@article{AkhoonGuptaTiwarietal.2019,
  author    = {Akhoon, Bashir A. and Gupta, Shishir K. and Tiwari, Sudeep and Rathor, Laxmi and Pant, Aakanksha and Singh, Nivedita and Gupta, Shailendra K. and Dandekar, Thomas and Pandey, Rakesh},
  title     = {C. elegans protein interaction network analysis probes RNAi validated pro-longevity effect of nhr-6, a human homolog of tumor suppressor Nr4a1},
  series = {Scientific Reports},
  volume    = {9},
  journal   = {Scientific Reports},
  doi       = {10.1038/s41598-019-51649-0},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202666},
  pages     = {15711},
  year      = {2019},
  abstract  = {Protein-protein interaction (PPI) studies are gaining momentum these days due to the plethora of various high-throughput experimental methods available for detecting PPIs. Proteins create complexes and networks by functioning in harmony with other proteins and here in silico network biology hold the promise to reveal new functionality of genes as it is very difficult and laborious to carry out experimental high-throughput genetic screens in living organisms. We demonstrate this approach by computationally screening C. elegans conserved homologs of already reported human tumor suppressor and aging associated genes. We select by this nhr-6, vab-3 and gst-23 as predicted longevity genes for RNAi screen. The RNAi results demonstrated the pro-longevity effect of these genes. Nuclear hormone receptor nhr-6 RNAi inhibition resulted in a C. elegans phenotype of 23.46\% lifespan reduction. Moreover, we show that nhr-6 regulates oxidative stress resistance in worms and does not affect the feeding behavior of worms. These findings imply the potential of nhr-6 as a common therapeutic target for aging and cancer ailments, stressing the power of in silico PPI network analysis coupled with RNAi screens to describe gene function.},
  language  = {en}
}
@article{BartelPeinPopperetal.2019,
  author    = {Bartel, Karin and Pein, Helmut and Popper, Bastian and Schmitt, Sabine and Janaki-Raman, Sudha and Schulze, Almut and Lengauer, Florian and Koeberle, Andreas and Werz, Oliver and Zischka, Hans and M{\"u}ller, Rolf and Vollmar, Angelika M. and Schwarzenberg, Karin von},
  title     = {Connecting lysosomes and mitochondria - a novel role for lipid metabolism in cancer cell death},
  series = {Cell Communication and Signaling},
  volume    = {17},
  journal   = {Cell Communication and Signaling},
  doi       = {10.1186/s12964-019-0399-2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221524},
  year      = {2019},
  abstract  = {Background The understanding of lysosomes has been expanded in recent research way beyond their view as cellular trash can. Lysosomes are pivotal in regulating metabolism, endocytosis and autophagy and are implicated in cancer. Recently it was discovered that the lysosomal V-ATPase, which is known to induce apoptosis, interferes with lipid metabolism in cancer, yet the interplay between these organelles is poorly understood. Methods LC-MS/MS analysis was performed to investigate lipid distribution in cells. Cell survival and signaling pathways were analyzed by means of cell biological methods (qPCR, Western Blot, flow cytometry, CellTiter-Blue). Mitochondrial structure was analyzed by confocal imaging and electron microscopy, their function was determined by flow cytometry and seahorse measurements. Results Our data reveal that interfering with lysosomal function changes composition and subcellular localization of triacylglycerids accompanied by an upregulation of PGC1α and PPARα expression, master regulators of energy and lipid metabolism. Furthermore, cardiolipin content is reduced driving mitochondria into fission, accompanied by a loss of membrane potential and reduction in oxidative capacity, which leads to a deregulation in cellular ROS and induction of mitochondria-driven apoptosis. Additionally, cells undergo a metabolic shift to glutamine dependency, correlated with the fission phenotype and sensitivity to lysosomal inhibition, most prominent in Ras mutated cells. Conclusion This study sheds mechanistic light on a largely uninvestigated triangle between lysosomes, lipid metabolism and mitochondrial function. Insight into this organelle crosstalk increases our understanding of mitochondria-driven cell death. Our findings furthermore provide a first hint on a connection of Ras pathway mutations and sensitivity towards lysosomal inhibitors.},
  language  = {en}
}
@phdthesis{Beck2019,
  author    = {Beck, Katharina},
  title     = {Die nitrerge Neurotransmission im Gastrointestinaltrakt der Maus},
  doi       = {10.25972/OPUS-15989},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159896},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2019},
  abstract  = {Die NO-sensitive Guanylyl-Cyclase (NO-GC) ist ein zentrales Enzym der NO/cGMP-Signalkaskade, das {\"u}ber die Aktivierung von NO zur Bildung des second messangers cGMP f{\"u}hrt. Die NO-GC setzt sich aus zwei Untereinheiten zusammen, sodass zwei Isoformen des Enzyms gebildet werden k{\"o}nnen (α1β1 und α2β1). Da die genaue Verteilung der beiden Isoformen im Colon nicht bekannt ist, wurde diese im ersten Teil dieser Arbeit charakterisiert. Immunhistochemie und In-situ-Hybridisierung zeigten die Expression beider Isoformen sowohl in der glatten Muskelschicht als auch in der Submukosa und Lamina propria. Dabei war die α1β1-Isoform ubiquit{\"a}r, die α2β1-Isoform dagegen haupts{\"a}chlich im Bereich des myenterischen Plexus vorzufinden. In der glatten Muskelschicht des Colons ist die NO-GC in glatten Muskelzellen (SMC), interstitiellen Zellen von Cajal (ICC) sowie Fibroblasten-{\"a}hnliche Zellen (FLC) exprimiert und haupts{\"a}chlich in die Modulation der gastrointestinalen Motilit{\"a}t involviert. Zur spezifischen Charakterisierung der Funktion der NO-GC in den einzelnen Zelltypen wurden Knockout-M{\"a}use generiert, denen die NO-GC global (GCKO) oder spezifisch in SMC (SMC-GCKO), ICC (ICC-GCKO) oder beiden Zelltypen (SMC/ICC-GCKO) fehlt. Anhand dieser Mausmodelle sollten im zweiten Teil dieser Arbeit die modulatorischen Effekte der NO-GC auf die spontanen Kontraktionen des Colons bestimmt werden. Zur Charakterisierung der spontanen Kontraktionen der zirkul{\"a}ren Muskelschicht wurden Myographiestudien mit 2,5 mm langen Colonringen durchgef{\"u}hrt. Hierbei konnten drei verschiedene Kontraktionen gemessen werden: Kleine, hochfrequente Ripples, mittlere Kontraktionen und große Kontraktionen. Die detaillierte Analyse der einzelnen Kontraktionen zeigte einerseits eine NO-unabh{\"a}ngige Regulation der Ripples, andererseits eine NO-abh{\"a}ngige Modulation der mittleren und großen Kontraktionen {\"u}ber die NO-GC in SMC und ICC. Die NO-GC in SMC beeinflusst die Kontraktionen vermutlich vor allem {\"u}ber die Regulation des Muskeltonus der zirkul{\"a}ren Muskelschicht. Die NO-GC in ICC dagegen modifiziert die spontanen Kontraktionen m{\"o}glicherweise {\"u}ber eine Ver{\"a}nderung der Schrittmacheraktivit{\"a}t. Allerdings f{\"u}hrt erst ein Funktionsverlust des NO/cGMP-Signalweges in beiden Zelltypen zu einem sichtbar ver{\"a}nderten Kontraktionsmuster, das dem von globalen Knockout-Tieren glich. Dies weist auf eine kompensatorische Wirkung der NO-GC im jeweils anderen Zelltyp hin. Zur Analyse der propulsiven Kontraktionen entlang des gesamten Colons wurden Videoaufnahmen der Darmbewegungen in Kontraktionsmusterkarten transformiert. Zudem wurde der Darm durchsp{\"u}lt und die Ausflusstropfen aufgezeichnet, um die Effektivit{\"a}t der Kontraktionen beurteilen zu k{\"o}nnen. Hierbei zeigte sich, dass eine Beeintr{\"a}chtigung des NO/cGMP-Signalweges eine verminderte Effektivit{\"a}t der Kontraktionen zur Folge hat und vermutlich durch eine beeintr{\"a}chtige Synchronisation der Kontraktionen erkl{\"a}rt werden kann. In diesem Regulationsmechanismus konnte vor allem der NO-GC in SMC eine {\"u}bergeordnete Rolle zugewiesen werden. Der dritte Teil der Arbeit thematisierte den Befund, dass SMC-GCKO-Tiere ca. 5 Monate nach Tamoxifen-Behandlung Entartungen der Mukosa entwickelten. Diese Entartung war lediglich in Tamoxifen-induzierten Knockout-Tieren vorzufinden. Histologische Analysen identifizierten die Entartungen als tubulovill{\"o}ses Adenom. Die Genexpressionsanalyse von Mukosafalten von SMC-GCKO- und heterozygoten Kontrolltieren zeigte eine Vielzahl von Genen, welche spezifisch bei colorectalem Karzinom differenziell exprimiert sind. Einer dieser Faktoren war der BMP-Antagonist Gremlin1. Dieser Faktor erschien von besonderem Interesse, da er in Zellen der Lamina muscularis mucosae und kryptennahen Myofibroblasten exprimiert wird. Immunhistochemische Analysen ließen vermuten, dass diese Zellen sowohl die NO-GC als auch die Cre-Rekombinase unter dem SMMHC-Promotor exprimieren. Diese Arbeit liefert demnach Hinweise darauf, dass die NO-GC einen wichtigen Regulator innerhalb der Stammzellnische bildet. Die Deletion der NO-GC f{\"u}hrt vermutlich zu einer verst{\"a}rkten Bildung bzw. Sekretion von Gremlin1, was die Hom{\"o}ostase der mukosalen Erneuerung st{\"o}rt und somit zur Entwicklung von Adenomen f{\"u}hrt.},
  subject      = {Gastrointestinaltrakt},
  language  = {de}
}
@article{BeerSchenkHelfrichFoersteretal.2019,
  author    = {Beer, Katharina and Schenk, Mariela and Helfrich-F{\"o}rster, Charlotte and Holzschuh, Andrea},
  title     = {The circadian clock uses different environmental time cues to synchronize emergence and locomotion of the solitary bee Osmia bicornis},
  series = {Scientific Reports},
  volume    = {9},
  journal   = {Scientific Reports},
  doi       = {10.1038/s41598-019-54111-3},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202721},
  pages     = {17748},
  year      = {2019},
  abstract  = {Life on earth adapted to the daily reoccurring changes in environment by evolving an endogenous circadian clock. Although the circadian clock has a crucial impact on survival and behavior of solitary bees, many aspects of solitary bee clock mechanisms remain unknown. Our study is the first to show that the circadian clock governs emergence in Osmia bicornis, a bee species which overwinters as adult inside its cocoon. Therefore, its eclosion from the pupal case is separated by an interjacent diapause from its emergence in spring. We show that this bee species synchronizes its emergence to the morning. The daily rhythms of emergence are triggered by temperature cycles but not by light cycles. In contrast to this, the bee's daily rhythms in locomotion are synchronized by light cycles. Thus, we show that the circadian clock of O. bicornis is set by either temperature or light, depending on what activity is timed. Light is a valuable cue for setting the circadian clock when bees have left the nest. However, for pre-emerged bees, temperature is the most important cue, which may represent an evolutionary adaptation of the circadian system to the cavity-nesting life style of O. bicornis.},
  language  = {en}
}
@article{BoetzlKonleKrauss2019,
  author    = {Boetzl, Fabian A. and Konle, Antonia and Krauss, Jochen},
  title     = {Aphid cards - useful model for assessing predation rates or bias prone nonsense?},
  series = {Journal of Applied Entomology},
  volume    = {144},
  journal   = {Journal of Applied Entomology},
  number    = {1-2},
  doi       = {10.1111/jen.12692},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-204798},
  pages     = {74-80},
  year      = {2019},
  abstract  = {Predation on pest organisms is an essential ecosystem function supporting yields in modern agriculture. However, assessing predation rates is intricate, and they can rarely be linked directly to predator densities or functions. We tested whether sentinel prey aphid cards are useful tools to assess predation rates in the field. Therefore, we looked at aphid cards of different sizes on the ground level as well as within the vegetation. Additionally, by trapping ground-dwelling predators, we examined whether obtained predation rates could be linked to predator densities and traits. Predation rates recorded with aphid cards were independent of aphid card size. However, predation rates on the ground level were three times higher than within the vegetation. We found both predatory carabid activity densities as well as community weighted mean body size to be good predictors for predation rates. Predation rates obtained from aphid cards are stable over card type and related to predator assemblages. Aphid cards, therefore, are a useful, efficient method for rapidly assessing the ecosystem function predation. Their use might especially be recommended for assessments on the ground level and when time and resource limitations rule out more elaborate sentinel prey methods using exclosures with living prey animals.},
  language  = {en}
}
@phdthesis{Breitenbach2019,
  author    = {Breitenbach, Tim},
  title     = {A mathematical optimal control based approach to pharmacological modulation with regulatory networks and external stimuli},
  doi       = {10.25972/OPUS-17436},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-174368},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2019},
  abstract  = {In this work models for molecular networks consisting of ordinary differential equations are extended by terms that include the interaction of the corresponding molecular network with the environment that the molecular network is embedded in. These terms model the effects of the external stimuli on the molecular network. The usability of this extension is demonstrated with a model of a circadian clock that is extended with certain terms and reproduces data from several experiments at the same time. Once the model including external stimuli is set up, a framework is developed in order to calculate external stimuli that have a predefined desired effect on the molecular network. For this purpose the task of finding appropriate external stimuli is formulated as a mathematical optimal control problem for which in order to solve it a lot of mathematical methods are available. Several methods are discussed and worked out in order to calculate a solution for the corresponding optimal control problem. The application of the framework to find pharmacological intervention points or effective drug combinations is pointed out and discussed. Furthermore the framework is related to existing network analysis tools and their combination for network analysis in order to find dedicated external stimuli is discussed. The total framework is verified with biological examples by comparing the calculated results with data from literature. For this purpose platelet aggregation is investigated based on a corresponding gene regulatory network and associated receptors are detected. Furthermore a transition from one to another type of T-helper cell is analyzed in a tumor setting where missing agents are calculated to induce the corresponding switch in vitro. Next a gene regulatory network of a myocardiocyte is investigated where it is shown how the presented framework can be used to compare different treatment strategies with respect to their beneficial effects and side effects quantitatively. Moreover a constitutively activated signaling pathway, which thus causes maleficent effects, is modeled and intervention points with corresponding treatment strategies are determined that steer the gene regulatory network from a pathological expression pattern to physiological one again.},
  subject      = {Bioinformatik},
  language  = {en}
}
@article{BreitenbachLorenzDandekar2019,
  author    = {Breitenbach, Tim and Lorenz, Kristina and Dandekar, Thomas},
  title     = {How to steer and control ERK and the ERK signaling cascade exemplified by looking at cardiac insufficiency},
  series = {International Journal of Molecular Sciences},
  volume    = {20},
  journal   = {International Journal of Molecular Sciences},
  number    = {9},
  issn      = {1422-0067},
  doi       = {10.3390/ijms20092179},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-285164},
  year      = {2019},
  abstract  = {Mathematical optimization framework allows the identification of certain nodes within a signaling network. In this work, we analyzed the complex extracellular-signal-regulated kinase 1 and 2 (ERK1/2) cascade in cardiomyocytes using the framework to find efficient adjustment screws for this cascade that is important for cardiomyocyte survival and maladaptive heart muscle growth. We modeled optimal pharmacological intervention points that are beneficial for the heart, but avoid the occurrence of a maladaptive ERK1/2 modification, the autophosphorylation of ERK at threonine 188 (ERK\(^{Thr188}\) phosphorylation), which causes cardiac hypertrophy. For this purpose, a network of a cardiomyocyte that was fitted to experimental data was equipped with external stimuli that model the pharmacological intervention points. Specifically, two situations were considered. In the first one, the cardiomyocyte was driven to a desired expression level with different treatment strategies. These strategies were quantified with respect to beneficial effects and maleficent side effects and then which one is the best treatment strategy was evaluated. In the second situation, it was shown how to model constitutively activated pathways and how to identify drug targets to obtain a desired activity level that is associated with a healthy state and in contrast to the maleficent expression pattern caused by the constitutively activated pathway. An implementation of the algorithms used for the calculations is also presented in this paper, which simplifies the application of the presented framework for drug targeting, optimal drug combinations and the systematic and automatic search for pharmacological intervention points. The codes were designed such that they can be combined with any mathematical model given by ordinary differential equations.},
  language  = {en}
}
@article{CecilGentschevAdelfingeretal.2019,
  author    = {Cecil, Alexander and Gentschev, Ivaylo and Adelfinger, Marion and Dandekar, Thomas and Szalay, Aladar A.},
  title     = {Vaccinia virus injected human tumors: oncolytic virus efficiency predicted by antigen profiling analysis fitted boolean models},
  series = {Bioengineered},
  volume    = {10},
  journal   = {Bioengineered},
  number    = {1},
  doi       = {10.1080/21655979.2019.1622220},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200507},
  pages     = {190-196},
  year      = {2019},
  abstract  = {Virotherapy on the basis of oncolytic vaccinia virus (VACV) strains is a promising approach for cancer therapy. Recently, we showed that the oncolytic vaccinia virus GLV-1h68 has a therapeutic potential in treating human prostate and hepatocellular carcinomas in xenografted mice. In this study, we describe the use of dynamic boolean modeling for tumor growth prediction of vaccinia virus-injected human tumors. Antigen profiling data of vaccinia virus GLV-1h68-injected human xenografted mice were obtained, analyzed and used to calculate differences in the tumor growth signaling network by tumor type and gender. Our model combines networks for apoptosis, MAPK, p53, WNT, Hedgehog, the T-killer cell mediated cell death, Interferon and Interleukin signaling networks. The in silico findings conform very well with in vivo findings of tumor growth. Similar to a previously published analysis of vaccinia virus-injected canine tumors, we were able to confirm the suitability of our boolean modeling for prediction of human tumor growth after virus infection in the current study as well. In summary, these findings indicate that our boolean models could be a useful tool for testing of the efficacy of VACV-mediated cancer therapy already before its use in human patients.},
  language  = {en}
}
@article{CoelhoAlvesMonteiroetal.2019,
  author    = {Coelho, Luis Pedro and Alves, Renato and Monteiro, Paulo and Huerta-Cepas, Jaime and Freitas, Ana Teresa and Bork, Peer},
  title     = {NG-meta-profiler: fast processing of metagenomes using NGLess, a domain-specific language},
  series = {Microbiome},
  volume    = {7},
  journal   = {Microbiome},
  number    = {84},
  doi       = {10.1186/s40168-019-0684-8},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223161},
  year      = {2019},
  abstract  = {Background Shotgun metagenomes contain a sample of all the genomic material in an environment, allowing for the characterization of a microbial community. In order to understand these communities, bioinformatics methods are crucial. A common first step in processing metagenomes is to compute abundance estimates of different taxonomic or functional groups from the raw sequencing data. Given the breadth of the field, computational solutions need to be flexible and extensible, enabling the combination of different tools into a larger pipeline. Results We present NGLess and NG-meta-profiler. NGLess is a domain specific language for describing next-generation sequence processing pipelines. It was developed with the goal of enabling user-friendly computational reproducibility. It provides built-in support for many common operations on sequencing data and is extensible with external tools with configuration files. Using this framework, we developed NG-meta-profiler, a fast profiler for metagenomes which performs sequence preprocessing, mapping to bundled databases, filtering of the mapping results, and profiling (taxonomic and functional). It is significantly faster than either MOCAT2 or htseq-count and (as it builds on NGLess) its results are perfectly reproducible. Conclusions NG-meta-profiler is a high-performance solution for metagenomics processing built on NGLess. It can be used as-is to execute standard analyses or serve as the starting point for customization in a perfectly reproducible fashion. NGLess and NG-meta-profiler are open source software (under the liberal MIT license) and can be downloaded from https://ngless.embl.de or installed through bioconda.},
  language  = {en}
}
@unpublished{Dandekar2019,
  author    = {Dandekar, Thomas},
  title     = {Biological heuristics applied to cosmology suggests a condensation nucleus as start of our universe and inflation cosmology replaced by a period of rapid Weiss domain-like crystal growth},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-183945},
  pages     = {24},
  year      = {2019},
  abstract  = {Cosmology often uses intricate formulas and mathematics to derive new theories and concepts. We do something different in this paper: We look at biological processes and derive from these heuristics so that the revised cosmology agrees with astronomical observations but does also agree with standard biological observations. We show that we then have to replace any type of singularity at the start of the universe by a condensation nucleus and that the very early period of the universe usually assumed to be inflation has to be replaced by a period of rapid crystal growth as in Weiss magnetization domains. Impressively, these minor modifications agree well with astronomical observations including removing the strong inflation perturbations which were never observed in the recent BICEP2 experiments. Furthermore, looking at biological principles suggests that such a new theory with a condensation nucleus at start and a first rapid phase of magnetization-like growth of the ordered, physical laws obeying lattice we live in is in fact the only convincing theory of the early phases of our universe that also is compatible with current observations. We show in detail in the following that such a process of crystal creation, breaking of new crystal seeds and ultimate evaporation of the present crystal readily leads over several generations to an evolution and selection of better, more stable and more self-organizing crystals. Moreover, this explains the "fine-tuning" question why our universe is fine-tuned to favor life: Our Universe is so self-organizing to have enough offspring and the detailed physics involved is at the same time highly favorable for all self-organizing processes including life. This biological theory contrasts with current standard inflation cosmologies. The latter do not perform well in explaining any phenomena of sophisticated structure creation or self-organization. As proteins can only thermodynamically fold by increasing the entropy in the solution around them we suggest for cosmology a condensation nucleus for a universe can form only in a "chaotic ocean" of string-soup or quantum foam if the entropy outside of the nucleus rapidly increases. We derive an interaction potential for 1 to n-dimensional strings or quantum-foams and show that they allow only 1D, 2D, 4D or octonion interactions. The latter is the richest structure and agrees to the E8 symmetry fundamental to particle physics and also compatible with the ten dimensional string theory E8 which is part of the M-theory. Interestingly, any other interactions of other dimensionality can be ruled out using Hurwitz compositional theorem. Crystallization explains also extremely well why we have only one macroscopic reality and where the worldlines of alternative trajectories exist: They are in other planes of the crystal and for energy reasons they crystallize mostly at the same time, yielding a beautiful and stable crystal. This explains decoherence and allows to determine the size of Planck´s quantum h (very small as separation of crystal layers by energy is extremely strong). Ultimate dissolution of real crystals suggests an explanation for dark energy agreeing with estimates for the "big rip". The halo distribution of dark matter favoring galaxy formation is readily explained by a crystal seed starting with unit cells made of normal and dark matter. That we have only matter and not antimatter can be explained as there may be right handed mattercrystals and left-handed antimatter crystals. Similarly, real crystals are never perfect and we argue that exactly such irregularities allow formation of galaxies, clusters and superclusters. Finally, heuristics from genetics suggest to look for a systems perspective to derive correct vacuum and Higgs Boson energies.},
  language  = {en}
}