@article{SchichorAlbrechtKorteetal.2012, author = {Schichor, Christian and Albrecht, Valerie and Korte, Benjamin and Buchner, Alexander and Riesenberg, Rainer and Mysliwietz, Josef and Paron, Igor and Motaln, Helena and Turnsek, Tamara Lah and Juerchott, Kathrin and Selbig, Joachim and Tonn, J{\"o}rg-Christian}, title = {Mesenchymal stem cells and glioma cells form a structural as well as a functional syncytium in vitro}, series = {Experimental neurology}, volume = {234}, journal = {Experimental neurology}, number = {1}, publisher = {Elsevier}, address = {San Diego}, issn = {0014-4886}, doi = {10.1016/j.expneurol.2011.12.033}, pages = {208 -- 219}, year = {2012}, abstract = {The interaction of human mesenchymal stem cells (hMSCs) and tumor cells has been investigated in various contexts. HMSCs are considered as cellular treatment vectors based on their capacity to migrate towards a malignant lesion. However, concerns about unpredictable behavior of transplanted hMSCs are accumulating. In malignant gliomas, the recruitment mechanism is driven by glioma-secreted factors which lead to accumulation of both, tissue specific stem cells as well as bone marrow derived hMSCs within the tumor. The aim of the present work was to study specific cellular interactions between hMSCs and glioma cells in vitro. We show, that glioma cells as well as hMSCs differentially express connexins. and that they interact via gap-junctional coupling. Besides this so-called functional syncytium formation, we also provide evidence of cell fusion events (structural syncytium). These complex cellular interactions led to an enhanced migration and altered proliferation of both, tumor and mesenchymal stem cell types in vitro. The presented work shows that glioma cells display signs of functional as well as structural syncytium formation with hMSCs in vitro. The described cellular phenomena provide new insight into the complexity of interaction patterns between tumor cells and host cells. Based on these findings, further studies are warranted to define the impact of a functional or structural syncytium formation on malignant tumors and cell based therapies in vivo.}, language = {en} } @article{GirbigGrimbsSelbig2012, author = {Girbig, Dorothee and Grimbs, Sergio and Selbig, Joachim}, title = {Systematic analysis of stability patterns in plant primary metabolism}, series = {PLoS one}, volume = {7}, journal = {PLoS one}, number = {4}, publisher = {PLoS}, address = {San Fransisco}, issn = {1932-6203}, doi = {10.1371/journal.pone.0034686}, pages = {12}, year = {2012}, abstract = {Metabolic networks are characterized by complex interactions and regulatory mechanisms between many individual components. These interactions determine whether a steady state is stable to perturbations. Structural kinetic modeling (SKM) is a framework to analyze the stability of metabolic steady states that allows the study of the system Jacobian without requiring detailed knowledge about individual rate equations. Stability criteria can be derived by generating a large number of structural kinetic models (SK-models) with randomly sampled parameter sets and evaluating the resulting Jacobian matrices. Until now, SKM experiments applied univariate tests to detect the network components with the largest influence on stability. In this work, we present an extended SKM approach relying on supervised machine learning to detect patterns of enzyme-metabolite interactions that act together in an orchestrated manner to ensure stability. We demonstrate its application on a detailed SK-model of the Calvin-Benson cycle and connected pathways. The identified stability patterns are highly complex reflecting that changes in dynamic properties depend on concerted interactions between several network components. In total, we find more patterns that reliably ensure stability than patterns ensuring instability. This shows that the design of this system is strongly targeted towards maintaining stability. We also investigate the effect of allosteric regulators revealing that the tendency to stability is significantly increased by including experimentally determined regulatory mechanisms that have not yet been integrated into existing kinetic models.}, language = {en} } @article{LarhlimiDavidSelbigetal.2012, author = {Larhlimi, Abdelhalim and David, Laszlo and Selbig, Joachim and Bockmayr, Alexander}, title = {F2C2: a fast tool for the computation of flux coupling in genome-scale metabolic networks}, series = {BMC bioinformatics}, volume = {13}, journal = {BMC bioinformatics}, publisher = {BioMed Central}, address = {London}, issn = {1471-2105}, doi = {10.1186/10.1186/1471-2105-13-57}, pages = {9}, year = {2012}, abstract = {Background: Flux coupling analysis (FCA) has become a useful tool in the constraint-based analysis of genome-scale metabolic networks. FCA allows detecting dependencies between reaction fluxes of metabolic networks at steady-state. On the one hand, this can help in the curation of reconstructed metabolic networks by verifying whether the coupling between reactions is in agreement with the experimental findings. On the other hand, FCA can aid in defining intervention strategies to knock out target reactions. Results: We present a new method F2C2 for FCA, which is orders of magnitude faster than previous approaches. As a consequence, FCA of genome-scale metabolic networks can now be performed in a routine manner. Conclusions: We propose F2C2 as a fast tool for the computation of flux coupling in genome-scale metabolic networks. F2C2 is freely available for non-commercial use at https://sourceforge.net/projects/f2c2/files/.}, language = {en} } @article{AndorfMeyerSelbigetal.2012, author = {Andorf, Sandra and Meyer, Rhonda C. and Selbig, Joachim and Altmann, Thomas and Repsilber, Dirk}, title = {Integration of a systems biological network analysis and QTL results for biomass heterosis in arabidopsis thaliana}, series = {PLoS one}, volume = {7}, journal = {PLoS one}, number = {11}, publisher = {PLoS}, address = {San Fransisco}, issn = {1932-6203}, doi = {10.1371/journal.pone.0049951}, pages = {10}, year = {2012}, abstract = {To contribute to a further insight into heterosis we applied an integrative analysis to a systems biological network approach and a quantitative genetics analysis towards biomass heterosis in early Arabidopsis thaliana development. The study was performed on the parental accessions C24 and Col-0 and the reciprocal crosses. In an over-representation analysis it was tested if the overlap between the resulting gene lists of the two approaches is significantly larger than expected by chance. Top ranked genes in the results list of the systems biological analysis were significantly over-represented in the heterotic QTL candidate regions for either hybrid as well as regarding mid-parent and best-parent heterosis. This suggests that not only a few but rather several genes that influence biomass heterosis are located within each heterotic QTL region. Furthermore, the overlapping resulting genes of the two integrated approaches were particularly enriched in biomass related pathways. A chromosome-wise over-representation analysis gave rise to the hypothesis that chromosomes number 2 and 4 probably carry a majority of the genes involved in biomass heterosis in the early development of Arabidopsis thaliana.}, language = {en} } @article{GuoJuerchottFuetal.2012, author = {Guo, Ke-Tai and J{\"u}rchott, Kathrin and Fu, Peng and Selbig, Joachim and Eigenbrod, Sabina and Tonn, J{\"o}rg-Christian and Schichor, Christian}, title = {Isolation and characterization of bone marrow-derived progenitor cells from malignant gliomas}, series = {Anticancer research : international journal of cancer research and treatment}, volume = {32}, journal = {Anticancer research : international journal of cancer research and treatment}, number = {11}, publisher = {International Institute of Anticancer Research}, address = {Athens}, issn = {0250-7005}, pages = {4971 -- 4982}, year = {2012}, abstract = {Background: Malignant gliomas are highly-vascularised tumours. Neoangiogenesis is a crucial factor in the malignant behaviour of tumour and prognosis of patients. Several mechanisms are suspected to lead to neoangiogenesis, one of them is the recruitment of multipotent progenitor cells towards the tumour. Factors such as Vascular endothelial growth factor-A (VEGF-A) were described to recruit bone marrow-derived endothelial progenitor cells (EPCs) to the glioma stroma and vasculature. Little is known about isolating EPCs from normal or malignant tissues. Materials and Methods: In this study, we addressed the topic of characterization of tumour-isolated EPCs and re-defined the clonal relationship between EPCs and hematopoietic stem cells (HSCs) in gliomas. We first checked public gene expression data of glioma for putative marker expression, pointing towards a prevalence of EPCs and HSCs in glioma. Immunohistochemical staining of glioma tissue confirmed the higher expression of these progenitor markers in glioma tissue. EPCs and HSCs were consequently isolated and characterized at the phenotypic and functional levels. We applied a new isolation method, for the first time, to specimen from patients with high grade glioma including seven grade IV glioblastoma, five-grade III astrocytoma, and three grade III oligoastrocytoma. Results: In all samples, we were able to isolate the tumour-derived EPCs, which were positive for characteristic markers: CD31, CD34 and VEGFR2. The EPCs formed capillary networks in vitro and had the ability to take up acetylated low-density lipoprotein. Glioma-derived HSCs were positive for CD34 and CD45, but they were unable to form a capillary network in vitro. These findings on tumour-derived EPCs/HSCs were in concordance with the results, derived from peripheral blood of healthy volunteers. Conclusion: In our study, we established a new method for EPC/HSC isolation from human gliomas, defined the contribution of EPCs and HSCs to the tumour tissue, and highlighted the intense in vivo tumour host interaction.}, language = {en} } @article{GrudenHrenHermanetal.2012, author = {Gruden, Kristina and Hren, Matjaz and Herman, Ana and Blejec, Andrej and Albrecht, Tanja and Selbig, Joachim and Bauer, Christian G. and Schuchardt, Johannes and Or-Guil, Michal and Zupancic, Klemen and Svajger, Urban and Stabuc, Borut and Ihan, Alojz and Kopitar, Andreja Natasa and Ravnikar, Maja and Knezevic, Miomir and Rozman, Primoz and Jeras, Matjaz}, title = {A "Crossomics" study analysing variability of different components in peripheral blood of healthy caucasoid individuals}, series = {PLoS one}, volume = {7}, journal = {PLoS one}, number = {1}, publisher = {PLoS}, address = {San Fransisco}, issn = {1932-6203}, doi = {10.1371/journal.pone.0028761}, pages = {12}, year = {2012}, abstract = {Background: Different immunotherapy approaches for the treatment of cancer and autoimmune diseases are being developed and tested in clinical studies worldwide. Their resulting complex experimental data should be properly evaluated, therefore reliable normal healthy control baseline values are indispensable. Methodology/Principal Findings: To assess intra- and inter-individual variability of various biomarkers, peripheral blood of 16 age and gender equilibrated healthy volunteers was sampled on 3 different days within a period of one month. Complex "crossomics'' analyses of plasma metabolite profiles, antibody concentrations and lymphocyte subset counts as well as whole genome expression profiling in CD4(+)T and NK cells were performed. Some of the observed age, gender and BMI dependences are in agreement with the existing knowledge, like negative correlation between sex hormone levels and age or BMI related increase in lipids and soluble sugars. Thus we can assume that the distribution of all 39.743 analysed markers is well representing the normal Caucasoid population. All lymphocyte subsets, 20\% of metabolites and less than 10\% of genes, were identified as highly variable in our dataset. Conclusions/Significance: Our study shows that the intra- individual variability was at least two-fold lower compared to the inter-individual one at all investigated levels, showing the importance of personalised medicine approach from yet another perspective.}, language = {en} } @article{GirbigSelbigGrimbs2012, author = {Girbig, Dorothee and Selbig, Joachim and Grimbs, Sergio}, title = {A MATLAB toolbox for structural kinetic modeling}, series = {Bioinformatics}, volume = {28}, journal = {Bioinformatics}, number = {19}, publisher = {Oxford Univ. Press}, address = {Oxford}, issn = {1367-4803}, doi = {10.1093/bioinformatics/bts473}, pages = {2546 -- 2547}, year = {2012}, abstract = {Structural kinetic modeling (SKM) enables the analysis of dynamical properties of metabolic networks solely based on topological information and experimental data. Current SKM-based experiments are hampered by the time-intensive process of assigning model parameters and choosing appropriate sampling intervals for MonteCarlo experiments. We introduce a toolbox for the automatic and efficient construction and evaluation of structural kinetic models (SK models). Quantitative and qualitative analyses of network stability properties are performed in an automated manner. We illustrate the model building and analysis process in detailed example scripts that provide toolbox implementations of previously published literature models.}, language = {en} } @article{MeyerWituckaWallBecheretal.2012, author = {Meyer, Rhonda C. and Witucka-Wall, Hanna and Becher, Martina and Blacha, Anna Maria and Boudichevskaia, Anastassia and D{\"o}rmann, Peter and Fiehn, Oliver and Friedel, Svetlana and von Korff, Maria and Lisec, Jan and Melzer, Michael and Repsilber, Dirk and Schmidt, Renate and Scholz, Matthias and Selbig, Joachim and Willmitzer, Lothar and Altmann, Thomas}, title = {Heterosis manifestation during early Arabidopsis seedling development is characterized by intermediate gene expression and enhanced metabolic activity in the hybrids}, series = {The plant journal}, volume = {71}, journal = {The plant journal}, number = {4}, publisher = {Wiley-Blackwell}, address = {Hoboken}, issn = {0960-7412}, doi = {10.1111/j.1365-313X.2012.05021.x}, pages = {669 -- 683}, year = {2012}, abstract = {Heterosis-associated cellular and molecular processes were analyzed in seeds and seedlings of Arabidopsis thaliana accessions Col-0 and C24 and their heterotic hybrids. Microscopic examination revealed no advantages in terms of hybrid mature embryo organ sizes or cell numbers. Increased cotyledon sizes were detectable 4 days after sowing. Growth heterosis results from elevated cell sizes and numbers, and is well established at 10 days after sowing. The relative growth rates of hybrid seedlings were most enhanced between 3 and 4 days after sowing. Global metabolite profiling and targeted fatty acid analysis revealed maternal inheritance patterns for a large proportion of metabolites in the very early stages. During developmental progression, the distribution shifts to dominant, intermediate and heterotic patterns, with most changes occurring between 4 and 6 days after sowing. The highest incidence of heterotic patterns coincides with establishment of size differences at 4 days after sowing. In contrast, overall transcript patterns at 4, 6 and 10 days after sowing are characterized by intermediate to dominant patterns, with parental transcript levels showing the largest differences. Overall, the results suggest that, during early developmental stages, intermediate gene expression and higher metabolic activity in the hybrids compared to the parents lead to better resource efficiency, and therefore enhanced performance in the hybrids.}, language = {en} } @article{HartmannHelmNickeletal.2012, author = {Hartmann, Stefanie and Helm, Conrad and Nickel, Birgit and Meyer, Matthias and Struck, Torsten H. and Tiedemann, Ralph and Selbig, Joachim and Bleidorn, Christoph}, title = {Exploiting gene families for phylogenomic analysis of myzostomid transcriptome data}, series = {PLoS one}, volume = {7}, journal = {PLoS one}, number = {1}, publisher = {PLoS}, address = {San Fransisco}, issn = {1932-6203}, doi = {10.1371/journal.pone.0029843}, pages = {8}, year = {2012}, abstract = {Background: In trying to understand the evolutionary relationships of organisms, the current flood of sequence data offers great opportunities, but also reveals new challenges with regard to data quality, the selection of data for subsequent analysis, and the automation of steps that were once done manually for single-gene analyses. Even though genome or transcriptome data is available for representatives of most bilaterian phyla, some enigmatic taxa still have an uncertain position in the animal tree of life. This is especially true for myzostomids, a group of symbiotic ( or parasitic) protostomes that are either placed with annelids or flatworms. Methodology: Based on similarity criteria, Illumina-based transcriptome sequences of one myzostomid were compared to protein sequences of one additional myzostomid and 29 reference metazoa and clustered into gene families. These families were then used to investigate the phylogenetic position of Myzostomida using different approaches: Alignments of 989 sequence families were concatenated, and the resulting superalignment was analyzed under a Maximum Likelihood criterion. We also used all 1,878 gene trees with at least one myzostomid sequence for a supertree approach: the individual gene trees were computed and then reconciled into a species tree using gene tree parsimony. Conclusions: Superalignments require strictly orthologous genes, and both the gene selection and the widely varying amount of data available for different taxa in our dataset may cause anomalous placements and low bootstrap support. In contrast, gene tree parsimony is designed to accommodate multilocus gene families and therefore allows a much more comprehensive data set to be analyzed. Results of this supertree approach showed a well-resolved phylogeny, in which myzostomids were part of the annelid radiation, and major bilaterian taxa were found to be monophyletic.}, language = {en} } @article{BaslerGrimbsEbenhoehetal.2012, author = {Basler, Georg and Grimbs, Sergio and Ebenh{\"o}h, Oliver and Selbig, Joachim and Nikoloski, Zoran}, title = {Evolutionary significance of metabolic network properties}, series = {Interface : journal of the Royal Society}, volume = {9}, journal = {Interface : journal of the Royal Society}, number = {71}, publisher = {Royal Society}, address = {London}, issn = {1742-5689}, doi = {10.1098/rsif.2011.0652}, pages = {1168 -- 1176}, year = {2012}, abstract = {Complex networks have been successfully employed to represent different levels of biological systems, ranging from gene regulation to protein-protein interactions and metabolism. Network-based research has mainly focused on identifying unifying structural properties, such as small average path length, large clustering coefficient, heavy-tail degree distribution and hierarchical organization, viewed as requirements for efficient and robust system architectures. However, for biological networks, it is unclear to what extent these properties reflect the evolutionary history of the represented systems. Here, we show that the salient structural properties of six metabolic networks from all kingdoms of life may be inherently related to the evolution and functional organization of metabolism by employing network randomization under mass balance constraints. Contrary to the results from the common Markov-chain switching algorithm, our findings suggest the evolutionary importance of the small-world hypothesis as a fundamental design principle of complex networks. The approach may help us to determine the biologically meaningful properties that result from evolutionary pressure imposed on metabolism, such as the global impact of local reaction knockouts. Moreover, the approach can be applied to test to what extent novel structural properties can be used to draw biologically meaningful hypothesis or predictions from structure alone.}, language = {en} }