843},
  doi       = {10.7717/peerj.328},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-116928},
  year      = {2014},
  abstract  = {Background. Up to 75\% of crop species benefit at least to some degree from animal pollination for fruit or seed set and yield. However, basic information on the level of pollinator dependence and pollinator contribution to yield is lacking for many crops. Even less is known about how insect pollination affects crop quality. Given that habitat loss and agricultural intensification are known to decrease pollinator richness and abundance, there is a need to assess the consequences for different components of crop production. Methods. We used pollination exclusion on flowers or inflorescences on a whole plant basis to assess the contribution of insect pollination to crop yield and quality in four flowering crops (spring oilseed rape, field bean, strawberry, and buckwheat) located in four regions of Europe. For each crop, we recorded abundance and species richness of flower visiting insects in ten fields located along a gradient from simple to heterogeneous landscapes. Results. Insect pollination enhanced average crop yield between 18 and 71\% depending on the crop. Yield quality was also enhanced in most crops. For instance, oilseed rape had higher oil and lower chlorophyll contents when adequately pollinated, the proportion of empty seeds decreased in buckwheat, and strawberries' commercial grade improved; however, we did not find higher nitrogen content in open pollinated field beans. Complex landscapes had a higher overall species richness of wild pollinators across crops, but visitation rates were only higher in complex landscapes for some crops. On the contrary, the overall yield was consistently enhanced by higher visitation rates, but not by higher pollinator richness. Discussion. For the four crops in this study, there is clear benefit delivered by pollinators on yield quantity and/or quality, but it is not maximized under current agricultural intensification. Honeybees, the most abundant pollinator, might partially compensate the loss of wild pollinators in some areas, but our results suggest the need of landscape-scale actions to enhance wild pollinator populations.},
  language  = {en}
}
@article{TomaszkiewiczChalopinSchartletal.2014,
  author    = {Tomaszkiewicz, Marta and Chalopin, Domitille and Schartl, Manfred and Galiana, Delphine and Volff, Jean-Nicolas},
  title     = {A multicopy Y-chromosomal SGNH hydrolase gene expressed in the testis of the platyfish has been captured and mobilized by a Helitron transposon},
  series = {BMC Genetics},
  volume    = {15},
  journal   = {BMC Genetics},
  number    = {44},
  doi       = {10.1186/1471-2156-15-44},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-116746},
  year      = {2014},
  abstract  = {Background: Teleost fish present a high diversity of sex determination systems, with possible frequent evolutionary turnover of sex chromosomes and sex-determining genes. In order to identify genes involved in male sex determination and differentiation in the platyfish Xiphophorus maculatus, bacterial artificial chromosome contigs from the sex-determining region differentiating the Y from the X chromosome have been assembled and analyzed. Results: A novel three-copy gene called teximY (for testis-expressed in Xiphophorus maculatus on the Y) was identified on the Y but not on the X chromosome. A highly related sequence called texim1, probably at the origin of the Y-linked genes, as well as three more divergent texim genes were detected in (pseudo) autosomal regions of the platyfish genome. Texim genes, for which no functional data are available so far in any organism, encode predicted esterases/lipases with a SGNH hydrolase domain. Texim proteins are related to proteins from very different origins, including proteins encoded by animal CR1 retrotransposons, animal platelet-activating factor acetylhydrolases (PAFah) and bacterial hydrolases. Texim gene distribution is patchy in animals. Texim sequences were detected in several fish species including killifish, medaka, pufferfish, sea bass, cod and gar, but not in zebrafish. Texim-like genes are also present in Oikopleura (urochordate), Amphioxus (cephalochordate) and sea urchin (echinoderm) but absent from mammals and other tetrapods. Interestingly, texim genes are associated with a Helitron transposon in different fish species but not in urochordates, cephalochordates and echinoderms, suggesting capture and mobilization of an ancestral texim gene in the bony fish lineage. RT-qPCR analyses showed that Y-linked teximY genes are preferentially expressed in testis, with expression at late stages of spermatogenesis (late spermatids and spermatozeugmata). Conclusions: These observations suggest either that TeximY proteins play a role in Helitron transposition in the male germ line in fish, or that texim genes are spermatogenesis genes mobilized and spread by transposable elements in fish genomes.},
  language  = {en}
}
@phdthesis{Weber2014,
  author    = {Weber, David},
  title     = {Hey target gene regulation in embryonic stem cells and cardiomyocytes},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-101663},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {The Notch signaling pathway is crucial for mammalian heart development. It controls cell-fate decisions, coordinates patterning processes and regulates proliferation and differentiation. Critical Notch effectors are Hey bHLH transcription factors (TF) that are expressed in atrial (Hey1) and ventricular (Hey2) cardiomyocytes (CM) and in the developing endocardium (Hey1/2/L). The importance of Hey proteins for cardiac development is demonstrated by knockout (KO) mice, which suffer from lethal cardiac defects, such as ventricular septum defects (VSD), valve defects and cardiomyopathy. Despite this clear functional relevance, little is known about Hey downstream targets in the heart and the molecular mechanism by which they are regulated. Here, I use a cell culture system with inducible Hey1, Hey2 or HeyL expression to study Hey target gene regulation in HEK293 cells, in murine embryonic stem cells (ESC) and in ESC derived CM. In HEK293 cells, I could show that genome wide binding sites largely overlap between all three Hey proteins, but HeyL has many additional binding sites that are not bound by Hey1 or Hey2. Shared binding sites are located close to transcription start sites (TSS) where Hey proteins preferentially bind to canonical E boxes, although more loosely defined modes of binding exist. Additional sites only bound by HeyL are more scattered across the genome. The ability of HeyL to bind these sites depends on the C-terminal part of the protein. Although there are genes which are differently regulated by HeyL, it is unclear whether this regulation results from binding of additional sites by HeyL. Additionally, Hey target gene regulation was studied in ESC and differentiated CM, which are more relevant for the observed cardiac phenotypes. ESC derived CM contract in culture and are positive for typical cardiac markers by qRT PCR and staining. According to these markers differentiation is unaffected by prolonged Hey1 or Hey2 overexpression. Regulated genes are largely redundant between Hey1 and Hey2. These are mainly other TF involved in e.g. developmental processes, apoptosis, cell migration and cell cycle. Many target genes are cell type specifically regulated causing a shift in Hey repression of genes involved in cell migration in ESC to repression of genes involved in cell cycle in CM. The number of Hey binding sites is reduced in CM and HEK293 cells compared to ESC, most likely due to more regions of dense chromatin in differentiated cells. Binding sites are enriched at the proximal promoters of down-regulated genes, compared to up-or non-regulated genes. This indicates that up-regulation primarily results from indirect effects, while down-regulation is the direct results of Hey binding to target promoters. The extent of repression generally correlates with the amount of Hey binding and subsequent recruitment of histone deacetylases (Hdac) to target promoters resulting in histone H3 deacetylation. However, in CM the repressive effect of Hey binding on a subset of genes can be annulled, likely due to binding of cardiac specific activators like Srf, Nkx2-5 and Gata4. These factors seem not to interfere with Hey binding in CM, but they recruit histone acetylases such as p300 that may counteract Hey mediated histone H3 deacetylation. Such a scenario explains differential regulation of Hey target genes between ESC and CM resulting in gene and cell-type specific regulation.},
  subject      = {Transkriptionsfaktor},
  language  = {en}
}
@article{BaurRautenbergFaulstichetal.2014,
  author    = {Baur, Stefanie and Rautenberg, Maren and Faulstich, Manuela and Grau, Timo and Severin, Yannik and Unger, Clemens and Hoffmann, Wolfgang H. and Rudel, Thomas and Autenrieth, Ingo B. and Weidenmaier, Christopher},
  title     = {A Nasal Epithelial Receptor for Staphylococcus aureus WTA Governs Adhesion to Epithelial Cells and Modulates Nasal Colonization},
  series = {PLOS PATHOGENS},
  volume    = {10},
  journal   = {PLOS PATHOGENS},
  number    = {5},
  issn      = {1553-7374},
  doi       = {10.1371/journal.ppat.1004089},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-116280},
  pages     = {e1004089},
  year      = {2014},
  abstract  = {Nasal colonization is a major risk factor for S. aureus infections. The mechanisms responsible for colonization are still not well understood and involve several factors on the host and the bacterial side. One key factor is the cell wall teichoic acid (WTA) of S. aureus, which governs direct interactions with nasal epithelial surfaces. We report here the first receptor for the cell wall glycopolymer WTA on nasal epithelial cells. In several assay systems this type F-scavenger receptor, termed SREC-I, bound WTA in a charge dependent manner and mediated adhesion to nasal epithelial cells in vitro. The impact of WTA and SREC-I interaction on epithelial adhesion was especially pronounced under shear stress, which resembles the conditions found in the nasal cavity. Most importantly, we demonstrate here a key role of the WTA-receptor interaction in a cotton rat model of nasal colonization. When we inhibited WTA mediated adhesion with a SREC-I antibody, nasal colonization in the animal model was strongly reduced at the early onset of colonization. More importantly, colonization stayed low over an extended period of 6 days. Therefore we propose targeting of this glycopolymer-receptor interaction as a novel strategy to prevent or control S. aureus nasal colonization.},
  language  = {en}
}
@article{DanielTraenknerWojtaszetal.2014,
  author    = {Daniel, Katrin and Tr{\"a}nkner, Daniel and Wojtasz, Lukasz and Shibuya, Hiroki and Watanabe, Yoshinori and Alsheimer, Manfred and Toth, Attila},
  title     = {Mouse CCDC79 (TERB1) is a meiosis-specific telomere associated protein},
  series = {BMC Cell Biology},
  volume    = {15},
  journal   = {BMC Cell Biology},
  number    = {17},
  issn      = {1471-2121},
  doi       = {10.1186/1471-2121-15-17},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-116248},
  year      = {2014},
  abstract  = {Background: Telomeres have crucial meiosis-specific roles in the orderly reduction of chromosome numbers and in ensuring the integrity of the genome during meiosis. One such role is the attachment of telomeres to trans-nuclear envelope protein complexes that connect telomeres to motor proteins in the cytoplasm. These trans-nuclear envelope connections between telomeres and cytoplasmic motor proteins permit the active movement of telomeres and chromosomes during the first meiotic prophase. Movements of chromosomes/telomeres facilitate the meiotic recombination process, and allow high fidelity pairing of homologous chromosomes. Pairing of homologous chromosomes is a prerequisite for their correct segregation during the first meiotic division. Although inner-nuclear envelope proteins, such as SUN1 and potentially SUN2, are known to bind and recruit meiotic telomeres, these proteins are not meiosis-specific, therefore cannot solely account for telomere-nuclear envelope attachment and/or for other meiosis-specific characteristics of telomeres in mammals. Results: We identify CCDC79, alternatively named TERB1, as a meiosis-specific protein that localizes to telomeres from leptotene to diplotene stages of the first meiotic prophase. CCDC79 and SUN1 associate with telomeres almost concurrently at the onset of prophase, indicating a possible role for CCDC79 in telomere-nuclear envelope interactions and/or telomere movements. Consistent with this scenario, CCDC79 is missing from most telomeres that fail to connect to SUN1 protein in spermatocytes lacking the meiosis-specific cohesin SMC1B. SMC1B-deficient spermatocytes display both reduced efficiency in telomere-nuclear envelope attachment and reduced stability of telomeres specifically during meiotic prophase. Importantly, CCDC79 associates with telomeres in SUN1-deficient spermatocytes, which strongly indicates that localization of CCDC79 to telomeres does not require telomere-nuclear envelope attachment. Conclusion: CCDC79 is a meiosis-specific telomere associated protein. Based on our findings we propose that CCDC79 plays a role in meiosis-specific telomere functions. In particular, we favour the possibility that CCDC79 is involved in telomere-nuclear envelope attachment and/or the stabilization of meiotic telomeres. These conclusions are consistent with the findings of an independently initiated study that analysed CCDC79/TERB1 functions.},
  language  = {en}
}
@article{GarciaMatosShenetal.2014,
  author    = {Garcia, Tzintzuni I. and Matos, Isa and Shen, Yingjia and Pabuwal, Vagmita and Coelho, Maria Manuela and Wakamatsu, Yuko and Schartl, Manfred and Walter, Ronald B.},
  title     = {Novel Method for Analysis of Allele Specific Expression in Triploid Oryzias latipes Reveals Consistent Pattern of Allele Exclusion},
  series = {PLOS ONE},
  volume    = {9},
  journal   = {PLOS ONE},
  number    = {6},
  issn      = {1932-6203},
  doi       = {10.1371/journal.pone.0100250},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-116000},
  pages     = {e100250},
  year      = {2014},
  abstract  = {Assessing allele-specific gene expression (ASE) on a large scale continues to be a technically challenging problem. Certain biological phenomena, such as X chromosome inactivation and parental imprinting, affect ASE most drastically by completely shutting down the expression of a whole set of alleles. Other more subtle effects on ASE are likely to be much more complex and dependent on the genetic environment and are perhaps more important to understand since they may be responsible for a significant amount of biological diversity. Tools to assess ASE in a diploid biological system are becoming more reliable. Non-diploid systems are, however, not uncommon. In humans full or partial polyploid states are regularly found in both healthy (meiotic cells, polynucleated cell types) and diseased tissues (trisomies, non-disjunction events, cancerous tissues). In this work we have studied ASE in the medaka fish model system. We have developed a method for determining ASE in polyploid organisms from RNAseq data and we have implemented this method in a software tool set. As a biological model system we have used nuclear transplantation to experimentally produce artificial triploid medaka composed of three different haplomes. We measured ASE in RNA isolated from the livers of two adult, triploid medaka fish that showed a high degree of similarity. The majority of genes examined (82\%) shared expression more or less evenly among the three alleles in both triploids. The rest of the genes (18\%) displayed a wide range of ASE levels. Interestingly the majority of genes (78\%) displayed generally consistent ASE levels in both triploid individuals. A large contingent of these genes had the same allele entirely suppressed in both triploids. When viewed in a chromosomal context, it is revealed that these genes are from large sections of 4 chromosomes and may be indicative of some broad scale suppression of gene expression.},
  language  = {en}
}
@article{BaalbergenHelwerdaSchelfhorstetal.2014,
  author    = {Baalbergen, Els and Helwerda, Renate and Schelfhorst, Rense and Castillo Cajas, Ruth F. and van Moorsel, Coline H. M. and Kundrata, Robin and Welter-Schultes, Francisco W. and Giokas, Sinos and Schilthuizen, Menno},
  title     = {Predator-Prey Interactions between Shell-Boring Beetle Larvae and Rock-Dwelling Land Snails},
  series = {PLOS ONE},
  volume    = {9},
  journal   = {PLOS ONE},
  number    = {6},
  issn      = {1932-6203},
  doi       = {10.1371/journal.pone.0100366},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115963},
  pages     = {e100366},
  year      = {2014},
  abstract  = {Drilus beetle larvae (Coleoptera: Elateridae) are specialized predators of land snails. Here, we describe various aspects of the predator-prey interactions between multiple Drilus species attacking multiple Albinaria (Gastropoda: Clausiliidae) species in Greece. We observe that Drilus species may be facultative or obligate Albinaria-specialists. We map geographically varying predation rates in Crete, where on average 24\% of empty shells carry fatal Drilus bore holes. We also provide first-hand observations and video-footage of prey entry and exit strategies of the Drilus larvae, and evaluate the potential mutual evolutionary impacts. We find limited evidence for an effect of shell features and snail behavioral traits on inter-and intraspecifically differing predation rates. We also find that Drilus predators adjust their predation behavior based on specific shell traits of the prey. In conclusion, we suggest that, with these baseline data, this interesting predator-prey system will be available for further, detailed more evolutionary ecology studies.},
  language  = {en}
}
@article{KleinStieglerKleinetal.2014,
  author    = {Klein, Barett Anthony and Stiegler, Martin and Klein, Arno and Tautz, J{\"u}rgen},
  title     = {Mapping Sleeping Bees within Their Nest: Spatial and Temporal Analysis of Worker Honey Bee Sleep},
  series = {PLOS ONE},
  volume    = {9},
  journal   = {PLOS ONE},
  number    = {7},
  issn      = {1932-6203},
  doi       = {10.1371/journal.pone.0102316},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115857},
  pages     = {e102316},
  year      = {2014},
  abstract  = {Patterns of behavior within societies have long been visualized and interpreted using maps. Mapping the occurrence of sleep across individuals within a society could offer clues as to functional aspects of sleep. In spite of this, a detailed spatial analysis of sleep has never been conducted on an invertebrate society. We introduce the concept of mapping sleep across an insect society, and provide an empirical example, mapping sleep patterns within colonies of European honey bees (Apis mellifera L.). Honey bees face variables such as temperature and position of resources within their colony's nest that may impact their sleep. We mapped sleep behavior and temperature of worker bees and produced maps of their nest's comb contents as the colony grew and contents changed. By following marked bees, we discovered that individuals slept in many locations, but bees of different worker castes slept in different areas of the nest relative to position of the brood and surrounding temperature. Older worker bees generally slept outside cells, closer to the perimeter of the nest, in colder regions, and away from uncapped brood. Younger worker bees generally slept inside cells and closer to the center of the nest, and spent more time asleep than awake when surrounded by uncapped brood. The average surface temperature of sleeping foragers was lower than the surface temperature of their surroundings, offering a possible indicator of sleep for this caste. We propose mechanisms that could generate caste-dependent sleep patterns and discuss functional significance of these patterns.},
  language  = {en}
}
@article{IoakeimidisOttKozjakPavlovicetal.2014,
  author    = {Ioakeimidis, Fotis and Ott, Christine and Kozjak-Pavlovic, Vera and Violitzi, Foteini and Rinotas, Vagelis and Makrinou, Eleni and Eliopoulos, Elias and Fasseas, Costas and Kollias, George and Douni, Eleni},
  title     = {A Splicing Mutation in the Novel Mitochondrial Protein DNAJC11 Causes Motor Neuron Pathology Associated with Cristae Disorganization, and Lymphoid Abnormalities in Mice},
  series = {PLOS ONE},
  volume    = {9},
  journal   = {PLOS ONE},
  number    = {8},
  doi       = {10.1371/journal.pone.0104237},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115581},
  pages     = {e104237},
  year      = {2014},
  abstract  = {Mitochondrial structure and function is emerging as a major contributor to neuromuscular disease, highlighting the need for the complete elucidation of the underlying molecular and pathophysiological mechanisms. Following a forward genetics approach with N-ethyl-N-nitrosourea (ENU)-mediated random mutagenesis, we identified a novel mouse model of autosomal recessive neuromuscular disease caused by a splice-site hypomorphic mutation in a novel gene of unknown function, DnaJC11. Recent findings have demonstrated that DNAJC11 protein co-immunoprecipitates with proteins of the mitochondrial contact site (MICOS) complex involved in the formation of mitochondrial cristae and cristae junctions. Homozygous mutant mice developed locomotion defects, muscle weakness, spasticity, limb tremor, leucopenia, thymic and splenic hypoplasia, general wasting and early lethality. Neuropathological analysis showed severe vacuolation of the motor neurons in the spinal cord, originating from dilatations of the endoplasmic reticulum and notably from mitochondria that had lost their proper inner membrane organization. The causal role of the identified mutation in DnaJC11 was verified in rescue experiments by overexpressing the human ortholog. The full length 63 kDa isoform of human DNAJC11 was shown to localize in the periphery of the mitochondrial outer membrane whereas putative additional isoforms displayed differential submitochondrial localization. Moreover, we showed that DNAJC11 is assembled in a high molecular weight complex, similarly to mitofilin and that downregulation of mitofilin or SAM50 affected the levels of DNAJC11 in HeLa cells. Our findings provide the first mouse mutant for a putative MICOS protein and establish a link between DNAJC11 and neuromuscular diseases.},
  language  = {en}
}
@article{MorrisCarusoBuscotetal.2014,
  author    = {Morris, E. Kathryn and Caruso, Tancredi and Buscot, Francois and Fischer, Markus and Hancock, Christine and Maier, Tanja S. and Meiners, Torsten and M{\"u}ller, Caroline and Obermaier, Elisabeth and Prati, Daniel and Socher, Stephanie A. and Sonnemann, Ilja and W{\"a}schke, Nicola and Wubet, Tesfaye and Wurst, Susanne and Rillig, Matthias C.},
  title     = {Choosing and using diversity indices: insights for ecological applications from the German Biodiversity Exploratories},
  series = {Ecology and Evolution},
  volume    = {4},
  journal   = {Ecology and Evolution},
  number    = {18},
  issn      = {2045-7758},
  doi       = {10.1002/ece3.1155},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115462},
  pages     = {3514-3524},
  year      = {2014},
  abstract  = {Biodiversity, a multidimensional property of natural systems, is difficult to quantify partly because of the multitude of indices proposed for this purpose. Indices aim to describe general properties of communities that allow us to compare different regions, taxa, and trophic levels. Therefore, they are of fundamental importance for environmental monitoring and conservation, although there is no consensus about which indices are more appropriate and informative. We tested several common diversity indices in a range of simple to complex statistical analyses in order to determine whether some were better suited for certain analyses than others. We used data collected around the focal plant Plantago lanceolata on 60 temperate grassland plots embedded in an agricultural landscape to explore relationships between the common diversity indices of species richness (S), Shannon's diversity (H'), Simpson's diversity (D-1), Simpson's dominance (D-2), Simpson's evenness (E), and Berger-Parker dominance (BP). We calculated each of these indices for herbaceous plants, arbuscular mycorrhizal fungi, aboveground arthropods, belowground insect larvae, and P.lanceolata molecular and chemical diversity. Including these trait-based measures of diversity allowed us to test whether or not they behaved similarly to the better studied species diversity. We used path analysis to determine whether compound indices detected more relationships between diversities of different organisms and traits than more basic indices. In the path models, more paths were significant when using H', even though all models except that with E were equally reliable. This demonstrates that while common diversity indices may appear interchangeable in simple analyses, when considering complex interactions, the choice of index can profoundly alter the interpretation of results. Data mining in order to identify the index producing the most significant results should be avoided, but simultaneously considering analyses using multiple indices can provide greater insight into the interactions in a system.},
  language  = {en}
}
@article{VolceanovHerbstBiniosseketal.2014,
  author    = {Volceanov, Larisa and Herbst, Katharina and Biniossek, Martin and Schilling, Oliver and Haller, Dirk and N{\"o}lke, Thilo and Subbarayal, Prema and Rudel, Thomas and Zieger, Barbara and H{\"a}cker, Georg},
  title     = {Septins Arrange F-Actin-Containing Fibers on the Chlamydia trachomatis Inclusion and Are Required for Normal Release of the Inclusion by Extrusion},
  series = {MBIO},
  volume    = {5},
  journal   = {MBIO},
  number    = {5},
  issn      = {2150-7511},
  doi       = {10.1128/mBio.01802-14},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115421},
  pages     = {e01802-14},
  year      = {2014},
  abstract  = {Chlamydia trachomatis is an obligate intracellular human pathogen that grows inside a membranous, cytosolic vacuole termed an inclusion. Septins are a group of 13 GTP-binding proteins that assemble into oligomeric complexes and that can form higher-order filaments. We report here that the septins SEPT2, -9, -11, and probably -7 form fibrillar structures around the chlamydial inclusion. Colocalization studies suggest that these septins combine with F actin into fibers that encase the inclusion. Targeting the expression of individual septins by RNA interference (RNAi) prevented the formation of septin fibers as well as the recruitment of actin to the inclusion. At the end of the developmental cycle of C. trachomatis, newly formed, infectious elementary bodies are released, and this release occurs at least in part through the organized extrusion of intact inclusions. RNAi against SEPT9 or against the combination of SEPT2/7/9 substantially reduced the number of extrusions from a culture of infected HeLa cells. The data suggest that a higher-order structure of four septins is involved in the recruitment or stabilization of the actin coat around the chlamydial inclusion and that this actin recruitment by septins is instrumental for the coordinated egress of C. trachomatis from human cells. The organization of F actin around parasite-containing vacuoles may be a broader response mechanism of mammalian cells to the infection by intracellular, vacuole-dwelling pathogens. IMPORTANCE Chlamydia trachomatis is a frequent bacterial pathogen throughout the world, causing mostly eye and genital infections. C. trachomatis can develop only inside host cells; it multiplies inside a membranous vacuole in the cytosol, termed an inclusion. The inclusion is covered by cytoskeletal "coats" or "cages," whose organization and function are poorly understood. We here report that a relatively little-characterized group of proteins, septins, is required to organize actin fibers on the inclusion and probably through actin the release of the inclusion. Septins are a group of GTP-binding proteins that can organize into heteromeric complexes and then into large filaments. Septins have previously been found to be involved in the interaction of the cell with bacteria in the cytosol. Our observation that they also organize a reaction to bacteria living in vacuoles suggests that they have a function in the recognition of foreign compartments by a parasitized human cell.},
  language  = {en}
}
@article{KernAgarwalHuberetal.2014,
  author    = {Kern, Selina and Agarwal, Shruti and Huber, Kilian and Gehring, Andre P. and Str{\"o}dke, Benjamin and Wirth, Christine C. and Br{\"u}gl, Thomas and Abodo, Liane Onambele and Dandekar, Thomas and Doerig, Christian and Fischer, Rainer and Tobin, Andrew B. and Alam, Mahmood M. and Bracher, Franz and Pradel, Gabriele},
  title     = {Inhibition of the SR Protein-Phosphorylating CLK Kinases of Plasmodium falciparum Impairs Blood Stage Replication and Malaria Transmission},
  series = {PLOS ONE},
  volume    = {9},
  journal   = {PLOS ONE},
  number    = {9},
  issn      = {1932-6203},
  doi       = {10.1371/journal.pone.0105732},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115405},
  pages     = {e105732},
  year      = {2014},
  abstract  = {Cyclin-dependent kinase-like kinases (CLKs) are dual specificity protein kinases that phosphorylate Serine/Arginine-rich (SR) proteins involved in pre-mRNA processing. Four CLKs, termed PfCLK-1-4, can be identified in the human malaria parasite Plasmodium falciparum, which show homology with the yeast SR protein kinase Sky1p. The four PfCLKs are present in the nucleus and cytoplasm of the asexual blood stages and of gametocytes, sexual precursor cells crucial for malaria parasite transmission from humans to mosquitoes. We identified three plasmodial SR proteins, PfSRSF12, PfSFRS4 and PfSF-1, which are predominantly present in the nucleus of blood stage trophozoites, PfSRSF12 and PfSF-1 are further detectable in the nucleus of gametocytes. We found that recombinantly expressed SR proteins comprising the Arginine/Serine (RS)-rich domains were phosphorylated by the four PfCLKs in in vitro kinase assays, while a recombinant PfSF-1 peptide lacking the RS-rich domain was not phosphorylated. Since it was hitherto not possible to knock-out the pfclk genes by conventional gene disruption, we aimed at chemical knock-outs for phenotype analysis. We identified five human CLK inhibitors, belonging to the oxo-beta-carbolines and aminopyrimidines, as well as the antiseptic chlorhexidine as PfCLK-targeting compounds. The six inhibitors block P. falciparum blood stage replication in the low micromolar to nanomolar range by preventing the trophozoite-to-schizont transformation. In addition, the inhibitors impair gametocyte maturation and gametogenesis in in vitro assays. The combined data show that the four PfCLKs are involved in phosphorylation of SR proteins with essential functions for the blood and sexual stages of the malaria parasite, thus pointing to the kinases as promising targets for antimalarial and transmission blocking drugs.},
  language  = {en}
}
@article{MuthalaguJunttilaWieseetal.2014,
  author    = {Muthalagu, Nathiya and Junttila, Melissa R. and Wiese, Kathrin E. and Wolf, Elmar and Morton, Jennifer and Bauer, Barbara and Evan, Gerard I. and Eilers, Martin and Murphy, Daniel J.},
  title     = {BIM Is the Primary Mediator of MYC-Induced Apoptosis in Multiple Solid Tissues},
  series = {Cell Reports},
  volume    = {8},
  journal   = {Cell Reports},
  number    = {5},
  doi       = {10.1016/j.celrep.2014.07.057},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115370},
  pages     = {1347-1353},
  year      = {2014},
  abstract  = {MYC is one of the most frequently overexpressed oncogenes in human cancer, and even modestly deregulated MYC can initiate ectopic proliferation in many postmitotic cell types in vivo. Sensitization of cells to apoptosis limits MYC's oncogenic potential. However, the mechanism through which MYC induces apoptosis is controversial. Some studies implicate p19ARF-mediated stabilization of p53, followed by induction of proapoptotic BH3 proteins NOXA and PUMA, whereas others argue for direct regulation of BH3 proteins, especially BIM. Here, we use a single experimental system to systematically evaluate the roles of p19ARF and BIM during MYC-induced apoptosis, in vitro, in vivo, and in combination with a widely used chemotherapeutic, doxorubicin. We find a common specific requirement for BIM during MYC-induced apoptosis in multiple settings, which does not extend to the p53-responsive BH3 family member PUMA, and find no evidence of a role for p19ARF during MYC-induced apoptosis in the tissues examined.},
  language  = {en}
}
@article{PamirSzyszkaScheineretal.2014,
  author    = {Pamir, Evren and Szyszka, Paul and Scheiner, Ricarda and Nawrot, Martin P.},
  title     = {Rapid learning dynamics in individual honeybees during classical conditioning},
  series = {Frontiers in Behavioral Neuroscience},
  volume    = {8},
  journal   = {Frontiers in Behavioral Neuroscience},
  number    = {313},
  issn      = {1662-5153},
  doi       = {10.3389/fnbeh.2014.00313},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115365},
  year      = {2014},
  abstract  = {Associative learning in insects has been studied extensively by a multitude of classical conditioning protocols. However, so far little emphasis has been put on the dynamics of learning in individuals. The honeybee is a well-established animal model for learning and memory. We here studied associative learning as expressed in individual behavior based on a large collection of data on olfactory classical conditioning (25 datasets, 3298 animals). We show that the group-averaged learning curve and memory retention score confound three attributes of individual learning: the ability or inability to learn a given task, the generally fast acquisition of a conditioned response (CR) in learners, and the high stability of the CR during consecutive training and memory retention trials. We reassessed the prevailing view that more training results in better memory performance and found that 24 h memory retention can be indistinguishable after single-trial and multiple-trial conditioning in individuals. We explain how inter-individual differences in learning can be accommodated within the Rescorla Wagner theory of associative learning. In both data-analysis and modeling we demonstrate how the conflict between population-level and single-animal perspectives on learning and memory can be disentangled.},
  language  = {en}
}
@article{StellamannsUppaluriHochstetteretal.2014,
  author    = {Stellamanns, Eric and Uppaluri, Sravanti and Hochstetter, Axel and Heddergott, Niko and Engstler, Markus and Pfohl, Thomas},
  title     = {Optical trapping reveals propulsion forces, power generation and motility efficiency of the unicellular parasites Trypanosoma brucei brucei},
  series = {Scientific Reports},
  volume    = {4},
  journal   = {Scientific Reports},
  number    = {6515},
  issn      = {2045-2322},
  doi       = {10.1038/srep06515},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115348},
  year      = {2014},
  abstract  = {Unicellular parasites have developed sophisticated swimming mechanisms to survive in a wide range of environments. Cell motility of African trypanosomes, parasites responsible for fatal illness in humans and animals, is crucial both in the insect vector and the mammalian host. Using millisecond-scale imaging in a microfluidics platform along with a custom made optical trap, we are able to confine single cells to study trypanosome motility. From the trapping characteristics of the cells, we determine the propulsion force generated by cells with a single flagellum as well as of dividing trypanosomes with two fully developed flagella. Estimates of the dissipative energy and the power generation of single cells obtained from the motility patterns of the trypanosomes within the optical trap indicate that specific motility characteristics, in addition to locomotion, may be required for antibody clearance. Introducing a steerable second optical trap we could further measure the force, which is generated at the flagellar tip. Differences in the cellular structure of the trypanosomes are correlated with the trapping and motility characteristics and in consequence with their propulsion force, dissipative energy and power generation.},
  language  = {en}
}
@phdthesis{Wurster2014,
  author    = {Wurster, Sebastian},
  title     = {Die Bedeutung von LIN9 f{\"u}r die Regulation der Genexpression, die genomische Stabilit{\"a}t und die Tumorsuppression},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-114967},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {Pocket proteins and E2F transcription factors regulate the expression of cell cycle associated genes and play a central role in the coordination of cell division, differentiation, and apoptosis. Disorders of these pathways contribute to the development of various human tumor entities. Despite intensive research in the field of cell cycle regulation many details are not yet understood. The LIN complex (LINC / DREAM) is a recently discovered human multiprotein complex, which dynamically interacts with pocket proteins and E2F transcription factors. An essential component of the LIN complex is the LIN9 protein. In order to obtain a better insight into the function of this protein in cell cycle regulation and tumorigenesis, a conditional Lin9 knockout mouse model was established in our laboratory. The primary objective of this study was the phenotypic characterization of embryonic fibroblasts (MEFs) from these mice. Shortly after inactivation of Lin9 cell proliferation was massively impaired. Multiple types of mitotic defects such as structural abnormalities of the spindle apparatus, aberrant nuclei, failed nuclear segregation and cytokinesis failure have been observed in Lin9-depleted cells leading to a dramatic increase in polyploid and aneuploid cells. Ultimately these serious aberrations result in premature cellular senescence. If the senescence of Lin9-deficient cells is overcome by the Large T antigen the cells can adhere to the loss of Lin9, but show severe genomic instability and grow anchorage-independently in soft-agar as a sign of oncogenic transformation. In the second part of the thesis the gene expression of Lin9-deficient cells was assessed by quantitative real time PCR analyses to determine, whether the mitotic abnormalities are caused by transcriptional defects. Here a significant reduction of mitotic gene expression was observed in Lin9-depleted cells. Additionally chromatin immunoprecipitation experiments were performed to clarify the underlying molecular mechanisms. Compared to control cells epigenetic alterations at the promoters of mitotic target genes with regard to activating histone modifications were found in Lin9-deficient MEFs. In the last section of this study, the effects of Lin9 heterozygosity were analyzed. Lin9 heterozygous MEFs showed normal proliferation, although expression of different mitotic genes was slightly reduced. It appeared, however, that the mitotic spindle checkpoint of Lin9 heterozygous MEFs is weakened and thus over several cell generations an increase in polyploid cells was observed. Soft-agar assays showed that Lin9 heterozygosity contributes to oncogenic transformation. Taken together, these results document a crucial role of LIN9 in the regulation of cell cycle-associated gene expression. LIN9 is an essential factor for cell proliferation on one hand, while at the same time it functions as a tumor suppressor.},
  subject      = {Zellzyklus},
  language  = {de}
}
@article{BensaadFavaroLewisetal.2014,
  author    = {Bensaad, Karim and Favaro, Elena and Lewis, Caroline A. and Peck, Barrie and Lord, Simon and Collins, Jennifer M. and Pinnick, Katherine E. and Wigfield, Simon and Buffa, Francesca M. and Li, Ji-Liang and Zhang, Qifeng and Wakelam, Michael J. O. and Karpe, Fredrik and Schulze, Almut and Harris, Adrian L.},
  title     = {Fatty Acid Uptake and Lipid Storage Induced by HIF-1 alpha Contribute to Cell Growth and Survival after Hypoxia-Reoxygenation},
  series = {Cell Reports},
  volume    = {9},
  journal   = {Cell Reports},
  number    = {1},
  issn      = {2211-1247},
  doi       = {10.1016/j.celrep.2014.08.056},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-115162},
  pages     = {349-365},
  year      = {2014},
  abstract  = {An in vivo model of antiangiogenic therapy allowed us to identify genes upregulated by bevacizumab treatment, including Fatty Acid Binding Protein 3 (FABP3) and FABP7, both of which are involved in fatty acid uptake. In vitro, both were induced by hypoxia in a hypoxia-inducible factor-1 alpha (HIF-1 alpha)-dependent manner. There was a significant lipid droplet (LD) accumulation in hypoxia that was time and O-2 concentration dependent. Knockdown of endogenous expression of FABP3, FABP7, or Adipophilin (an essential LD structural component) significantly impaired LD formation under hypoxia. We showed that LD accumulation is due to FABP3/7-dependent fatty acid uptake while de novo fatty acid synthesis is repressed in hypoxia. We also showed that ATP production occurs via beta-oxidation or glycogen degradation in a cell-type-dependent manner in hypoxia-reoxygenation. Finally, inhibition of lipid storage reduced protection against reactive oxygen species toxicity, decreased the survival of cells subjected to hypoxia-reoxygenation in vitro, and strongly impaired tumorigenesis in vivo.},
  language  = {en}
}
@article{AkhoonSinghVarshneyetal.2014,
  author    = {Akhoon, Bashir A. and Singh, Krishna P. and Varshney, Megha and Gupta, Shishir K. and Shukla, Yogeshwar and Gupta, Shailendra K.},
  title     = {Understanding the Mechanism of Atovaquone Drug Resistance in Plasmodium falciparum Cytochrome b Mutation Y268S Using Computational Methods},
  series = {PLOS ONE},
  volume    = {9},
  journal   = {PLOS ONE},
  number    = {10},
  doi       = {10.1371/journal.pone.0110041},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-114882},
  pages     = {e110041},
  year      = {2014},
  abstract  = {The rapid appearance of resistant malarial parasites after introduction of atovaquone (ATQ) drug has prompted the search for new drugs as even single point mutations in the active site of Cytochrome b protein can rapidly render ATQ ineffective. The presence of Y268 mutations in the Cytochrome b (Cyt b) protein is previously suggested to be responsible for the ATQ resistance in Plasmodium falciparum (P. falciparum). In this study, we examined the resistance mechanism against ATQ in P. falciparum through computational methods. Here, we reported a reliable protein model of Cyt bc1 complex containing Cyt b and the Iron-Sulphur Protein (ISP) of P. falciparum using composite modeling method by combining threading, ab initio modeling and atomic-level structure refinement approaches. The molecular dynamics simulations suggest that Y268S mutation causes ATQ resistance by reducing hydrophobic interactions between Cyt bc1 protein complex and ATQ. Moreover, the important histidine contact of ATQ with the ISP chain is also lost due to Y268S mutation. We noticed the induced mutation alters the arrangement of active site residues in a fashion that enforces ATQ to find its new stable binding site far away from the wild-type binding pocket. The MM-PBSA calculations also shows that the binding affinity of ATQ with Cyt bc1 complex is enough to hold it at this new site that ultimately leads to the ATQ resistance.},
  language  = {en}
}
@article{SenecalIsabelleFritzleretal.2014,
  author    = {Senecal, Jean-Luc and Isabelle, Catherine and Fritzler, Marvin J. and Targoff, Ira N. and Goldstein, Rose and Gagne, Michel and Raynauld, Jean-Pierre and Joyal, France and Troyanov, Yves and Dabauvalle, Marie-Christine},
  title     = {An Autoimmune Myositis-Overlap Syndrome Associated With Autoantibodies to Nuclear Pore Complexes Description and Long-Term Follow-up of the Anti-Nup Syndrome},
  series = {Medicine},
  volume    = {93},
  journal   = {Medicine},
  number    = {24},
  issn      = {0025-7974},
  doi       = {10.1097/MD.0000000000000223},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-114829},
  pages     = {361-372},
  year      = {2014},
  abstract  = {Autoimmune myositis encompasses various myositis-overlap syndromes, each being identified by the presence of serum marker autoantibodies. We describe a novel myositis-overlap syndrome in 4 patients characterized by the presence of a unique immunologic marker, autoantibodies to nuclear pore complexes. The clinical phenotype was characterized by prominent myositis in association with erosive, anti-CCP, and rheumatoid factor-positive arthritis, trigeminal neuralgia, mild interstitial lung disease, Raynaud phenomenon, and weight loss. The myositis was typically chronic, relapsing, and refractory to corticosteroids alone, but remitted with the addition of a second immuno-modulating drug. There was no clinical or laboratory evidence for liver disease. The prognosis was good with 100\% long-term survival (mean follow-up 19.5 yr). By indirect immunofluorescence on HEp-2 cells, sera from all 4 patients displayed a high titer of antinuclear autoantibodies (ANA) with a distinct punctate peripheral (rim) fluorescent pattern of the nuclear envelope characteristic of nuclear pore complexes. Reactivity with nuclear pore complexes was confirmed by immunoelectron microscopy. In a cohort of 100 French Canadian patients with autoimmune myositis, the nuclear pore complex fluorescent ANA pattern was restricted to these 4 patients (4\%). It was not observed in sera from 393 adult patients with systemic sclerosis (n = 112), mixed connective tissue disease (n = 35), systemic lupus (n = 94), rheumatoid arthritis (n = 45), or other rheumatic diseases (n = 107), nor was it observed in 62 normal adults. Autoantibodies to nuclear pore complexes were predominantly of IgG isotype. No other IgG autoantibody markers for defined connective tissue diseases or overlap syndromes were present, indicating a selective and highly focused immune response. In 3 patients, anti-nuclear pore complex autoantibody titers varied in parallel with myositis activity, suggesting a pathogenic link to pathophysiology. The nuclear pore complex proteins, that is, nucleoporins (nup), recognized by these sera were heterogeneous and included Nup358/RanBP2 (n = 2 patients), Nup90 (n = 1), Nup62 (n = 1), and gp210 (n = 1). Taken together the data suggest that nup autoantigens themselves drive the anti-nup autoimmune response. Immunogenetically, the 4 patients shared the DQA1*0501 allele associated with an increased risk for autoimmune myositis. In conclusion, we report an apparent novel subset of autoimmune myositis in our population of French Canadian patients with connective tissue diseases. This syndrome is recognized by the presence of a unique immunologic marker, autoantibodies to nuclear pore complexes that react with nups, consistent with an "anti-nupsyndrome.''},
  language  = {en}
}
@phdthesis{Klein2014,
  author    = {Klein, Teresa},
  title     = {Lokalisationsmikroskopie f{\"u}r die Visualisierung zellul{\"a}rer Strukturen},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-99260},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {Die Einf{\"u}hrung der Fluoreszenzmikroskopie erm{\"o}glicht es, Strukturen in Zellen spezifisch und mit hohem Kontrast zu markieren und zu untersuchen. Da die Lichtmikroskopie jedoch in ihrer Aufl{\"o}sung begrenzt ist, bleiben Strukturinformationen auf molekularer Ebene verborgen. Diese als Beugungsgrenze bekannte Limitierung, kann mit modernen Verfahren umgangen werden. Die Lokalisationsmikroskopie nutzt hierf{\"u}r photoschaltbare Fluorophore, deren Fluoreszenz r{\"a}umlich und zeitlich separiert wird, um so einzelne Fluorophore mit Nanometer-Genauigkeit lokalisieren zu k{\"o}nnen. Aus tausenden Einzelmolek{\"u}l-Lokalisationen wird ein k{\"u}nstliches, hochaufgel{\"o}stes Bild rekonstruiert. Die hochaufl{\"o}sende Mikroskopie ist grade f{\"u}r die Lebendzell-Beobachtung ein wertvolles Werkzeug, um subzellul{\"a}re Strukturen und Proteindynamiken jenseits der Beugungsgrenze unter physiologischen Bedingungen untersuchen zu k{\"o}nnen. Als Marker k{\"o}nnen sowohl photoaktivierbare fluoreszierende Proteine als auch photoschaltbare organische Fluorophore eingesetzt werden. W{\"a}hrend die Markierung mit fluoreszierenden Proteinen einfach zu verwirklichen ist, haben organische Farbstoffe hingegen den Vorteil, dass sie auf Grund der h{\"o}heren Photonenausbeute eine pr{\"a}zisere Lokalisation erlauben. In lebenden Zellen wird die Markierung von Strukturen mit synthetischen Fluorophoren {\"u}ber sogenannte chemische Tags erm{\"o}glicht. Diese sind olypeptidsequenzen, die genetisch an das Zielprotein fusioniert werden und anschließend mit Farbstoff-gekoppelten Substraten gef{\"a}rbt werden. An der Modellstruktur des Histonproteins H2B werden in dieser Arbeit Farbstoffe in Kombination mit chemischen Tags identifiziert, die erfolgreich f{\"u}r die Hochaufl{\"o}sung mit direct stochastic optical reconstruction microscopy (dSTORM) in lebenden Zellen eingesetzt werden k{\"o}nnen. F{\"u}r besonders geeignet erweisen sich die Farbstoffe Tetramethylrhodamin, 505 und Atto 655, womit der gesamte spektrale Bereich vertreten ist. Allerdings k{\"o}nnen unspezifische Bindung und Farbstoffaggregation ein Problem bei der effizienten Markierung in lebenden Zellen darstellen. Es wird gezeigt, dass die Beschichtung der Glasoberfl{\"a}che mit Glycin die unspezifische Adsorption der Fluorophore erfolgreich minimieren kann. Weiterhin wird der Einfluss des Anregungslichtes auf die lebende Zelle diskutiert. Es werden Wege beschrieben, um die Photosch{\"a}digung m{\"o}glichst gering zu halten, beispielsweise durch die Wahl eines Farbstoffs im rotem Anregungsbereich. Die M{\"o}glichkeit lebende Zellen mit photoschaltbaren organischen Fluorophoren spezifisch markieren zu k{\"o}nnen, stellt einen großen Gewinn f{\"u}r die Lokalisationsmikroskopie dar, bei der urspr{\"u}nglich farbstoffgekoppelte Antik{\"o}rper zum Einsatz kamen. Diese Markierungsmethode wird in dieser Arbeit eingesetzt, um das Aggregationsverhalten von Alzheimer verursachenden � -Amyloid Peptiden im Rahmen einer Kooperation zu untersuchen. Es werden anhand von HeLa Zellen verschiedene beugungsbegrenzte Morphologien der Aggregate aufgekl{\"a}rt. Dabei wird gezeigt, dass intrazellul{\"a}r vorhandene Peptide gr{\"o}ßere Aggregate formen als die im extrazellul{\"a}ren Bereich. In einer zweiten Kollaboration wird mit Hilfe des photoaktivierbaren Proteins mEos2 und photoactivated localization microscopy (PALM) die strukturelle Organisation zweier Flotillinproteine in der Membran von Bakterien untersucht. Diese Proteine bilden zwei Cluster mit unterschiedlichen Durchmessern, die mit Nanometer-Genauigkeit bestimmt werden konnten. Es wurde außerdem festgestellt, dass beide Proteine in unterschiedlichen Anzahlen im Bakterium vorliegen.},
  subject      = {Hochaufl{\"o}sendes Verfahren},
  language  = {de}
}
@article{HudsonNewboldContuetal.2014,
  author    = {Hudson, Lawrence N. and Newbold, Tim and Contu, Sara and Hill, Samantha L. L. and Lysenko, Igor and De Palma, Adriana and Phillips, Helen R. P. and Senior, Rebecca A. and Bennett, Dominic J. and Booth, Hollie and Choimes, Argyrios and Correia, David L. P. and Day, Julie and Echeverria-Londono, Susy and Garon, Morgan and Harrison, Michelle L. K. and Ingram, Daniel J. and Jung, Martin and Kemp, Victoria and Kirkpatrick, Lucinda and Martin, Callum D. and Pan, Yuan and White, Hannah J. and Aben, Job and Abrahamczyk, Stefan and Adum, Gilbert B. and Aguilar-Barquero, Virginia and Aizen, Marcelo and Ancrenaz, Marc and Arbelaez-Cortes, Enrique and Armbrecht, Inge and Azhar, Badrul and Azpiroz, Adrian B. and Baeten, Lander and B{\´a}ldi, Andr{\´a}s and Banks, John E. and Barlow, Jos and Bat{\´a}ry, P{\´e}ter and Bates, Adam J. and Bayne, Erin M. and Beja, Pedro and Berg, Ake and Berry, Nicholas J. and Bicknell, Jake E. and Bihn, Jochen H. and B{\"o}hning-Gaese, Katrin and Boekhout, Teun and Boutin, Celine and Bouyer, Jeremy and Brearley, Francis Q. and Brito, Isabel and Brunet, J{\"o}rg and Buczkowski, Grzegorz and Buscardo, Erika and Cabra-Garcia, Jimmy and Calvino-Cancela, Maria and Cameron, Sydney A. and Cancello, Eliana M. and Carrijo, Tiago F. and Carvalho, Anelena L. and Castro, Helena and Castro-Luna, Alejandro A. and Cerda, Rolando and Cerezo, Alexis and Chauvat, Matthieu and Clarke, Frank M. and Cleary, Daniel F. R. and Connop, Stuart P. and D'Aniello, Biagio and da Silva, Pedro Giovani and Darvill, Ben and Dauber, Jens and Dejean, Alain and Diek{\"o}tter, Tim and Dominguez-Haydar, Yamileth and Dormann, Carsten F. and Dumont, Bertrand and Dures, Simon G. and Dynesius, Mats and Edenius, Lars and Elek, Zolt{\´a}n and Entling, Martin H. and Farwig, Nina and Fayle, Tom M. and Felicioli, Antonio and Felton, Annika M. and Ficetola, Gentile F. and Filgueiras, Bruno K. C. and Fonte, Steve J. and Fraser, Lauchlan H. and Fukuda, Daisuke and Furlani, Dario and Ganzhorn, J{\"o}rg U. and Garden, Jenni G. and Gheler-Costa, Carla and Giordani, Paolo and Giordano, Simonetta and Gottschalk, Marco S. and Goulson, Dave and Gove, Aaron D. and Grogan, James and Hanley, Mick E. and Hanson, Thor and Hashim, Nor R. and Hawes, Joseph E. and H{\´e}bert, Christian and Helden, Alvin J. and Henden, John-Andr{\´e} and Hern{\´a}ndez, Lionel and Herzog, Felix and Higuera-Diaz, Diego and Hilje, Branko and Horgan, Finbarr G. and Horv{\´a}th, Roland and Hylander, Kristoffer and Horv{\´a}th, Roland and Isaacs-Cubides, Paola and Ishitani, Mashiro and Jacobs, Carmen T. and Jaramillo, Victor J. and Jauker, Birgit and Jonsell, Matts and Jung, Thomas S. and Kapoor, Vena and Kati, Vassiliki and Katovai, Eric and Kessler, Michael and Knop, Eva and Kolb, Annette and K{\"o}r{\"o}si, {\`A}d{\´a}m and Lachat, Thibault and Lantschner, Victoria and Le F{\´e}on, Violette and LeBuhn, Gretchen and L{\´e}gar{\´e}, Jean-Philippe and Letcher, Susan G. and Littlewood, Nick A. and L{\´o}pez-Quintero, Carlos A. and Louhaichi, Mounir and L{\"o}vei, Gabor L. and Lucas-Borja, Manuel Esteban and Luja, Victor H. and Maeto, Kaoru and Magura, Tibor and Mallari, Neil Aldrin and Marin-Spiotta, Erika and Marhall, E. J. P. and Mart{\´i}nez, Eliana and Mayfield, Margaret M. and Mikusinski, Gregorz and Milder, Jeffery C. and Miller, James R. and Morales, Carolina L. and Muchane, Mary N. and Muchane, Muchai and Naidoo, Robin and Nakamura, Akihiro and Naoe, Shoji and Nates-Parra, Guiomar and Navarerete Gutierrez, Dario A. and Neuschulz, Eike L. and Noreika, Norbertas and Norfolk, Olivia and Noriega, Jorge Ari and N{\"o}ske, Nicole M. and O'Dea, Niall and Oduro, William and Ofori-Boateng, Caleb and Oke, Chris O. and Osgathorpe, Lynne M. and Paritsis, Juan and Parrah, Alejandro and Pelegrin, Nicol{\´a}s and Peres, Carlos A. and Persson, Anna S. and Petanidou, Theodora and Phalan, Ben and Philips, T. Keith and Poveda, Katja and Power, Eileen F. and Presley, Steven J. and Proen{\c{c}}a, V{\^a}nia and Quaranta, Marino and Quintero, Carolina and Redpath-Downing, Nicola A. and Reid, J. Leighton and Reis, Yana T. and Ribeiro, Danilo B. and Richardson, Barbara A. and Richardson, Michael J. and Robles, Carolina A. and R{\"o}mbke, J{\"o}rg and Romero-Duque, Luz Piedad and Rosselli, Loreta and Rossiter, Stephen J. and Roulston, T'ai H. and Rousseau, Laurent and Sadler, Jonathan P. and S{\´a}fi{\´a}n, Szbolcs and Salda{\~n}a-V{\´a}squez, Romeo A. and Samneg{\aa}rd, Ulrika and Sch{\"u}epp, Christof and Schweiger, Oliver and Sedlock, Jodi L. and Shahabuddin, Ghazala and Sheil, Douglas and Silva, Fernando A. B. and Slade, Eleanor and Smith-Pardo, Allan H. and Sodhi, Navjot S. and Somarriba, Eduardo J. and Sosa, Ram{\´o}n A. and Stout, Jane C. and Struebig, Matthew J. and Sung, Yik-Hei and Threlfall, Caragh G. and Tonietto, Rebecca and T{\´o}thm{\´e}r{\´e}sz, B{\´e}la and Tscharntke, Teja and Turner, Edgar C. and Tylianakis, Jason M. and Vanbergen, Adam J. and Vassilev, Kiril and Verboven, Hans A. F. and Vergara, Carlos H. and Vergara, Pablo M. and Verhulst, Jort and Walker, Tony R. and Wang, Yanping and Watling, James I. and Wells, Konstans and Williams, Christopher D. and Willig, Michael R. and Woinarski, John C. Z. and Wolf, Jan H. D. and Woodcock, Ben A. and Yu, Douglas W. and Zailsev, Andreys and Collen, Ben and Ewers, Rob M. and Mace, Georgina M. and Purves, Drew W. and Scharlemann, J{\"o}rn P. W. and Pervis, Andy},
  title     = {The PREDICTS database: a global database of how local terrestrial biodiversity responds to human impacts},
  series = {Ecology and Evolution},
  volume    = {4},
  journal   = {Ecology and Evolution},
  number    = {24},
  doi       = {10.1002/ece3.1303},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-114425},
  pages     = {4701 - 4735},
  year      = {2014},
  abstract  = {Biodiversity continues to decline in the face of increasing anthropogenic pressures such as habitat destruction, exploitation, pollution and introduction of alien species. Existing global databases of species' threat status or population time series are dominated by charismatic species. The collation of datasets with broad taxonomic and biogeographic extents, and that support computation of a range of biodiversity indicators, is necessary to enable better understanding of historical declines and to project - and avert - future declines. We describe and assess a new database of more than 1.6 million samples from 78 countries representing over 28,000 species, collated from existing spatial comparisons of local-scale biodiversity exposed to different intensities and types of anthropogenic pressures, from terrestrial sites around the world. The database contains measurements taken in 208 (of 814) ecoregions, 13 (of 14) biomes, 25 (of 35) biodiversity hotspots and 16 (of 17) megadiverse countries. The database contains more than 1\% of the total number of all species described, and more than 1\% of the described species within many taxonomic groups - including flowering plants, gymnosperms, birds, mammals, reptiles, amphibians, beetles, lepidopterans and hymenopterans. The dataset, which is still being added to, is therefore already considerably larger and more representative than those used by previous quantitative models of biodiversity trends and responses. The database is being assembled as part of the PREDICTS project (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems - ). We make site-level summary data available alongside this article. The full database will be publicly available in 2015.},
  language  = {en}
}
@article{RozyckaWojtasJakobetal.2014,
  author    = {Rozycka, Miroslawa and Wojtas, Magdalena and Jakob, Michal and Stigloher, Christian and Grzeszkowiak, Mikolaj and Mazur, Maciej and Ozyhar, Andrzej},
  title     = {Intrinsically Disordered and Pliable Starmaker-Like Protein from Medaka (Oryzias latipes) Controls the Formation of Calcium Carbonate Crystals},
  series = {PLOS ONE},
  volume    = {9},
  journal   = {PLOS ONE},
  number    = {12},
  issn      = {1932-6203},
  doi       = {10.1371/journal.pone.0114308},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-114251},
  year      = {2014},
  abstract  = {Fish otoliths, biominerals composed of calcium carbonate with a small amount of organic matrix, are involved in the functioning of the inner ear. Starmaker (Stm) from zebrafish (Danio rerio) was the first protein found to be capable of controlling the formation of otoliths. Recently, a gene was identified encoding the Starmaker-like (Stm-l) protein from medaka (Oryzias latipes), a putative homologue of Stm and human dentine sialophosphoprotein. Although there is no sequence similarity between Stm-l and Stm, Stm-l was suggested to be involved in the biomineralization of otoliths, as had been observed for Stm even before. The molecular properties and functioning of Stm-l as a putative regulatory protein in otolith formation have not been characterized yet. A comprehensive biochemical and biophysical analysis of recombinant Stm-l, along with in silico examinations, indicated that Stm-l exhibits properties of a coil-like intrinsically disordered protein. Stm-l possesses an elongated and pliable structure that is able to adopt a more ordered and rigid conformation under the influence of different factors. An in vitro assay of the biomineralization activity of Stm-l indicated that Stm-l affected the size, shape and number of calcium carbonate crystals. The functional significance of intrinsically disordered properties of Stm-l and the possible role of this protein in controlling the formation of calcium carbonate crystals is discussed.},
  language  = {en}
}
@phdthesis{Sibilski2014,
  author    = {Sibilski, Claudia},
  title     = {Identification and characterization of the novel mKSR1 phosphorylation site Tyr728 and its role in MAPK signaling},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-114672},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {In mammals, KSR1 functions as an essential scaffold that coordinates the assembly of RAF/MEK/ERK complexes and regulates intracellular signal transduction upon extracellular stimulation. Aberrant activation of the equivalent MAPK signaling pathway has been implicated in multiple human cancers and some developmental disorders. The mechanism of KSR1 regulation is highly complex and involves several phosphorylation/dephosphorylation steps. In the present study, a number of novel in vivo phosphorylation sites were detected in mKSR1 by use of mass spectrometry analysis. Among others, Tyr728 was identified as a unique regulatory residue phosphorylated by LCK, a Src kinase family member. To understand how phosphorylation of Tyr728 may regulate the function of KSR1 in signal transduction and cellular processes, structural modeling and biochemical studies were integrated in this work. Computational modeling of the mKSR1(KD) protein structure revealed strong hydrogen bonding between phospho-Tyr728 and the residues surrounding Arg649. Remarkably, this pattern was altered when Tyr728 was non-phosphorylated or substituted. As confirmed by biochemical analysis, Arg649 may serve as a major anchor point for phospho-Tyr728 in order to stabilize internal structures of KSR1. In line with the protein modeling results, mutational studies revealed that substitution of Tyr728 by phenylalanine leads to a less compact interaction between KSR1 and MEK, a facilitated KSR1/B-RAF binding and an increased phosphorylation of MEK in complex with KSR1. From these findings it can be concluded that phospho-Tyr728 is involved in tightening the KSR1/MEK interaction interface and in regulating the phosphorylation of KSR1-bound MEK by either RAF or KSR1 kinases. Beside the Tyr728, Ser722 was identified as a novel regulatory phosphorylation site. Amino acid exchanges at the relevant position demonstrated that Ser722 regulates KSR1-bound MEK phosphorylation without affecting KSR1/MEK binding per se. Due to its localization, Ser722 might consequently control the catalytic activity of KSR1 by interfering with the access of substrate (possibly MEK) to the active site of KSR1 kinase. Together with Ser722, phosphorylated Tyr728 may further positively affect the kinase activity of KSR1 as a consequence of its vicinity to the activation and catalytic loop in the KSR1(KD). As revealed by structural modeling, phospho-Tyr728 builds a hydrogen bond with the highly conserved Lys685. Consequently, phospho-Tyr728 has a stabilizing effect on internal structures involved in the catalytic reaction and possibly enhances the phosphate transfer within the catalytic cleft in KSR1. Considering these facts, it seems very likely that the LCK-dependent phosphorylation of Tyr728 plays a crucial role in the regulation of KSR1 catalytic activity. Results of fractionation and morphology analyses revealed that KSR1 recruits LCK to cytoskeleton for its phosphorylation at Tyr728 suggesting that this residue may regulate cytoskeleton dynamics and, consequently, cell motility. Beside that, phosphorylation of Tyr728 is involved in the regulation of cell proliferation, as shown by a significantly reduced population doubling time of KSR1-Y728F cells compared to cells expressing wild type KSR1. Taken together, tyrosine phosphorylation in KSR1 uncovers a new link between Src family kinases and MAPK signaling. Tyr728, the novel regulatory phosphorylation site in murine KSR1, may coordinate the transition between the scaffolding and the catalytic function of KSR1 serving as a control point used to fine-tune cellular responses.},
  subject      = {MAP-Kinase},
  language  = {en}
}
@phdthesis{Wenzel2014,
  author    = {Wenzel, Jens},
  title     = {Regulation of TLR-induced macrophage responses by cytoskeleton-associated phosphoproteins},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-98843},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {Toll-like receptors (TLR) are pattern recognition receptors (PRR) by which macrophages (M{\O}) sense pathogen-associated molecular patterns (PAMPs). The recognition of lipopolysaccharide (LPS), the PAMP of gram negative bacteria, by TLR4 triggers signaling cascades and leads to the pro-inflammatory activation of the cells. A recent quantitative and kinetic analysis of the phosphoproteome of LPS-activated primary macrophages highlighted the cytoskeleton as a cell compartment with an enriched protein phosphorylation. In total 44 cytoskeleton-associated proteins were regulated by this post-translational modification and thus might be involved in the control and regulation of key macrophage functions like spreading, motility and phagocytosis. To investigate the control of cytoskeleton-associated cell functions by TLR4 activation, we first developed a method to quantitatively measure the spreading response of bone marrow M{\O} after stimulation with LPS. Fluorescence microscopy was used for cell imaging and visualisation of the M{\O} contact area. In collaboration with the Fraunhofer Institute Erlangen, we developed and validated a software tool for the semi-automated segmentation and quantitation of M{\O} fluorescence microscopy data, which allowed fast, robust and objective image analysis. Using this method, we observed that LPS caused time-dependent spreading, which was detectable after 1-2 h and maximal after 24 h. Next, the impact of genetic or pharmacological inhibition of known TLR signaling components was investigated. Deficiency in the adapter protein MYD88 strongly reduced spreading activity at the late time points, but had no impact early after LPS-stimulation. A similar effect was observed upon pharmacological inhibition of ERK1/2 signaling, indicating that ERK1/2 mediates MYD88-dependent M{\O} spreading. In contrast, M{\O} lacking the MAPK p38 were impaired in the initial spreading response but responded normally 8-24 h after stimulation. The genetic deletion of the MAPK phosphatases DUSP1 and DUSP16 resulted in impaired late spreading, corroborating the essential role for functional MAPK signaling in TLR4-driven M{\O} spreading. To identify the contribution of other cytoskeletal phosphoproteins to M{\O} spreading, siRNA knockdown of selected candidate genes in primary murine M{\O} was employed and combined with automated quantitative image analysis. These experiments revealed a functional role for the Myosins MYO1e and MYO1f in M{\O} spreading. These motor proteins are strongly phosphorylated in LPS-activated M{\O}. Because of their ability to simultaneously bind to actin filaments and cell membrane or other proteins, we investigated their role in phagocytosis, cytokine production and antigen presentation. Phagocytosis and killing of bacteria were not affected in Myo1e-/- macrophages. However, MYO1e plays a role in chemokine secretion and antigen presentation processes. MCP1 (CCL2) release was selectively increased in Myo1e-deficient M{\O} and dendritic cells (DC), while cytokine secretion was unaffected. Furthermore, macrophages and DCs lacking MYO1e showed lower levels of MHC-II on the cell surface. However, mRNA levels of CCL2 and of MHC-II were unaltered. These data suggest a role for MYO1e in the transport of selected chemokines and of MHC-II molecules to the cell surface. MHC-II-restricted antigen presentation assays revealed an impaired capacity of macrophages and DC lacking MYO1e to stimulate antigen-specific T cells, suggesting that the reduced MHC-II expression is functionally relevant. Taken together, in this study first a quantitative image analysis method was developed which allows the unbiased, robust and efficient investigation of the macrophage spreading response. Combination of this method with siRNA knockdown of selected cytoskeleton-associated phosphoproteins led to the identification of MYO1e and MYO1f as regulators of macrophage spreading. Furthermore, we identified MYO1e in M{\O} and DC to be essential for the intracellular transport of CCL2 and MHC-II to the cell surface and for optimal stimulation of antigen-specific CD4 T cells.},
  subject      = {Toll-like-Rezeptoren},
  language  = {en}
}
@article{RemmeleXianAlbrechtetal.2014,
  author    = {Remmele, Christian W. and Xian, Yibo and Albrecht, Marco and Faulstich, Michaela and Fraunholz, Martin and Heinrichs, Elisabeth and Dittrich, Marcus T. and M{\"u}ller, Tobias and Reinhardt, Richard and Rudel, Thomas},
  title     = {Transcriptional landscape and essential genes of Neisseria gonorrhoeae},
  doi       = {10.1093/nar/gku762},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-113676},
  year      = {2014},
  abstract  = {The WHO has recently classified Neisseria gonorrhoeae as a super-bacterium due to the rapid spread of antibiotic resistant derivatives and an overall dramatic increase in infection incidences. Genome sequencing has identified potential genes, however, little is known about the transcriptional organization and the presence of non-coding RNAs in gonococci. We performed RNA sequencing to define the transcriptome and the transcriptional start sites of all gonococcal genes and operons. Numerous new transcripts including 253 potentially non-coding RNAs transcribed from intergenic regions or antisense to coding genes were identified. Strikingly, strong antisense transcription was detected for the phase-variable opa genes coding for a family of adhesins and invasins in pathogenic Neisseria, that may have regulatory functions. Based on the defined transcriptional start sites, promoter motifs were identified. We further generated and sequenced a high density Tn5 transposon library to predict a core of 827 gonococcal essential genes, 133 of which have no known function. Our combined RNA-Seq and Tn-Seq approach establishes a detailed map of gonococcal genes and defines the first core set of essential gonococcal genes.},
  language  = {en}
}
@article{LinderHirmerGaletal.2014,
  author    = {Linder, Bastian and Hirmer, Anja and Gal, Andreas and R{\"u}ther, Klaus and Bolz, Hanno J{\"o}rn and Winkler, Christoph and Laggerbauer, Bernhard and Fischer, Utz},
  title     = {Identification of a PRPF4 Loss-of-Function Variant That Abrogates U4/U6.U5 Tri-snRNP Integration and Is Associated with Retinitis Pigmentosa},
  doi       = {10.1371/journal.pone.0111754},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-113663},
  year      = {2014},
  abstract  = {Pre-mRNA splicing by the spliceosome is an essential step in the maturation of nearly all human mRNAs. Mutations in six spliceosomal proteins, PRPF3, PRPF4, PRPF6, PRPF8, PRPF31 and SNRNP200, cause retinitis pigmentosa (RP), a disease characterized by progressive photoreceptor degeneration. All splicing factors linked to RP are constituents of the U4/U6.U5 tri-snRNP subunit of the spliceosome, suggesting that the compromised function of this particle may lead to RP. Here, we report the identification of the p.R192H variant of the tri-snRNP factor PRPF4 in a patient with RP. The mutation affects a highly conserved arginine residue that is crucial for PRPF4 function. Introduction of a corresponding mutation into the zebrafish homolog of PRPF4 resulted in a complete loss of function in vivo. A series of biochemical experiments suggested that p.R192H disrupts the binding interface between PRPF4 and its interactor PRPF3. This interferes with the ability of PRPF4 to integrate into the tri-snRNP, as shown in a human cell line and in zebrafish embryos. These data suggest that the p.R192H variant of PRPF4 represents a functional null allele. The resulting haploinsufficiency of PRPF4 compromises the function of the tri-snRNP, reinforcing the notion that this spliceosomal particle is of crucial importance in the physiology of the retina.},
  language  = {en}
}
@article{VerghoKneitzKalogirouetal.2014,
  author    = {Vergho, Daniel Claudius and Kneitz, Susanne and Kalogirou, Charis and Burger, Maximilian and Krebs, Markus and Rosenwald, Andreas and Spahn, Martin and L{\"o}ser, Andreas and Kocot, Arkadius and Riedmiller, Hubertus and Kneitz, Burkhard},
  title     = {Impact of miR-21, miR-126 and miR-221 as Prognostic Factors of Clear Cell Renal Cell Carcinoma with Tumor Thrombus of the Inferior Vena Cava},
  doi       = {10.1371/journal.pone.0109877},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-113633},
  year      = {2014},
  abstract  = {Clear cell renal cell carcinoma (ccRCC) characterized by a tumor thrombus (TT) extending into the inferior vena cava (IVC) generally indicates poor prognosis. Nevertheless, the risk for tumor recurrence after nephrectomy and thrombectomy varies. An applicable and accurate prediction system to select ccRCC patients with TT of the IVC (ccRCC/TT) at high risk after nephrectomy is urgently needed, but has not been established up to now. To our knowledge, a possible role of microRNAs (miRs) for the development of ccRCC/TT or their impact as prognostic markers in ccRCC/TT has not been explored yet. Therefore, we analyzed the expression of the previously described onco-miRs miR-200c, miR-210, miR-126, miR-221, let-7b, miR-21, miR-143 and miR-141 in a study collective of 74 ccRCC patients. Using the expression profiles of these eight miRs we developed classification systems that accurately differentiate ccRCC from non-cancerous renal tissue and ccRCC/TT from tumors without TT. In the subgroup of 37 ccRCC/TT cases we found that miR-21, miR-126, and miR-221 predicted cancer related death (CRD) accurately and independently from other clinico-pathological features. Furthermore, a combined risk score based on the expression of miR-21, miR-126 and miR-221 was developed and showed high sensitivity and specificity to predict cancer specific survival (CSS) in ccRCC/TT. Using the combined risk score we were able to classify ccRCC/TT patients correctly into high and low risk cases. The risk stratification by the combined risk score (CRS) will benefit from further cohort validation and might have potential for clinical application as a molecular prediction system to identify high- risk ccRCC/TT patients.},
  language  = {en}
}
@phdthesis{Gjorgjevikj2014,
  author    = {Gjorgjevikj, Maja},
  title     = {IL-4 analogues with site-specific chemical modification as screening tools for foldamers},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-113531},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {The cytokine Interleukin-4 (IL-4) plays a crucial role in the pathophysiology and progression of asthma and other atopic diseases. Its activities are signaled into the cells upon binding to and signaling through a shared receptor complex composed of the subunits IL-4Rα and common γc. Another cytokine, Interleukin-13 shares many functions with IL-4. This can be explained by the fact that both, IL-4 and IL-13, can signal via a shared receptor complex comprising the IL-4R and the IL-13R1 subunit. Therefore, the IL-4Rα receptor subunit has become a highly promising drug target, since it mediates IL-4 and IL-13 responses and blocking IL-4Rα will abrogate IL-4 as well as IL-13 effector functions. Currently, an IL-4 based mutein (Pitrakinra), acting as a dual IL-4/IL-13 receptor antagonist is in clinical development. This work describes the generation and production of biologically active IL-4 muteins, which contain a single additional engineered cysteine. The introduction of a free thiol group allows site-specific chemical modification. The muteins were expressed in E. coli in insoluble form, refolded and purified. The thiol group of the mutein was protected as mixed disulfide with the tripeptide glutathione. A first attempt to chemically reduce the engineered cysteine residue failed, because the three native disulfide bonds of IL-4 exhibit a similar reactivity and chemical reduction of the native disulfide resulted in full deactivation and precipitation of the IL-4 protein. Therefore, an enzymatic approach was developed which specifically reduces the mixed disulfide bonds with an attached glutathion moiety and thus leaves the native structurally essential disulfide bonds unaltered. For optimization, four different IL-4 cysteine muteins with four cysteine residues introduced at positions close to the IL-4Rα binding site were tested and their reduction rates by glutaredoxin was determined. The enzymatic reduction occured at different rates for all four muteins indicating that accessibility is an important influence and must be determined individually for each mutant protein. After optimization of the pH value and particularly the reaction time, all muteins could be prepared with the engineered thiol group being released in reasonable yield. The proteins exhibiting the free thiol group were then modified by N-ethylmaleimide (NEM) or maleimido-PEG. The effects of these modifications at different positions on binding to IL-4R were measured employing SPR biosensor technology. In the second project of this study, foldamers, which represent a new class of stable, compactly folded biomolecules and can specifically interact with proteins and nucleic acids, were examined to identify their potential as new drugs to interfere with IL-4 activities. Fragment-based drug discovery offers great promise for providing new starting points for drug discovery and facilitates the lead optimization. As foldamers equipped with a thiol-group for tethering could not to be produced; only the effect of foldamers present in a synthesized foldamer library on the binding to IL-4R could be tested. Two libraries containing different foldamers based on aromatic amide were synthesized by Michael Grotz and Dr. Michael Deligny and tested in our lab for their capability to disrupt the ligand-receptor interaction of IL-4 and its receptor IL-4Rα [ECD] using surface plasmon resonance technology. None of the studied foldamers could specifically inhibit the IL-4/IL-4Rα interaction. Some foldamers showed non-specific binding. The study presented here shows the design and production of a potentially new type of IL-4 antagonists, which employ site-specific chemical modification to exert their antagonistic function.},
  subject      = {Il 4},
  language  = {en}
}
@phdthesis{Axmacher2014,
  author    = {Axmacher, Franz},
  title     = {Die SVM-gest{\"u}tzte Pr{\"a}diktabilit{\"a}t der Bindungsspezifit{\"a}t ‎von SH3-Dom{\"a}nen anhand ihrer Aminos{\"a}uresequenz},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-113349},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {Die Identifikation der Bindungsspezifit{\"a}ten von Proteininteraktionsdom{\"a}nen und damit letztlich auch ‎die F{\"a}higkeit potentielle Bindungspartner dieser in vivo vorherzusagen bildet ein grundlegendes ‎Element f{\"u}r das Verst{\"a}ndnis der biologischen Funktionen dieser Dom{\"a}nen. In dieser Arbeit wurde ‎untersucht, inwieweit solche Vorhersagen bez{\"u}glich der SH3-Dom{\"a}ne - als Beispiel f{\"u}r eine ‎Proteininteraktionsdom{\"a}ne - mithilfe von Support-Vector-Machines (SVMs) m{\"o}glich sind, wenn ‎diesen als Informationsquelle ausschließlich die innerhalb der Aminos{\"a}uresequenz der Dom{\"a}ne ‎konservierten Informationen zur Verf{\"u}gung stehen. Um den SVM-basierten Klassifikator zu ‎trainieren und zu validieren, wurde ein Satz aus 51 SH3-Dom{\"a}nen verwendet, die zuvor ‎entsprechend ihrer Ligandenpr{\"a}ferenz in ein System aus acht verschiedenen Klassen eingeteilt ‎worden waren. Da die innerhalb der Aminos{\"a}uresequenzen konservierten Informationen in ‎abstrakte Zahlenwerte konvertiert werden mussten (Voraussetzung f{\"u}r mathematisch basierte ‎Klassifikatoren wie SVMs), wurde jede Aminos{\"a}uresequenz durch ihren jeweiligen Fisher-Score-‎Vektor ausgedr{\"u}ckt. Die Ergebnisse erbrachten einen Klassifikationserror, welcher weit unterhalb des ‎Zufallsniveaus lag, was darauf hindeutet, dass sich die Bindungsspezifit{\"a}t (Klasse) einer SH3-Dom{\"a}ne ‎in der Tat von seiner Aminos{\"a}uresequenz ableiten lassen d{\"u}rfte. Mithilfe klassenspezifisch ‎emittierter, artifizieller Sequenzen, implementiert in den Trainingsprozess des Klassifikators, um ‎etwaigen nachteiligen Auswirkungen von Overfitting zu entgegenzuwirken, sowie durch ‎Ber{\"u}cksichtigung taxonomischer Informationen des Klassensystems w{\"a}hrend Training und ‎Validierung, ließ sich der Klassifikationserror sogar noch weiter senken und lag schließlich bei lediglich ‎‎35,29\% (vergleiche Zufall: 7/8 = 87.50\%). Auch die Nutzung von Feature Selections zur Abmilderung ‎Overfitting-bedingter, negativer Effekte lieferte recht vielversprechende Ergebnisse, wenngleich ihr ‎volles Potential aufgrund von Software-Beschr{\"a}nkungen nicht ausgenutzt werden konnte.‎ Die Analyse der Positionen im Sequence-Alignment, welche f{\"u}r den SVM- basierten Klassifikator am ‎relevantesten waren, zeigte, dass diese h{\"a}ufig mit Positionen korrelierten, von denen angenommen ‎wird auch in vivo eine Schl{\"u}sselrolle bei der Determination der Bindungsspezifit{\"a}t (Klasse) zu spielen. ‎Dies unterstreicht nicht nur die Reliabilit{\"a}t des pr{\"a}sentierten Klassifikators, es gibt auch Grund zur ‎Annahme, dass das Verfahren m{\"o}glicherweise auch als Supplement anderer Ans{\"a}tze genutzt werden ‎k{\"o}nnte, welche zum Ziel haben die Positionen zu identifizieren, die die Ligandenpr{\"a}ferenz in vivo ‎determinieren. Informationen, die nicht nur f{\"u}r ein besseres Verst{\"a}ndnis der SH3-Dom{\"a}ne (und ‎m{\"o}glicherweise auch anderer Proteininteraktionsdom{\"a}nen) von grundlegender Bedeutung sind, ‎sondern auch aus pharmakologischer Sicht von großem Interesse sein d{\"u}rften.‎},
  subject      = {Support-Vektor-Maschine},
  language  = {de}
}
@article{MortonFliesserDittrichetal.2014,
  author    = {Morton, Charles Oliver and Fliesser, Mirjam and Dittrich, Marcus and M{\"u}ller, Tobias and Bauer, Ruth and Kneitz, Susanne and Hope, William and Rogers, Thomas Richard and Einsele, Hermann and L{\"o}ffler, J{\"u}rgen},
  title     = {Gene Expression Profiles of Human Dendritic Cells Interacting with Aspergillus fumigatus in a Bilayer Model of the Alveolar Epithelium/Endothelium Interface},
  doi       = {10.1371/journal.pone.0098279},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112893},
  year      = {2014},
  abstract  = {The initial stages of the interaction between the host and Aspergillus fumigatus at the alveolar surface of the human lung are critical in the establishment of aspergillosis. Using an in vitro bilayer model of the alveolus, including both the epithelium (human lung adenocarcinoma epithelial cell line, A549) and endothelium (human pulmonary artery epithelial cells, HPAEC) on transwell membranes, it was possible to closely replicate the in vivo conditions. Two distinct sub-groups of dendritic cells (DC), monocyte-derived DC (moDC) and myeloid DC (mDC), were included in the model to examine immune responses to fungal infection at the alveolar surface. RNA in high quantity and quality was extracted from the cell layers on the transwell membrane to allow gene expression analysis using tailored custom-made microarrays, containing probes for 117 immune-relevant genes. This microarray data indicated minimal induction of immune gene expression in A549 alveolar epithelial cells in response to germ tubes of A. fumigatus. In contrast, the addition of DC to the system greatly increased the number of differentially expressed immune genes. moDC exhibited increased expression of genes including CLEC7A, CD209 and CCL18 in the absence of A. fumigatus compared to mDC. In the presence of A. fumigatus, both DC subgroups exhibited up-regulation of genes identified in previous studies as being associated with the exposure of DC to A. fumigatus and exhibiting chemotactic properties for neutrophils, including CXCL2, CXCL5, CCL20, and IL1B. This model closely approximated the human alveolus allowing for an analysis of the host pathogen interface that complements existing animal models of IA.},
  language  = {en}
}
@article{HopfenmuellerSteffanDewenterHolzschuh2014,
  author    = {Hopfenmueller, Sebastian and Steffan-Dewenter, Ingolf and Holzschuh, Andrea},
  title     = {Trait-Specific Responses of Wild Bee Communities to Landscape Composition, Configuration and Local Factors},
  doi       = {10.1371/journal.pone.0104439},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112872},
  year      = {2014},
  abstract  = {Land-use intensification and loss of semi-natural habitats have induced a severe decline of bee diversity in agricultural landscapes. Semi-natural habitats like calcareous grasslands are among the most important bee habitats in central Europe, but they are threatened by decreasing habitat area and quality, and by homogenization of the surrounding landscape affecting both landscape composition and configuration. In this study we tested the importance of habitat area, quality and connectivity as well as landscape composition and configuration on wild bees in calcareous grasslands. We made detailed trait-specific analyses as bees with different traits might differ in their response to the tested factors. Species richness and abundance of wild bees were surveyed on 23 calcareous grassland patches in Southern Germany with independent gradients in local and landscape factors. Total wild bee richness was positively affected by complex landscape configuration, large habitat area and high habitat quality (i.e. steep slopes). Cuckoo bee richness was positively affected by complex landscape configuration and large habitat area whereas habitat specialists were only affected by the local factors habitat area and habitat quality. Small social generalists were positively influenced by habitat area whereas large social generalists (bumblebees) were positively affected by landscape composition (high percentage of semi-natural habitats). Our results emphasize a strong dependence of habitat specialists on local habitat characteristics, whereas cuckoo bees and bumblebees are more likely affected by the surrounding landscape. We conclude that a combination of large high-quality patches and heterogeneous landscapes maintains high bee species richness and communities with diverse trait composition. Such diverse communities might stabilize pollination services provided to crops and wild plants on local and landscape scales.},
  language  = {en}
}
@article{RoemerRoces2014,
  author    = {R{\"o}mer, Daniela and Roces, Flavio},
  title     = {Nest Enlargement in Leaf-Cutting Ants: Relocated Brood and Fungus Trigger the Excavation of New Chambers},
  doi       = {10.1371/journal.pone.0097872},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112860},
  year      = {2014},
  abstract  = {During colony growth, leaf-cutting ants enlarge their nests by excavating tunnels and chambers housing their fungus gardens and brood. Workers are expected to excavate new nest chambers at locations across the soil profile that offer suitable environmental conditions for brood and fungus rearing. It is an open question whether new chambers are excavated in advance, or will emerge around brood or fungus initially relocated to a suitable site in a previously-excavated tunnel. In the laboratory, we investigated the mechanisms underlying the excavation of new nest chambers in the leaf-cutting ant Acromyrmex lundi. Specifically, we asked whether workers relocate brood and fungus to suitable nest locations, and to what extent the relocated items trigger the excavation of a nest chamber and influence its shape. When brood and fungus were exposed to unfavorable environmental conditions, either low temperatures or low humidity, both were relocated, but ants clearly preferred to relocate the brood first. Workers relocated fungus to places containing brood, demonstrating that subsequent fungus relocation spatially follows the brood deposition. In addition, more ants aggregated at sites containing brood. When presented with a choice between two otherwise identical digging sites, but one containing brood, ants' excavation activity was higher at this site, and the shape of the excavated cavity was more rounded and chamber-like. The presence of fungus also led to the excavation of rounder shapes, with higher excavation activity at the site that also contained brood. We argue that during colony growth, workers preferentially relocate brood to suitable locations along a tunnel, and that relocated brood spatially guides fungus relocation and leads to increased digging activity around them. We suggest that nest chambers are not excavated in advance, but emerge through a self-organized process resulting from the aggregation of workers and their density-dependent digging behavior around the relocated brood and fungus.},
  language  = {en}
}
@article{KellerSchultz2014,
  author    = {Keller, Daniela Barbara and Schultz, J{\"o}rg},
  title     = {Word Formation Is Aware of Morpheme Family Size},
  doi       = {10.1371/journal.pone.0093978},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112848},
  year      = {2014},
  abstract  = {Words are built from smaller meaning bearing parts, called morphemes. As one word can contain multiple morphemes, one morpheme can be present in different words. The number of distinct words a morpheme can be found in is its family size. Here we used Birth-Death-Innovation Models (BDIMs) to analyze the distribution of morpheme family sizes in English and German vocabulary over the last 200 years. Rather than just fitting to a probability distribution, these mechanistic models allow for the direct interpretation of identified parameters. Despite the complexity of language change, we indeed found that a specific variant of this pure stochastic model, the second order linear balanced BDIM, significantly fitted the observed distributions. In this model, birth and death rates are increased for smaller morpheme families. This finding indicates an influence of morpheme family sizes on vocabulary changes. This could be an effect of word formation, perception or both. On a more general level, we give an example on how mechanistic models can enable the identification of statistical trends in language change usually hidden by cultural influences.},
  language  = {en}
}
@article{LeingaertnerHoissKraussetal.2014,
  author    = {Leing{\"a}rtner, Annette and Hoiss, Bernhard and Krauss, Jochen and Steffan-Dewenter, Ingolf},
  title     = {Combined Effects of Extreme Climatic Events and Elevation on Nutritional Quality and Herbivory of Alpine Plants},
  doi       = {10.1371/journal.pone.0093881},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112812},
  year      = {2014},
  abstract  = {Climatic extreme events can cause the shift or disruption of plant-insect interactions due to altered plant quality, e.g. leaf carbon to nitrogen ratios, and phenology. However, the response of plant-herbivore interactions to extreme events and climatic gradients has been rarely studied, although climatic extremes will increase in frequency and intensity in the future and insect herbivores represent a highly diverse and functionally important group. We set up a replicated climate change experiment along elevational gradients in the German Alps to study the responses of three plant guilds and their herbivory by insects to extreme events (extreme drought, advanced and delayed snowmelt) versus control plots under different climatic conditions on 15 grassland sites. Our results indicate that elevational shifts in CN (carbon to nitrogen) ratios and herbivory depend on plant guild and season. CN ratios increased with altitude for grasses, but decreased for legumes and other forbs. In contrast to our hypotheses, extreme climatic events did not significantly affect CN ratios and herbivory. Thus, our study indicates that nutritional quality of plants and antagonistic interactions with insect herbivores are robust against seasonal climatic extremes. Across the three functional plant guilds, herbivory increased with nitrogen concentrations. Further, increased CN ratios indicate a reduction in nutritional plant quality with advancing season. Although our results revealed no direct effects of extreme climatic events, the opposing responses of plant guilds along elevation imply that competitive interactions within plant communities might change under future climates, with unknown consequences for plant-herbivore interactions and plant community composition.},
  language  = {en}
}
@article{ShityakovFoersterRethwilmetal.2014,
  author    = {Shityakov, Sergey and F{\"o}rster, Carola and Rethwilm, Axel and Dandekar, Thomas},
  title     = {Evaluation and Prediction of the HIV-1 Central Polypurine Tract Influence on Foamy Viral Vectors to Transduce Dividing and Growth-Arrested Cells},
  doi       = {10.1155/2014/487969},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112763},
  year      = {2014},
  abstract  = {Retroviral vectors are potent tools for gene delivery and various biomedical applications. To accomplish a gene transfer task successfully, retroviral vectors must effectively transduce diverse cell cultures at different phases of a cell cycle. However, very promising retroviral vectors based on the foamy viral (FV) backbone lack the capacity to efficiently transduce quiescent cells. It is hypothesized that this phenomenon might be explained as the inability of foamy viruses to form a pre-integration complex (PIC) with nuclear import activity in growth-arrested cells, which is the characteristic for lentiviruses (HIV-1). In this process, the HIV-1 central polypurine tract (cPPT) serves as a primer for plus-strand synthesis to produce a "flap" element and is believed to be crucial for the subsequent double-stranded cDNA formation of all retroviral RNA genomes. In this study, the effects of the lentiviral cPPT element on the FV transduction potential in dividing and growth-arrested (G1/S phase) adenocarcinomic human alveolar basal epithelial (A549) cells are investigated by experimental and theoretical methods. The results indicated that the HIV-1 cPPT element in a foamy viral vector background will lead to a significant reduction of the FV transduction and viral titre in growth-arrested cells due to the absence of PICs with nuclear import activity.},
  subject      = {Evaluation},
  language  = {en}
}
@article{AlbertSpaetheGruebeletal.2014,
  author    = {Albert, Štefan and Spaethe, Johannes and Gr{\"u}bel, Kornelia and R{\"o}ssler, Wolfgang},
  title     = {Royal jelly-like protein localization reveals differences in hypopharyngeal glands buildup and conserved expression pattern in brains of bumblebees and honeybees},
  doi       = {10.1242/bio.20147211},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112733},
  year      = {2014},
  abstract  = {Royal jelly proteins (MRJPs) of the honeybee bear several open questions. One of them is their expression in tissues other than the hypopharyngeal glands (HGs), the site of royal jelly production. The sole MRJP-like gene of the bumblebee, Bombus terrestris (BtRJPL), represents a pre-diversification stage of the MRJP gene evolution in bees. Here we investigate the expression of BtRJPL in the HGs and the brain of bumblebees. Comparison of the HGs of bumblebees and honeybees revealed striking differences in their morphology with respect to sex- and caste-specific appearance, number of cells per acinus, and filamentous actin (F-actin) rings. At the cellular level, we found a temporary F-actin-covered meshwork in the secretory cells, which suggests a role for actin in the biogenesis of the end apparatus in HGs. Using immunohistochemical localization, we show that BtRJPL is expressed in the bumblebee brain, predominantly in the Kenyon cells of the mushroom bodies, the site of sensory integration in insects, and in the optic lobes. Our data suggest that a dual glandbrain function preceded the multiplication of MRJPs in the honeybee lineage. In the course of the honeybee evolution, HGs dramatically changed their morphology in order to serve a food-producing function.},
  language  = {en}
}
@phdthesis{Vona2014,
  author    = {Vona, Barbara C.},
  title     = {Molecular Characterization of Genes Involved in Hearing Loss},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-112170},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {The auditory system is an exquisitely complex sensory organ dependent upon the synchronization of numerous processes for proper function. The molecular characterization of hereditary hearing loss is complicated by extreme genetic heterogeneity, wherein hundreds of genes dispersed genome-wide play a central and irreplaceable role in normal hearing function. The present study explores this area on a genome-wide and single gene basis for the detection of genetic mutations playing critical roles in human hearing. This work initiated with a high resolution SNP array study involving 109 individuals. A 6.9 Mb heterozygous deletion on chromosome 4q35.1q35.2 was identified in a syndromic patient that was in agreement with a chromosome 4q deletion syndrome diagnosis. A 99.9 kb heterozygous deletion of exons 58-64 in USH2A was identified in one patient. Two homozygous deletions and five heterozygous deletions in STRC (DFNB16) were also detected. The homozygous deletions alone were enough to resolve the hearing impairment in the two patients. A Sanger sequencing assay was developed to exclude a pseudogene with a high percentage sequence identity to STRC from the analysis, which further solved three of the six heterozygous deletion patients with the hemizygous, in silico predicted pathogenic mutations c.2726A>T (p.H909L), c.4918C>T (p.L1640F), and c.4402C>T (p.R1468X). A single patient who was copy neutral for STRC and without pathogenic copy number variations had compound heterozygous mutations [c. 2303_2313+1del12 (p.G768Vfs*77) and c.5125A>G (p.T1709A)] in STRC. It has been shown that STRC has been previously underestimated as a hearing loss gene. One additional patient is described who does not have pathogenic copy number variation but is the only affected member of his family having hearing loss with a paternally segregating translocation t(10;15)(q26.13;q21.1). Twenty-four patients without chromosomal aberrations and the above described patient with an USH2A heterozygous deletion were subjected to a targeted hearing loss gene next generation sequencing panel consisting of either 80 or 129 hearing-relevant genes. The patient having the USH2A heterozygous deletion also disclosed a second mutation in this gene [c.2276G>T (p.C759F)]. This compound heterozygous mutation is the most likely cause of hearing loss in this patient. Nine mutations in genes conferring autosomal dominant hearing loss [ACTG1 (DFNA20/26); CCDC50 (DFNA44); EYA4 (DFNA10); GRHL2 (DFNA28); MYH14 (DFNA4A); MYO6 (DFNA22); TCF21 and twice in MYO1A (DFNA48)] and four genes causing autosomal recessive hearing loss were detected [GJB2 (DFNB1A); MYO7A (DFNB2); MYO15A (DFNB3), and USH2A]. Nine normal hearing controls were also included. Statistical significance was achieved comparing controls and patients that revealed an excess of mutations in the hearing loss patients compared to the control group. The family with the GRHL2 c.1258-1G>A mutation is only the second family published worldwide with a mutation described in this gene to date, supporting the initial claim of this gene causing DFNA28 hearing loss. Audiogram analysis of five affected family members uncovered the progressive nature of DFNA28 hearing impairment. Regression analysis predicted the annual threshold deterioration in each of the five family members with multiple audiograms available over a number of years.},
  subject      = {Molekularbiologie},
  language  = {en}
}
@phdthesis{Hovhanyan2014,
  author    = {Hovhanyan, Anna},
  title     = {Functional analyses of Mushroom body miniature (Mbm) in growth and proliferation of neural progenitor cells in the central brain of Drosophila melanogaster},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-91303},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {Zellwachstum und Zellteilung stellen zwei miteinander verkn{\"u}pfte Prozesse dar, die dennoch grunds{\"a}tzlich voneinander zu unterscheiden sind. Die Wiederaufnahme der Proliferation von neuralen Vorl{\"a}uferzellen (Neuroblasten) im Zentralhirn von Drosophila nach der sp{\"a}t-embryonalen Ruhephase erfordert zun{\"a}chst Zellwachstum. Der Erhalt der regul{\"a}ren Zellgr{\"o}ße ist eine wichtige Voraussetzung f{\"u}r die kontinuierliche Proliferation der Neuroblasten {\"u}ber die gesamte larvale Entwicklungsphase. Neben extrinsischen Ern{\"a}hrungssignalen ist f{\"u}r das Zellwachstum eine kontinuierliche Versorgung mit funktionellen Ribosomen notwendig, damit die Proteinsynthese aufrechterhalten werden kann. Mutationen im mushroom body miniature (mbm) Gen wurden {\"u}ber einen genetischen Screen nach strukturellen Gehirnmutanten identifiziert. Der Schwerpunkt dieser Arbeit lag in der funktionellen Charakterisierung des Mbm Proteins als neues nukleol{\"a}res Protein und damit seiner m{\"o}glichen Beteiligung in der Ribosomenbiogenese. Der Vergleich der relativen Expressionslevel von Mbm und anderen nuklearen Proteinen in verschiedenen Zelltypen zeigte eine verst{\"a}rkte Expression von Mbm in der fibrill{\"a}ren Komponente des Nukleolus von Neuroblasten. Diese Beobachtung legte die Vermutung nahe, dass in Neuroblasten neben generell ben{\"o}tigten Faktoren der Ribosomenbiogenese auch Zelltyp-spezifische Faktoren existieren. Mutationen in mbm verursachen Proliferationsdefekte von Neuroblasten, wirken sich jedoch nicht auf deren Zellpolarit{\"a}t, die Orientierung der mitotischen Spindel oder die Asymmetrie der Zellteilung aus. Stattdessen wurde eine Reduktion der Zellgr{\"o}ße beobachtet, was im Einklang mit einer Beeintr{\"a}chtigung der Ribosomenbiogenese steht. Insbesondere f{\"u}hrt der Verlust der Mbm Funktion zu einer Retention der kleinen ribosomalen Untereinheit im Nukleolus, was eine verminderte Proteinsynthese zur Folge hat. Interessanterweise wurden St{\"o}rungen der Ribosomenbiogenese nur in den Neuroblasten beobachtet. Zudem ist Mbm offensichtlich nicht erforderlich, um Wachstum oder die Proliferation von Zellen der Fl{\"u}gelimginalscheibe und S2-Zellen zu steuern, was wiederum daf{\"u}r spricht, dass Mbm eine Neuroblasten-spezifische Funktion erf{\"u}llt. Dar{\"u}ber hinaus wurden die transkriptionelle Regulation des mbm-Gens und die funktionelle Bedeutung von posttranslationalen Modifikationen analysiert. Mbm Transkription wird von dMyc reguliert. Ein gemeinsames Merkmal von dMyc Zielgenen ist das Vorhandensein einer konservierten „E-Box"-Sequenz in deren Promotorregionen. In der Umgebung der mbm-Transkriptionsstartstelle befinden sich zwei „E-Box"-Motive. Mit Hilfe von Genreporteranalysen konnte nachgewiesen werden, dass nur eine von ihnen die dMyc-abh{\"a}ngige Transkription vermittelt. Die dMyc-abh{\"a}ngige Expression von Mbm konnte auch in Neuroblasten verifiziert werden. Auf posttranslationaler Ebene wird Mbm durch die Proteinkinase CK2 phosphoryliert. In der C-terminalen H{\"a}lfte des Mbm Proteins wurden in zwei Clustern mit einer Abfolge von sauren Aminos{\"a}uren sechs Serin- und Threoninreste als CK2- Phosphorylierungsstellen identifiziert. Eine Mutationsanalyse dieser Stellen best{\"a}tigte deren Bedeutung f{\"u}r die Mbm Funktion in vivo. Weiterhin ergaben sich Evidenzen, dass die Mbm-Lokalisierung durch die CK2-vermittelte Phosphorylierung gesteuert wird. Obwohl die genaue molekulare Funktion von Mbm in der Ribosomenbiogenese noch im Unklaren ist, unterstreichen die Ergebnisse dieser Studie die besondere Rolle von Mbm in der Ribosomenbiogenese von Neuroblasten um Zellwachstum und Proliferation zu regulieren.},
  subject      = {Taufliege},
  language  = {en}
}
@article{FlorenMupepeleMuelleretal.2014,
  author    = {Floren, Andreas and Mupepele, Anne-Christine and M{\"u}ller, Tobias and Dittrich, Marcus},
  title     = {Are Temperate Canopy Spiders Tree-Species Specific?},
  doi       = {10.1371/journal.pone.0086571},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111413},
  year      = {2014},
  abstract  = {Arboreal spiders in deciduous and coniferous trees were investigated on their distribution and diversity. Insecticidal knock-down was used to comprehensively sample spiders from 175 trees from 2001 to 2003 in the Białowieża forest and three remote forests in Poland. We identified 140 species from 9273 adult spiders. Spider communities were distinguished between deciduous and coniferous trees. The richest fauna was collected from Quercus where beta diversity was also highest. A tree-species-specific pattern was clearly observed for Alnus, Carpinus, Picea and Pinus trees and also for those tree species that were fogged in only four or three replicates, namely Betula and Populus. This hitherto unrecognised association was mainly due to the community composition of common species identified in a Dufrene-Legendre indicator species analysis. It was not caused by spatial or temporal autocorrelation. Explaining tree-species specificity for generalist predators like spiders is difficult and has to involve physical and ecological tree parameters like linkage with the abundance of prey species. However, neither did we find a consistent correlation of prey group abundances with spiders nor could differences in spider guild composition explain the observed pattern. Our results hint towards the importance of deterministic mechanisms structuring communities of generalist canopy spiders although the casual relationship is not yet understood.},
  language  = {en}
}
@article{AlsheimerLinkLeubneretal.2014,
  author    = {Alsheimer, Manfred and Link, Jana and Leubner, Monika and Schmitt, Johannes and G{\"o}b, Eva and Benavente, Ricardo and Jeang, Kuan-Teh and Xu, Rener},
  title     = {Analysis of Meiosis in SUN1 Deficient Mice Reveals a Distinct Role of SUN2 in Mammalian Meiotic LINC Complex Formation and Function},
  doi       = {10.1371/journal.pgen.1004099},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111355},
  year      = {2014},
  abstract  = {LINC complexes are evolutionarily conserved nuclear envelope bridges, composed of SUN (Sad-1/UNC-84) and KASH (Klarsicht/ANC-1/Syne/homology) domain proteins. They are crucial for nuclear positioning and nuclear shape determination, and also mediate nuclear envelope (NE) attachment of meiotic telomeres, essential for driving homolog synapsis and recombination. In mice, SUN1 and SUN2 are the only SUN domain proteins expressed during meiosis, sharing their localization with meiosis-specific KASH5. Recent studies have shown that loss of SUN1 severely interferes with meiotic processes. Absence of SUN1 provokes defective telomere attachment and causes infertility. Here, we report that meiotic telomere attachment is not entirely lost in mice deficient for SUN1, but numerous telomeres are still attached to the NE through SUN2/KASH5-LINC complexes. In Sun12/2 meiocytes attached telomeres retained the capacity to form bouquetlike clusters. Furthermore, we could detect significant numbers of late meiotic recombination events in Sun12/2 mice. Together, this indicates that even in the absence of SUN1 telomere attachment and their movement within the nuclear envelope per se can be functional. Author summary: Correct genome haploidization during meiosis requires tightly regulated chromosome movements that follow a highly conserved choreography during prophase I. Errors in these movements cause subsequent meiotic defects, which typically lead to infertility. At the beginning of meiotic prophase, chromosome ends are tethered to the nuclear envelope (NE). This attachment of telomeres appears to be mediated by well-conserved membrane spanning protein complexes within the NE (LINC complexes). In mouse meiosis, the two main LINC components SUN1 and SUN2 were independently described to localize at the sites of telomere attachment. While SUN1 has been demonstrated to be critical for meiotic telomere attachment, the precise role of SUN2 in this context, however, has been discussed controversially in the field. Our current study was targeted to determine the factual capacity of SUN2 in telomere attachment and chromosome movements in SUN1 deficient mice. Remarkably, although telomere attachment is impaired in the absence of SUN1, we could find a yet undescribed SUN1-independent telomere attachment, which presumably is mediated by SUN2 and KASH5. This SUN2 mediated telomere attachment is stable throughout prophase I and functional in moving telomeres within the NE. Thus, our results clearly indicate that SUN1 and SUN2, at least partially, fulfill redundant meiotic functions.},
  language  = {en}
}
@phdthesis{Kaiser2014,
  author    = {Kaiser, Dorkas},
  title     = {Termites and ants in BURKINA FASO (WEST AFRICA): taxonomic and functional diversity along land-use gradients; ecosystem services of termites in the traditional ZA{\"I} SYSTEM},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-107001},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {The consequences of habitat change for human well-being are assumed to be especially extreme in Burkina Faso. The country is located in a highly drought-sensitive zone of West Africa, and small-scale subsistence farmers may be especially affected if losses of biodiversity lead to changes in ecosystem functioning; many depend on more or less degraded lands for agricultural production. The overall aim of the present thesis consequently was to characterize the functional traits of soil-organisms which are crucial for a productive and balanced soil environment in the study region - termites and ants. They are true ecosystem engineers whose activity alters the habitat. Through soil-turnover in the course of constructing biogenic structures of varying size and nature (mounds, nests, galleries, soil-sheetings, foraging-holes), they bioturbate huge amounts of soil masses and exert massive effects on soil structure, positively influencing the fertility, stability, aeration and water infiltration rate into soils; and they provide habitats for other species. In sub-Saharan Africa, ants and termites are the only active soil macrofauna during the long dry season; in the sub-Sahel zone of Burkina Faso, termites even represent the only active, quantitatively remarkable decomposers all year round. Since no information was available about the actual diversity of the focal arthropods, I divided the thesis in two main parts: In the first part, a baseline study, I assessed the local termite and ant fauna, and investigated their quantitative and qualitative response to changing habitat parameters resulting from increasing human impact ('functional response traits'). In the second and applied part, I addressed the impact of the biogenic structures which are important for the restoration of degraded soils ('functional effect traits'). Two traditional agricultural systems characteristic for the study region were selected. Each system represented a land-use intensification gradient comprising four distinct habitats now differing in the magnitude of human intervention but formerly having the same initial state. The first disturbance gradient, the temporal cross-section of a traditional soil water conservation technique to restore degraded heavily encrusted, barren soil named Za{\"i} in Ouahigouya (Yatenga province, sub-Sahel zone); the second disturbance gradient, an agriculture type using crop rotation and fallow as nutrient management techniques near Fada N'Gourma (Gourma province, North-Sudanese zone). No standard protocol existed for the assessment of termite and ant diversity in semi-arid (agro-) ecosystems; two widely accepted standard protocols provided the basis for the newly revised and combined rapid assessment protocol 'RAP': the ALL protocol for leaf litter ants of Agosti and Alonso (2000), and the transect protocol for termites in tropical forests of Jones and Eggleton (2000). In each study site, three to four replicate transects were conducted during the rainy seasons (2004—2008). The RAP-protocol turned out to be very effective to characterize, compare and monitor the taxonomic and functional diversity of termites and ants; between 70\% and 90\% of the estimated total species richness were collected on all levels (transects, habitats, regions). Together in both regions, 65 ant species (25 genera) and 39 termite species (13 genera) were collected. These findings represent the first records for Burkina Faso. The data indicate a high sensitivity of termites and ants to land-use intensification. The diversity strongly decreased with increasing anthropogenic impact in the North-Sudan region. In total, 53 ant species (23 genera) and 31 termite species (12 genera) were found. Very promising results concerning the recovery potential of the soil-arthropods' diversity were gathered in the Za{\"i} system. The diversity of both taxa strongly increased with increasing habitat rehabilitation - in total, 41 ant species (16 genera) and 33 termite species (11 genera) were collected. For both taxa significant differences could be noted in the shape of the density variations along the gradient. For instance termites: Fungus-growers showed the greatest adaptability to different management practices. The greatest variations between the habitats were observed in soil and grass-feeding termites. Whole functional groups were missing in heavily impacted habitats, e.g. soil-, grass-, and wood-feeders were absent in the degraded site in the sub-Sahel zone. Several environmental parameters could be identified which significantly explained a great part of the variations in the composition of the arthropods' communities; they indicate the importance of the habitats' structural complexity (vegetation structure) and concomitant effects on diurnal temperature and moisture fluctuations, the availability of food sources, and the soil-structure. The diversity of termites in the sub-Sahel region was strongly correlated with the crown-cover percentages, the topsoils' sand-content, and the availability of litter; in the North-Sudan region with the cumulated woody plant basal area, the topsoils' clay- and organic matter-content. The parameters identified for ant communities in the Za{\"i} system, were the height of trees, the topsoils' clay-content and air humidity; in the North-Sudan region the habitats' crown-cover percentages, the quantity of litter and again the height of trees. In the second part of the thesis, I first rapidly assessed the (natural) variations in the amount of epigeal soil-structures along the two disturbance gradients in order to judge the relative importance of termites and ants for soil-turnover. The results illustrated impressively that a) in all study sites, termites were the main bioturbators while ant structures were of minor importance for soil turn-over; b) earthworms and grass-feeding termites contributed significantly to soil turn-over in the more humid North-Sudan region; and c) the bioturbated soil mass varied between seasons and years, however, the relative importance of the different taxa seemed to be fairly constant. In the sub-Sahel zone, fungus-growing Odontotermes and Macrotermes species fully take over the important function of bioturbation, leading to the transport of huge amounts of fine-textured soil material to the surface; with increasing habitat restoration, coarse fragments decreased in the upper horizons and became concentrated deeper along the soil profile. Consequently, in the applied part, I concentrated on the bioturbation activity of fungus-growing termites in the four main stages of the Za{\"i} system: crusted bare soil (initial stage), millet field, young and old forest. In each of the four Za{\"i} sites nine experimental blocks (each comprising four plots of 1m2) were used to stimulate the foraging activity of fungus-growing termites with different, locally available organic materials (Aristida kerstingii hay, Bombax costatum wooden blocks, compost and a control without any organic amendment). The experiment was conducted twice for the duration of four weeks (rainy season 2005, dry season 2006). The plots were regularly checked and the increase of the area covered by sheetings chronologically followed. After four weeks a) all sheeting-soil was collected, air dried and separately weighed according to the different genera, and b) the foraging-holes were counted and their diameter measured. Additionally, c) ponded water infiltration was measured in selected plots, and d) the physicochemical properties of sheeting-soil were analyzed. In case of complete consumption of the offered hay during the experimental 4-weeks-duration, the same procedure (a, b) was followed before adding new hay to the respective plot. The comparison between the different plots, sites and seasons revealed clearly that hay was the most attractive bait; for each gram of hay removed, Odontotermes brought about 12 g soil to the surface, Macrotermes 4 g. Odontotermes was the only genus attracted by organic material to the degraded area, and was therefore the decisive primary physical ecosystem engineer in the Za{\"i} system, initiating the restoration process. The mass of soil bioturbated in the course of foraging increased strongly from the degraded, barren towards the most rehabilitated reforested site. Combining all 36 experimental plots per Za{\"i} stage, Odontotermes bioturbated 31.8 tons of soil per hectare and month dry season in the degraded area, and 32.4 tons ha-1 mon-1 in the millet fields; both genera moved 138.9 tons ha-1 mon-1 in the young and 215.5 tons ha-1 mon-1 in the old Za{\"i} forest. Few comparable figures were found in the literature. In northern Burkina Faso, both genera constructed 20 tons of sheetings ha-1 mon-1 after mulching with a straw-wood mixture (Mando \& Miedema 1997), and in Senegal, around 10 tons ha-1 mon-1 were moved in heavily foraged plots (Rouland et al. 2003). Within a site, soil turn-over and the number of foraging holes created was always highest in hay, followed by compost, then by wood and in the end control. The fungus-growers' foraging-activity was leading to an enormous increase in surface pore space - after one month of induced foraging activity in hay-plots, the median number of foraging-holes increased from 142 m-2 in the degraded site up to 921 m-2 in the old Za{\"i} forest. The creation of subterranean galleries and macropores significantly increased the water infiltration rate by a mean factor 2-4. Laboratory analyses revealed that sheeting-soil differed strongly from the respective control soil as well as between the seasons, the food-type covered, and the two genera. Odontotermes-sheetings differed in more parameters than Macrotermes-sheetings, and dry season sheetings differed in more parameters (and more strongly) than rainy season sheetings. In the present study, soil organic matter, carbon and nitrogen contents were significantly increased in all dry season sheetings; in the rainy season mainly in those built on compost. Texture analysis pointed out that both genera used topsoil and soil from deeper horizons in varying mixture ratios, thereby supporting findings of Jouquet et al. (2006). To summarize, the present thesis contributes to a better understanding of the functional response traits of termites and ants to changing environmental parameters resulting from increasing human impact. The RAP-protocol represents an easy-to-learn and very effective method to representatively characterize, compare and monitor the taxonomic and functional diversity of termites and ants. The experiment has provided conclusive evidence of the importance of the consideration of fungus-growing termites (particularly Odontotermes and Macrotermes species) when aiming to restore infertile, degraded and crusted soils and to maintain a sustainable agricultural production in the Sahel-Sudanese zone of West Africa.},
  subject      = {Termiten},
  language  = {en}
}
@phdthesis{KubischgebWiegand2014,
  author    = {Kubisch (geb. Wiegand), Franziska},
  title     = {Learning in botanical gardens: Investigating educational methods during an instruction about plants and water},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111620},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2014},
  abstract  = {The contribution of botanical gardens to out-of-school education should be larger than it is currently in Germany. In the curricula of all school types botany plays only a minor role, although plants form the base for all animal life on earth. To increase the attractiveness of botanical gardens for teachers, offers and programs should be created and conducted in didactically sensible manners and allow students an emotional approach towards the topics through trial and experiments. Therefore it is insufficient to conduct guided tours, which are still most common. Student-centered methods, like learning at workstations, or experimental courses, can lead to an improved retention of the contents learned at the out-of-school learning setting. There are, however, methodological differences even within learning at workstations. In the first part of my study I compared a student- (S) and a teacher-centered (T) type of learning at workstations (chapter III). My intention was to find out, which of both methods results in more positive emotions at the out-of-school learning location and a higher sustainable knowledge increase. Like in all three parts of my study, 8th grade students from so-called "Mittelschulen" and "Realschulen" from Lower Franconia participated in the programs. I evaluated them by using multiple-choice tests assessing the students' knowledge regarding the topic 'plants and water' (see Appendix), following a before-after / control-impact study design. The students' emotions were assessed using the intrinsic motivation inventory directly after the garden visit. Using generalized linear mixed models, I did not find a significant difference between either of the two approaches. A reason for this could be that the students could be practically active in both methods, which made them fairly similar. Given that there was a significant knowledge increase in both methods, and the effort to develop the teacher-centered learning at workstations was much lower, I would suggest to follow that method for educational work in botanical gardens. Students already have many predefined concepts regarding many topics, especially when these are important in everyday life. These concepts do often not match the scientific state-of-the-art. Still, students bring their so-called 'alternative conceptions' into visits to the botanical garden. According to theory, confronting them with their own conceptions in the light of scientific facts, should foster updating their concepts with scientifically correct additions. To investigate this method regarding my topic 'plants and water', I developed an intervention with experiments on the lotus effect, which also plays a role in everyday life (chapter IV). Topics like the surface tension of the water, which is also found in 6th grade curricula in German schools, were included. Prior to the intervention, I assessed the students' conceptions using questionnaires and used the three most frequent alternative conceptions to develop a multiple-choice test, which was also used in a before-after / control-impact design. A group of students was also confronted with their conceptions during an introductory talk (AC), whereas another was not (NAC). This was conducted in a way, that likely led to dissatisfaction of the students with their own concepts. The analysis of the questionnaires with the Mann-Whitney U test showed, however, no difference between the two groups directly following the treatment. Over longer time, however, the NAC group retained significantly more knowledge. Probably the students confronted with the alternative conceptions remembered the illustrations of these more easily than the scientifically correct view. For some botanical topics it is certainly helpful to include this conceptual change approach, but apparently not for the lotus effect. In this case it is most sensible to focus on the surface structure of water-repellent leaves and fruits, as we describe it in a publication in 'Unterricht Biologie'. For the practical work in botanical gardens I would suggest to rather assess the students' concepts and assumptions in the beginning of an intervention in a botanical garden, especially with respect to feasibility. In the third part of my study I concentrate on the application of concept maps (chapter V). This method of cross-linking old and newly acquired knowledge is effective, but not very common in Germany, neither in schools, nor in botanical gardens. One group of students followed exclusively a teacher-centered learning at workstations regarding 'plants and water' (NCM), a second group created concept maps directly after the treatment and a second directly before the retention test (CM). The first map was intended to be a means of consolidation, whereas the late map was rather focused on recapitulation of what was learned about six weeks ago. To evaluate that I used the same multiple-choice tests as I did for the first part. The CM group showed a significantly higher knowledge increase, over short and long time-scales, although these students did significantly worse in the pretest than those of the NCM group. Regarding genders, female students profited especially from the first concept map (consolidation), males rather from the second (recapitulation). From the results one can conclude that prominently weaker students benefit from this method. Additionally the gender-related results show that using concept maps multiple times can be beneficial for different types of learners. In every study there also was a control group (C), which only had to fill out the questionnaires at the same time as the participating students, to account for external factors (like media, etc.). Especially learning at workstations and concept maps are very appropriate to be conducted at the out-of-school learning location botanical garden and are likely to strongly increase learning success. It is beneficial to mix several methods to achieve the best results in different types of learners. Additionally, when methods in school are mixed with those of out-of-school learning, the education gets more open, practical and colorful. That all resulted in a substantial long-term knowledge gain of all participating students.},
  subject      = {Konstruktive Didaktik},
  language  = {en}
}
@article{DjuzenovaMemmelSukhorukovetal.2014,
  author    = {Djuzenova, Cholpon S. and Memmel, Simon and Sukhorukov, Vladimir L. and H{\"o}ring, Marcus and Westerling, Katherine and Fiedler, Vanessa and Katzer, Astrid and Krohne, Georg and Flentje, Michael},
  title     = {Cell Surface Area and Membrane Folding in Glioblastoma Cell Lines Differing in PTEN and p53 Status},
  doi       = {10.1371/journal.pone.0087052},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111322},
  year      = {2014},
  abstract  = {Glioblastoma multiforme (GBM) is characterized by rapid growth, invasion and resistance to chemo-/radiotherapy. The complex cell surface morphology with abundant membrane folds, microvilli, filopodia and other membrane extensions is believed to contribute to the highly invasive behavior and therapy resistance of GBM cells. The present study addresses the mechanisms leading to the excessive cell membrane area in five GBM lines differing in mutational status for PTEN and p53. In addition to scanning electron microscopy (SEM), the membrane area and folding were quantified by dielectric measurements of membrane capacitance using the single-cell electrorotation (ROT) technique. The osmotic stability and volume regulation of GBM cells were analyzed by video microscopy. The expression of PTEN, p53, mTOR and several other marker proteins involved in cell growth and membrane synthesis were examined by Western blotting. The combined SEM, ROT and osmotic data provided independent lines of evidence for a large variability in membrane area and folding among tested GBM lines. Thus, DK-MG cells (wild type p53 and wild type PTEN) exhibited the lowest degree of membrane folding, probed by the area-specific capacitance Cm = 1.9 µF/cm2. In contrast, cell lines carrying mutations in both p53 and PTEN (U373-MG and SNB19) showed the highest Cm values of 3.7-4.0 µF/cm2, which corroborate well with their heavily villated cell surface revealed by SEM. Since PTEN and p53 are well-known inhibitors of mTOR, the increased membrane area/folding in mutant GBM lines may be related to the enhanced protein and lipid synthesis due to a deregulation of the mTOR-dependent downstream signaling pathway. Given that membrane folds and extensions are implicated in tumor cell motility and metastasis, the dielectric approach presented here provides a rapid and simple tool for screening the biophysical cell properties in studies on targeting chemo- or radiotherapeutically the migration and invasion of GBM and other tumor types.},
  language  = {en}
}
@article{RocesPielstroem2014,
  author    = {Roces, Flavio and Pielstr{\"o}m, Steffen},
  title     = {Soil Moisture and Excavation Behaviour in the Chaco Leaf-Cutting Ant (Atta vollenweideri): Digging Performance and Prevention of Water Inflow into the Nest},
  doi       = {10.1371/journal.pone.0095658},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111298},
  year      = {2014},
  abstract  = {The Chaco leaf-cutting ant Atta vollenweideri is native to the clay-heavy soils of the Gran Chaco region in South America. Because of seasonal floods, colonies are regularly exposed to varying moisture across the soil profile, a factor that not only strongly influences workers' digging performance during nest building, but also determines the suitability of the soil for the rearing of the colony's symbiotic fungus. In this study, we investigated the effects of varying soil moisture on behaviours associated with underground nest building in A. vollenweideri. This was done in a series of laboratory experiments using standardised, plastic clay-water mixtures with gravimetric water contents ranging from relatively brittle material to mixtures close to the liquid limit. Our experiments showed that preference and group-level digging rate increased with increasing water content, but then dropped considerably for extremely moist materials. The production of vibrational recruitment signals during digging showed, on the contrary, a slightly negative linear correlation with soil moisture. Workers formed and carried clay pellets at higher rates in moist clay, even at the highest water content tested. Hence, their weak preference and low group-level excavation rate observed for that mixture cannot be explained by any inability to work with the material. More likely, extremely high moistures may indicate locations unsuitable for nest building. To test this hypothesis, we simulated a situation in which workers excavated an upward tunnel below accumulated surface water. The ants stopped digging about 12 mm below the interface soil/water, a behaviour representing a possible adaptation to the threat of water inflow field colonies are exposed to while digging under seasonally flooded soils. Possible roles of soil water in the temporal and spatial pattern of nest growth are discussed.},
  language  = {en}
}
@article{WiegeringKorbThalheimeretal.2014,
  author    = {Wiegering, Armin and Korb, Doreen and Thalheimer, Andreas and K{\"a}mmerer, Ulrike and Allmanritter, Jan and Matthes, Niels and Linnebacher, Michael and Schlegel, Nicolas and Klein, Ingo and Erg{\"u}n, S{\"u}leyman and Germer, Christoph-Thomas and Otto, Christoph},
  title     = {E7080 (Lenvatinib), a Multi-Targeted Tyrosine Kinase Inhibitor, Demonstrates Antitumor Activities Against Colorectal Cancer Xenografts},
  doi       = {10.1016/j.neo.2014.09.008},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111165},
  year      = {2014},
  abstract  = {Clinical prognosis of metastasized colorectal carcinoma (CRC) is still not at desired levels and novel drugs are needed. Here, we focused on the multi-tyrosine kinase inhibitor E7080 (Lenvatinib) and assessed its therapeutic efficacy against human CRC cell lines in vitro and human CRC xenografts in vivo. The effect of E7080 on cell viability was examined on 10 humanCRCcell lines and humanendothelial cells (HUVEC). The inhibitory effect of E7080 on VEGF-induced angiogenesis was studied in an ex vivo mouse aortic ring angiogenesis assay. In addition, the efficacy of E7080 against xenografts derived fromCRC cell lines and CRC patient resection specimenswithmutated KRASwas investigated in vivo. Arelatively low cytotoxic effect of E7080 on CRC cell viabilitywas observed in vitro. Endothelial cells (HUVEC)weremore susceptible to the incubation with E7080. This is in line with the observation that E7080 demonstrated an anti-angiogenic effect in a three-dimensional ex vivo mouse aortic ring angiogenesis assay. E7080 effectively disrupted CRC cell-mediated VEGF-stimulated growth of HUVEC in vitro. Daily in vivo treatment with E7080 (5 mg/kg) significantly delayed the growth of KRAS mutated CRC xenografts with decreased density of tumor-associated vessel formations and without tumor regression. This observation is in line with results that E7080 did not significantly reduce the number of Ki67-positive cells in CRC xenografts. The results suggest antiangiogenic activity of E7080 at a dosage thatwas well tolerated by nudemice. E7080 may provide therapeutic benefits in the treatment of CRC with mutated KRAS.},
  language  = {en}
}
@article{RudelPrustySiegletal.2014,
  author    = {Rudel, Thomas and Prusty, Bhupesh K. and Siegl, Christine and Gulve, Nitish and Mori, Yasuko},
  title     = {GP96 Interacts with HHV-6 during Viral Entry and Directs It for Cellular Degradation},
  doi       = {10. 1371/journal.pone.0113962},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111068},
  year      = {2014},
  abstract  = {CD46 and CD134 mediate attachment of Human Herpesvirus 6A (HHV-6A) and HHV-6B to host cell, respectively. But many cell types interfere with viral infection through rapid degradation of viral DNA. Hence, not all cells expressing these receptors are permissive to HHV-6 DNA replication and production of infective virions suggesting the involvement of additional factors that influence HHV-6 propagation. Here, we used a proteomics approach to identify other host cell proteins necessary for HHV-6 binding and entry. We found host cell chaperone protein GP96 to interact with HHV-6A and HHV-6B and to interfere with virus propagation within the host cell. In human peripheral blood mononuclear cells (PBMCs), GP96 is transported to the cell surface upon infection with HHV-6 and interacts with HHV-6A and -6B through its C-terminal end. Suppression of GP96 expression decreased initial viral binding but increased viral DNA replication. Transient expression of human GP96 allowed HHV-6 entry into CHO-K1 cells even in the absence of CD46. Thus, our results suggest an important role for GP96 during HHV-6 infection, which possibly supports the cellular degradation of the virus.},
  language  = {en}
}
@article{WiegeringIsbertDietzetal.2014,
  author    = {Wiegering, Armin and Isbert, Christoph and Dietz, Ulrich A. and Kunzmann, Volker and Ackermann, Sabine and Kerscher, Alexander and Maeder, Uwe and Flentje, Michael and Schlegel, Nicolas and Reibetanz, Joachim and Germer, Christoph-Thomas and Klein, Ingo},
  title     = {Multimodal therapy in treatment of rectal cancer is associated with improved survival and reduced local recurrence - a retrospective analysis over two decades},
  doi       = {10.1186/1471-2407-14-816},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110606},
  year      = {2014},
  abstract  = {Background The management of rectal cancer (RC) has substantially changed over the last decades with the implementation of neoadjuvant chemoradiotherapy, adjuvant therapy and improved surgery such as total mesorectal excision (TME). It remains unclear in which way these approaches overall influenced the rate of local recurrence and overall survival. Methods Clinical, histological and survival data of 658 out of 662 consecutive patients with RC were analyzed for treatment and prognostic factors from a prospectively expanded single-institutional database. Findings were then stratified according to time of diagnosis in patient groups treated between 1993 and 2001 and 2002 and 2010. Results The study population included 658 consecutive patients with rectal cancer between 1993 and 2010. Follow up data was available for 99.6\% of all 662 treated patients. During the time period between 2002 and 2010 significantly more patients underwent neoadjuvant chemoradiotherapy (17.6\% vs. 60\%) and adjuvant chemotherapy (37.9\% vs. 58.4\%). Also, the rate of reported TME during surgery increased. The rate of local or distant metastasis decreased over time, and tumor related 5-year survival increased significantly with from 60\% to 79\%. Conclusion In our study population, the implementation of treatment changes over the last decade improved the patient's outcome significantly. Improvements were most evident for UICC stage III rectal cancer.},
  language  = {en}
}
@article{BrehmHemerKonradetal.2014,
  author    = {Brehm, Klaus and Hemer, Sarah and Konrad, Christian and Spiliotis, Markus and Koziol, Uriel and Schaack, Dominik and F{\"o}rster, Sabine and Gelmedin, Verena and Stadelmann, Britta and Dandekar, Thomas and Hemphill, Andrew},
  title     = {Host insulin stimulates Echinococcus multilocularis insulin signalling pathways and larval development},
  doi       = {10.1186/1741-7007-12-5},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110357},
  year      = {2014},
  abstract  = {Background The metacestode of the tapeworm Echinococcus multilocularis is the causative agent of alveolar echinococcosis, a lethal zoonosis. Infections are initiated through establishment of parasite larvae within the intermediate host's liver, where high concentrations of insulin are present, followed by tumour-like growth of the metacestode in host organs. The molecular mechanisms determining the organ tropism of E. multilocularis or the influences of host hormones on parasite proliferation are poorly understood. Results Using in vitro cultivation systems for parasite larvae we show that physiological concentrations (10 nM) of human insulin significantly stimulate the formation of metacestode larvae from parasite stem cells and promote asexual growth of the metacestode. Addition of human insulin to parasite larvae led to increased glucose uptake and enhanced phosphorylation of Echinococcus insulin signalling components, including an insulin receptor-like kinase, EmIR1, for which we demonstrate predominant expression in the parasite's glycogen storage cells. We also characterized a second insulin receptor family member, EmIR2, and demonstrated interaction of its ligand binding domain with human insulin in the yeast two-hybrid system. Addition of an insulin receptor inhibitor resulted in metacestode killing, prevented metacestode development from parasite stem cells, and impaired the activation of insulin signalling pathways through host insulin. Conclusions Our data indicate that host insulin acts as a stimulant for parasite development within the host liver and that E. multilocularis senses the host hormone through an evolutionarily conserved insulin signalling pathway. Hormonal host-parasite cross-communication, facilitated by the relatively close phylogenetic relationship between E. multilocularis and its mammalian hosts, thus appears to be important in the pathology of alveolar echinococcosis. This contributes to a closer understanding of organ tropism and parasite persistence in larval cestode infections. Furthermore, our data show that Echinococcus insulin signalling pathways are promising targets for the development of novel drugs.},
  language  = {en}
}
@article{BrehmKoziolRauschendorferetal.2014,
  author    = {Brehm, Klaus and Koziol, Uriel and Rauschendorfer, Theresa and Rodr{\´i}guez, Luis Zanon and Krohne, Georg},
  title     = {The unique stem cell system of the immortal larva of the human parasite Echinococcus multilocularis},
  doi       = {10.1186/2041-9139-5-10},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110315},
  year      = {2014},
  abstract  = {Background It is believed that in tapeworms a separate population of undifferentiated cells, the germinative cells, is the only source of cell proliferation throughout the life cycle (similar to the neoblasts of free living flatworms). In Echinococcus multilocularis, the metacestode larval stage has a unique development, growing continuously like a mass of vesicles that infiltrate the tissues of the intermediate host, generating multiple protoscoleces by asexual budding. This unique proliferation potential indicates the existence of stem cells that are totipotent and have the ability for extensive self-renewal. Results We show that only the germinative cells proliferate in the larval vesicles and in primary cell cultures that undergo complete vesicle regeneration, by using a combination of morphological criteria and by developing molecular markers of differentiated cell types. The germinative cells are homogeneous in morphology but heterogeneous at the molecular level, since only sub-populations express homologs of the post-transcriptional regulators nanos and argonaute. Important differences are observed between the expression patterns of selected neoblast marker genes of other flatworms and the E. multilocularis germinative cells, including widespread expression in E. multilocularis of some genes that are neoblast-specific in planarians. Hydroxyurea treatment results in the depletion of germinative cells in larval vesicles, and after recovery following hydroxyurea treatment, surviving proliferating cells grow as patches that suggest extensive self-renewal potential for individual germinative cells. Conclusions In E. multilocularis metacestodes, the germinative cells are the only proliferating cells, presumably driving the continuous growth of the larval vesicles. However, the existence of sub-populations of the germinative cells is strongly supported by our data. Although the germinative cells are very similar to the neoblasts of other flatworms in function and in undifferentiated morphology, their unique gene expression pattern and the evolutionary loss of conserved stem cells regulators suggest that important differences in their physiology exist, which could be related to the unique biology of E. multilocularis larvae.},
  language  = {en}
}
@article{SchultzBaier2014,
  author    = {Schultz, J{\"o}rg and Baier, Herbert},
  title     = {ISAAC - InterSpecies Analysing Application using Containers},
  doi       = {10.1186/1471-2105-15-18},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110124},
  year      = {2014},
  abstract  = {Background Information about genes, transcripts and proteins is spread over a wide variety of databases. Different tools have been developed using these databases to identify biological signals in gene lists from large scale analysis. Mostly, they search for enrichments of specific features. But, these tools do not allow an explorative walk through different views and to change the gene lists according to newly upcoming stories. Results To fill this niche, we have developed ISAAC, the InterSpecies Analysing Application using Containers. The central idea of this web based tool is to enable the analysis of sets of genes, transcripts and proteins under different biological viewpoints and to interactively modify these sets at any point of the analysis. Detailed history and snapshot information allows tracing each action. Furthermore, one can easily switch back to previous states and perform new analyses. Currently, sets can be viewed in the context of genomes, protein functions, protein interactions, pathways, regulation, diseases and drugs. Additionally, users can switch between species with an automatic, orthology based translation of existing gene sets. As todays research usually is performed in larger teams and consortia, ISAAC provides group based functionalities. Here, sets as well as results of analyses can be exchanged between members of groups. Conclusions ISAAC fills the gap between primary databases and tools for the analysis of large gene lists. With its highly modular, JavaEE based design, the implementation of new modules is straight forward. Furthermore, ISAAC comes with an extensive web-based administration interface including tools for the integration of third party data. Thus, a local installation is easily feasible. In summary, ISAAC is tailor made for highly explorative interactive analyses of gene, transcript and protein sets in a collaborative environment.},
  language  = {en}
}