@article{WuPonsGoudetetal.2017, author = {Wu, Yu and Pons, Val{\´e}rie and Goudet, Am{\´e}lie and Panigai, Laetitia and Fischer, Annette and Herweg, Jo-Ana and Kali, Sabrina and Davey, Robert A. and Laporte, J{\´e}r{\^o}me and Bouclier, C{\´e}line and Yousfi, Rahima and Aubenque, C{\´e}line and Merer, Goulven and Gobbo, Emilie and Lopez, Roman and Gillet, Cynthia and Cojean, Sandrine and Popoff, Michel R. and Clayette, Pascal and Le Grand, Roger and Boulogne, Claire and Tordo, No{\"e}l and Lemichez, Emmanuel and Loiseau, Philippe M. and Rudel, Thomas and Sauvaire, Didier and Cintrat, Jean-Christophe and Gillet, Daniel and Barbier, Julien}, title = {ABMA, a small molecule that inhibits intracellular toxins and pathogens by interfering with late endosomal compartments}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, doi = {10.1038/s41598-017-15466-7}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173170}, year = {2017}, abstract = {Intracellular pathogenic microorganisms and toxins exploit host cell mechanisms to enter, exert their deleterious effects as well as hijack host nutrition for their development. A potential approach to treat multiple pathogen infections and that should not induce drug resistance is the use of small molecules that target host components. We identifed the compound 1-adamantyl (5-bromo-2-methoxybenzyl) amine (ABMA) from a cell-based high throughput screening for its capacity to protect human cells and mice against ricin toxin without toxicity. This compound efciently protects cells against various toxins and pathogens including viruses, intracellular bacteria and parasite. ABMA provokes Rab7-positive late endosomal compartment accumulation in mammalian cells without affecting other organelles (early endosomes, lysosomes, the Golgi apparatus, the endoplasmic reticulum or the nucleus). As the mechanism of action of ABMA is restricted to host-endosomal compartments, it reduces cell infection by pathogens that depend on this pathway to invade cells. ABMA may represent a novel class of broad-spectrum compounds with therapeutic potential against diverse severe infectious diseases.}, language = {en} } @article{RuppertFranzSaratisetal.2017, author = {Ruppert, Manuela and Franz, Mirjam and Saratis, Anastasios and Escarcena, Laura Velo and Hendrich, Oliver and Gooi, Li Ming and Schwenkert, Isabell and Klebes, Ansgar and Scholz, Henrike}, title = {Hangover links nuclear RNA signaling to cAMP regulation via the phosphodiesterase 4d ortholog dunce}, series = {Cell Reports}, volume = {18}, journal = {Cell Reports}, number = {2}, doi = {10.1016/j.celrep.2016.12.048}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171950}, pages = {533-544}, year = {2017}, abstract = {The hangover gene defines a cellular stress pathway that is required for rapid ethanol tolerance in Drosophila melanogaster. To understand how cellular stress changes neuronal function, we analyzed Hangover function on a cellular and neuronal level. We provide evidence that Hangover acts as a nuclear RNA binding protein and we identified the phosphodiesterase 4d ortholog dunce as a target RNA. We generated a transcript-specific dunce mutant that is impaired not only in ethanol tolerance but also in the cellular stress response. At the neuronal level, Dunce and Hangover are required in the same neuron pair to regulate experience-dependent motor output. Within these neurons, two cyclic AMP (cAMP)-dependent mechanisms balance the degree of tolerance. The balance is achieved by feedback regulation of Hangover and dunce transcript levels. This study provides insight into how nuclear Hangover/RNA signaling is linked to the cytoplasmic regulation of cAMP levels and results in neuronal adaptation and behavioral changes.}, language = {en} } @phdthesis{Sauerwein2023, author = {Sauerwein, Till}, title = {Implementation and application of bioinformatical software for the analysis of dual RNA sequencing data of host and pathogen during infection}, doi = {10.25972/OPUS-30307}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-303075}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2023}, abstract = {Since the advent of high-throughput sequencing technologies in the mid-2010s, RNA se- quencing (RNA-seq) has been established as the method of choice for studying gene expression. In comparison to microarray-based methods, which have mainly been used to study gene expression before the rise of RNA-seq, RNA-seq is able to profile the entire transcriptome of an organism without the need to predefine genes of interest. Today, a wide variety of RNA-seq methods and protocols exist, including dual RNA sequenc- ing (dual RNA-seq) and multi RNA sequencing (multi RNA-seq). Dual RNA-seq and multi RNA-seq simultaneously investigate the transcriptomes of two or more species, re- spectively. Therefore, the total RNA of all interacting species is sequenced together and only separated in silico. Compared to conventional RNA-seq, which can only investi- gate one species at a time, dual RNA-seq and multi RNA-seq analyses can connect the transcriptome changes of the species being investigated and thus give a clearer picture of the interspecies interactions. Dual RNA-seq and multi RNA-seq have been applied to a variety of host-pathogen, mutualistic and commensal interaction systems. We applied dual RNA-seq to a host-pathogen system of human mast cells and Staphylo- coccus aureus (S. aureus). S. aureus, a commensal gram-positive bacterium, can become an opportunistic pathogen and infect skin lesions of atopic dermatitis (AD) patients. Among the first immune cells S. aureus encounters are mast cells, which have previously been shown to be able to kill the bacteria by discharging antimicrobial products and re- leasing extracellular traps made of protein and deoxyribonucleic acid (DNA). However, S. aureus is known to evade the host's immune response by internalizing within mast cells. Our dual RNA-seq analysis of different infection settings revealed that mast cells and S. aureus need physical contact to influence each other's gene expression. We could show that S. aureus cells internalizing within mast cells undergo profound transcriptome changes to adjust their metabolism to survive in the intracellular niche. On the host side, we found out that infected mast cells elicit a type-I interferon (IFN-I) response in an autocrine manner and in a paracrine manner to non-infected bystander-cells. Our study provides the first evidence that mast cells are capable to produce IFN-I upon infection with a bacterial pathogen.}, subject = {Biologie}, language = {en} } @article{MendeLetunicHuertaCepasetal.2017, author = {Mende, Daniel R. and Letunic, Ivica and Huerta-Cepas, Jaime and Li, Simone S. and Forslund, Kristoffer and Sunagawa, Shinichi and Bork, Peer}, title = {proGenomes: a resource for consistent functional and taxonomic annotations of prokaryotic genomes}, series = {Nucleic Acids Research}, volume = {45}, journal = {Nucleic Acids Research}, number = {D1}, doi = {10.1093/nar/gkw989}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171987}, pages = {D529-D534}, year = {2017}, abstract = {The availability of microbial genomes has opened many new avenues of research within microbiology. This has been driven primarily by comparative genomics approaches, which rely on accurate and consistent characterization of genomic sequences. It is nevertheless difficult to obtain consistent taxonomic and integrated functional annotations for defined prokaryotic clades. Thus, we developed proGenomes, a resource that provides user-friendly access to currently 25 038 high-quality genomes whose sequences and consistent annotations can be retrieved individually or by taxonomic clade. These genomes are assigned to 5306 consistent and accurate taxonomic species clusters based on previously established methodology. proGenomes also contains functional information for almost 80 million protein-coding genes, including a comprehensive set of general annotations and more focused annotations for carbohydrate-active enzymes and antibiotic resistance genes. Additionally, broad habitat information is provided for many genomes. All genomes and associated information can be downloaded by user-selected clade or multiple habitat-specific sets of representative genomes. We expect that the availability of high-quality genomes with comprehensive functional annotations will promote advances in clinical microbial genomics, functional evolution and other subfields of microbiology. proGenomes is available at http://progenomes.embl.de.}, language = {en} } @article{LukešGlatzovaKvičalovaetal.2017, author = {Lukeš, Tom{\´a}š and Glatzov{\´a}, Daniela and Kv{\´i}čalov{\´a}, Zuzana and Levet, Florian and Benda, Aleš and Letschert, Sebastian and Sauer, Markus and Brdička, Tom{\´a}š and Lasser, Theo and Cebecauer, Marek}, title = {Quantifying protein densities on cell membranes using super-resolution optical fluctuation imaging}, series = {Nature Communications}, volume = {8}, journal = {Nature Communications}, doi = {10.1038/s41467-017-01857-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172993}, year = {2017}, abstract = {Quantitative approaches for characterizing molecular organization of cell membrane molecules under physiological and pathological conditions profit from recently developed super-resolution imaging techniques. Current tools employ statistical algorithms to determine clusters of molecules based on single-molecule localization microscopy (SMLM) data. These approaches are limited by the ability of SMLM techniques to identify and localize molecules in densely populated areas and experimental conditions of sample preparation and image acquisition. We have developed a robust, model-free, quantitative clustering analysis to determine the distribution of membrane molecules that excels in densely labeled areas and is tolerant to various experimental conditions, i.e. multiple-blinking or high blinking rates. The method is based on a TIRF microscope followed by a super-resolution optical fluctuation imaging (SOFI) analysis. The effectiveness and robustness of the method is validated using simulated and experimental data investigating nanoscale distribution of CD4 glycoprotein mutants in the plasma membrane of T cells.}, language = {en} } @article{MitjansBegemannJuetal.2017, author = {Mitjans, M. and Begemann, M. and Ju, A. and Dere, E. and W{\"u}stefeld, L. and Hofer, S. and Hassouna, I. and Balkenhol, J. and Oliveira, B. and Van der Auwera, S. and Tammer, R. and Hammerschmidt, K. and V{\"o}lzke, H. and Homuth, G. and Cecconi, F. and Chowdhury, K. and Grabe, H. and Frahm, J. and Boretius, S. and Dandekar, T. and Ehrenreich, H.}, title = {Sexual dimorphism of \(AMBRA1\)-related autistic features in human and mouse}, series = {Translational Psychiatry}, volume = {2017}, journal = {Translational Psychiatry}, number = {7}, doi = {10.1038/tp.2017.213}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173782}, year = {2017}, abstract = {\(Ambra1\) is linked to autophagy and neurodevelopment. Heterozygous \(Ambra1\) deficiency induces autism-like behavior in a sexually dimorphic manner. Extraordinarily, autistic features are seen in female mice only, combined with stronger Ambra1 protein reduction in brain compared to males. However, significance of \(AMBRA1\) for autistic phenotypes in humans and, apart from behavior, for other autism-typical features, namely early brain enlargement or increased seizure propensity, has remained unexplored. Here we show in two independent human samples that a single normal \(AMBRA1\) genotype, the intronic SNP rs3802890-AA, is associated with autistic features in women, who also display lower \(AMBRA1\) mRNA expression in peripheral blood mononuclear cells relative to female GG carriers. Located within a non-coding RNA, likely relevant for mRNA and protein interaction, rs3802890 (A versus G allele) may affect its stability through modification of folding, as predicted by \(in\) \(silico\) analysis. Searching for further autism-relevant characteristics in \(Ambra1^{+/-}\) mice, we observe reduced interest of female but not male mutants regarding pheromone signals of the respective other gender in the social intellicage set-up. Moreover, altered pentylentetrazol-induced seizure propensity, an \(in\) \(vivo\) readout of neuronal excitation-inhibition dysbalance, becomes obvious exclusively in female mutants. Magnetic resonance imaging reveals mild prepubertal brain enlargement in both genders, uncoupling enhanced brain dimensions from the primarily female expression of all other autistic phenotypes investigated here. These data support a role of \(AMBRA1/Ambra1\) partial loss-of-function genotypes for female autistic traits. Moreover, they suggest \(Ambra1\) heterozygous mice as a novel multifaceted and construct-valid genetic mouse model for female autism.}, language = {en} } @article{AlizadehradKruegerEngstleretal.2015, author = {Alizadehrad, Davod and Kr{\"u}ger, Timothy and Engstler, Markus and Stark, Holger}, title = {Simulating the complex cell design of Trypanosoma brucei and its motility}, series = {PLOS Computational Biology}, volume = {11}, journal = {PLOS Computational Biology}, number = {1}, doi = {10.1371/journal.pcbi.1003967}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144610}, pages = {e1003967}, year = {2015}, abstract = {The flagellate Trypanosoma brucei, which causes the sleeping sickness when infecting a mammalian host, goes through an intricate life cycle. It has a rather complex propulsion mechanism and swims in diverse microenvironments. These continuously exert selective pressure, to which the trypanosome adjusts with its architecture and behavior. As a result, the trypanosome assumes a diversity of complex morphotypes during its life cycle. However, although cell biology has detailed form and function of most of them, experimental data on the dynamic behavior and development of most morphotypes is lacking. Here we show that simulation science can predict intermediate cell designs by conducting specific and controlled modifications of an accurate, nature-inspired cell model, which we developed using information from live cell analyses. The cell models account for several important characteristics of the real trypanosomal morphotypes, such as the geometry and elastic properties of the cell body, and their swimming mechanism using an eukaryotic flagellum. We introduce an elastic network model for the cell body, including bending rigidity and simulate swimming in a fluid environment, using the mesoscale simulation technique called multi-particle collision dynamics. The in silico trypanosome of the bloodstream form displays the characteristic in vivo rotational and translational motility pattern that is crucial for survival and virulence in the vertebrate host. Moreover, our model accurately simulates the trypanosome's tumbling and backward motion. We show that the distinctive course of the attached flagellum around the cell body is one important aspect to produce the observed swimming behavior in a viscous fluid, and also required to reach the maximal swimming velocity. Changing details of the flagellar attachment generates less efficient swimmers. We also simulate different morphotypes that occur during the parasite's development in the tsetse fly, and predict a flagellar course we have not been able to measure in experiments so far.}, language = {en} } @article{KasaragodMidekessaSridharetal.2017, author = {Kasaragod, Prasad and Midekessa, Getnet B. and Sridhar, Shruthi and Schmitz, Werner and Kiema, Tiila-Riikka and Hiltunen, Jukka K. and Wierenga, Rik K.}, title = {Structural enzymology comparisons of multifunctional enzyme, type-1 (MFE1): the flexibility of its dehydrogenase part}, series = {FEBS Open Bio}, volume = {7}, journal = {FEBS Open Bio}, number = {12}, doi = {10.1002/2211-5463.12337}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172732}, pages = {1830-1842}, year = {2017}, abstract = {Multifunctional enzyme, type-1 (MFE1) is a monomeric enzyme with a 2E-enoyl-CoA hydratase and a 3S-hydroxyacyl-CoA dehydrogenase (HAD) active site. Enzyme kinetic data of rat peroxisomal MFE1 show that the catalytic efficiencies for converting the short-chain substrate 2E-butenoyl-CoA into acetoacetyl-CoA are much lower when compared with those of the homologous monofunctional enzymes. The mode of binding of acetoacetyl-CoA (to the hydratase active site) and the very similar mode of binding of NAD\(^+\) and NADH (to the HAD part) are described and compared with those of their monofunctional counterparts. Structural comparisons suggest that the conformational flexibility of the HAD and hydratase parts of MFE1 are correlated. The possible importance of the conformational flexibility of MFE1 for its biocatalytic properties is discussed.}, language = {en} } @article{CosteaCoelhoSunagawaetal.2017, author = {Costea, Paul I. and Coelho, Louis Pedro and Sunagawa, Shinichi and Munch, Robin and Huerta-Cepas, Jaime and Forslund, Kristoffer and Hildebrand, Falk and Kushugulova, Almagul and Zeller, Georg and Bork, Peer}, title = {Subspecies in the global human gut microbiome}, series = {Molecular Systems Biology}, volume = {13}, journal = {Molecular Systems Biology}, number = {12}, doi = {10.15252/msb.20177589}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-172674}, year = {2017}, abstract = {Population genomics of prokaryotes has been studied in depth in only a small number of primarily pathogenic bacteria, as genome sequences of isolates of diverse origin are lacking for most species. Here, we conducted a large-scale survey of population structure in prevalent human gut microbial species, sampled from their natural environment, with a culture-independent metagenomic approach. We examined the variation landscape of 71 species in 2,144 human fecal metagenomes and found that in 44 of these, accounting for 72\% of the total assigned microbial abundance, single-nucleotide variation clearly indicates the existence of sub-populations (here termed subspecies). A single subspecies (per species) usually dominates within each host, as expected from ecological theory. At the global scale, geographic distributions of subspecies differ between phyla, with Firmicutes subspecies being significantly more geographically restricted. To investigate the functional significance of the delineated subspecies, we identified genes that consistently distinguish them in a manner that is independent of reference genomes. We further associated these subspecies-specific genes with properties of the microbial community and the host. For example, two of the three Eubacterium rectale subspecies consistently harbor an accessory pro-inflammatory flagellum operon that is associated with lower gut community diversity, higher host BMI, and higher blood fasting insulin levels. Using an additional 676 human oral samples, we further demonstrate the existence of niche specialized subspecies in the different parts of the oral cavity. Taken together, we provide evidence for subspecies in the majority of abundant gut prokaryotes, leading to a better functional and ecological understanding of the human gut microbiome in conjunction with its host.}, language = {en} } @article{KadochovaFrouzRoces2017, author = {Kadochov{\´a}, Štěp{\´a}nka and Frouz, Jan and Roces, Flavio}, title = {Sun basking in red wood ants Formica polyctena (Hymenoptera, Formicidae): Individual behaviour and temperature-dependent respiration rates}, series = {PLoS ONE}, volume = {12}, journal = {PLoS ONE}, number = {1}, doi = {10.1371/journal.pone.0170570}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171936}, year = {2017}, abstract = {In early spring, red wood ants Formica polyctena are often observed clustering on the nest surface in large numbers basking in the sun. It has been hypothesized that sun-basking behaviour may contribute to nest heating because of both heat carriage into the nest by sunbasking workers, and catabolic heat production from the mobilization of the workers' lipid reserves. We investigated sun-basking behaviour in laboratory colonies of F. polyctena exposed to an artificial heat source. Observations on identified individuals revealed that not all ants bask in the sun. Sun-basking and non-sun-basking workers did not differ in body size nor in respiration rates. The number of sun-basking ants and the number of their visits to the hot spot depended on the temperature of both the air and the hot spot. To investigate whether sun basking leads to a physiological activation linked with increased lipolysis, we measured respiration rates of individual workers as a function of temperature, and compared respiration rates of sun-basking workers before and two days after they were allowed to expose themselves to a heat source over 10 days, at self-determined intervals. As expected for ectothermic animals, respiration rates increased with increasing temperatures in the range 5 to 35˚C. However, the respiration rates of sun-basking workers measured two days after a long-term exposure to the heat source were similar to those before sun basking, providing no evidence for a sustained increase of the basal metabolic rates after prolonged sun basking. Based on our measurements, we argue that self-heating of the nest mound in early spring has therefore to rely on alternative heat sources, and speculate that physical transport of heat in the ant bodies may have a significant effect.}, language = {en} }