TY  - JOUR
A1  - Karl, Stefan
A1  - Dandekar, Thomas
T1  - Convergence behaviour and control in non-linear biological networks
JF  - Scientific Reports
N2  - Control of genetic regulatory networks is challenging to define and quantify. Previous control centrality metrics, which aim to capture the ability of individual nodes to control the system, have been found to suffer from plausibility and applicability problems. Here we present a new approach to control centrality based on network convergence behaviour, implemented as an extension of our genetic regulatory network simulation framework Jimena (http://stefan-karl.de/jimena). We distinguish three types of network control, and show how these mathematical concepts correspond to experimentally verified node functions and signalling pathways in immunity and cell differentiation: Total control centrality quantifies the impact of node mutations and identifies potential pharmacological targets such as genes involved in oncogenesis (e.g. zinc finger protein GLI2 or bone morphogenetic proteins in chondrocytes). Dynamic control centrality describes relaying functions as observed in signalling cascades (e.g. src kinase or Jak/Stat pathways). Value control centrality measures the direct influence of the value of the node on the network (e.g. Indian hedgehog as an essential regulator of proliferation in chondrocytes). Surveying random scale-free networks and biological networks, we find that control of the network resides in few high degree driver nodes and networks can be controlled best if they are sparsely connected.
KW  - complex networks
KW  - control profiles
KW  - differentiation
KW  - pathways
KW  - tumors
KW  - models
KW  - centrality
KW  - chondrosarcoma
KW  - transcriptional regulation
KW  - regulatory networks
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148510
VL  - 5
IS  - 09746
ER  - 
TY  - JOUR
A1  - Dühring, Sybille
A1  - Germerodt, Sebastian
A1  - Skerka, Christine
A1  - Zipfel, Peter F.
A1  - Dandekar, Thomas
A1  - Schuster, Stefan
T1  - Host-pathogen interactions between the human innate immune system and Candida albicans - understanding and modeling defense and evasion strategies
JF  - Frontiers in Microbiology
N2  - The diploid, polymorphic yeast Candida albicans is one of the most important human pathogenic fungi. C. albicans can grow, proliferate and coexist as a commensal on or within the human host for a long time. However, alterations in the host environment can render C. albicans virulent. In this review, we describe the immunological cross-talk between C. albicans and the human innate immune system. We give an overview in form of pairs of human defense strategies including immunological mechanisms as well as general stressors such as nutrient limitation, pH, fever etc. and the corresponding fungal response and evasion mechanisms. Furthermore, Computational Systems Biology approaches to model and investigate these complex interactions are highlighted with a special focus on game-theoretical methods and agent-based models. An outlook on interesting questions to be tackled by Systems Biology regarding entangled defense and evasion mechanisms is given.
KW  - agent-based model
KW  - antimicrobial peptides
KW  - fungal pathogens
KW  - Candida albicans
KW  - immunological cross-talk
KW  - beta-lactamase inhibition
KW  - in vitro
KW  - biomaterial surfaces
KW  - biofilm formation
KW  - dendritic cells
KW  - infection
KW  - resistance
KW  - human immune system
KW  - host-pathogen interaction
KW  - computational systems biology
KW  - defense and evasion strategies
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-151621
VL  - 6
IS  - 625
ER  - 
TY  - JOUR
A1  - Dandekar, Thomas
A1  - Eisenreich, Wolfgang
T1  - Host-adapted metabolism and its regulation in bacterial pathogens
JF  - Frontiers in Cellular and Infection Microbiology
N2  - No abstract available.
KW  - bacterial pathogens
KW  - enteric pathogens
KW  - metabolism
KW  - host-pathogen adaption
KW  - isotopolog profiling
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196876
SN  - 2235-2988
VL  - 5
IS  - 28
ER  - 
TY  - JOUR
A1  - Dandekar, Thomas
A1  - Fieselmann, Astrid
A1  - Fischer, Eva
A1  - Popp, Jasmin
A1  - Hensel, Michael
A1  - Noster, Janina
T1  - Salmonella - how a metabolic generalist adopts an intracellular lifestyle during infection
JF  - Frontiers in Cellular and Infection Microbiology
N2  - 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.
KW  - enterica serovar Typhimurium
KW  - bacterial invasion
KW  - mouse model
KW  - defenses
KW  - regulation
KW  - "-omics"
KW  - virulence
KW  - Salmonella-containing vacuole (SCV)
KW  - metabolism
KW  - nitric oxide
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-149029
VL  - 4
IS  - 191
ER  - 
TY  - JOUR
A1  - Dandekar, Thomas
A1  - Fieselmann, Astrid
A1  - Fischer, Eva
A1  - Popp, Jasmin
A1  - Hensel, Michael
A1  - Noster, Janina
T1  - Salmonella—how a metabolic generalist adopts an intracellular lifestyle during infection
JF  - Frontiers in Cellular and Infection Microbiology
N2  - 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.
KW  - regulation
KW  - virulence
KW  - "-omics"
KW  - metabolism
KW  - Salmonella-containing vacuole (SCV)
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120686
SN  - 2235-2988
VL  - 4
IS  - 191
ER  - 
TY  - JOUR
A1  - Wirth, Christine C.
A1  - Glushakova, Svetlana
A1  - Scheuermayer, Matthias
A1  - Repnik, Urska
A1  - Garg, Swatl
A1  - Schaack, Dominik
A1  - Kachman, Marika M.
A1  - Weißbach, Tim
A1  - Zimmerberg, Joshua
A1  - Dandekar, Thomas
A1  - Griffiths, Gareth
A1  - Chitnis, Chetan E.
A1  - Singh, Shallja
A1  - Fischer, Rainer
A1  - Pradel, Gabriele
T1  - Perforin-like protein PPLP2 permeabilizes the red blood cell membrane during egress of Plasmodium falciparum gametocytes
JF  - Cellular Microbiology
N2  - 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.
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120895
VL  - 16
IS  - 5
ER  - 
TY  - JOUR
A1  - Naseem, Muhammad
A1  - Kunz, Meik
A1  - Dandekar, Thomas
T1  - Probing the unknowns in cytokinin-mediated immune defense in Arabidopsis with systems biology approaches
JF  - Bioinformatics and Biology Insights
N2  - 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.
KW  - plant hormones
KW  - systems biology
KW  - interaction networks
KW  - gene expression
KW  - cytokinin
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120199
SN  - 1177-9322
VL  - 8
ER  - 
TY  - JOUR
A1  - Naseem, Muhammad
A1  - Srivastava, Mugdha
A1  - Dandekar, Thomas
T1  - Stem-cell-triggered immunity safeguards cytokinin enriched plant shoot apexes from pathogen infection
JF  - Frontiers in Plant Science
N2  - 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.
KW  - auxin
KW  - stem cell niche
KW  - FLS2 receptor
KW  - CLAVATA3
KW  - cytokinins
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-118247
SN  - 1664-462X
VL  - 5
ER  - 
TY  - JOUR
A1  - Ahmed, Zeeshan
A1  - Zeeshan, Saman
A1  - Huber, Claudia
A1  - Hensel, Michael
A1  - Schomburg, Dietmar
A1  - Münch, Richard
A1  - Eylert, Eva
A1  - Eisenreich, Wolfgang
A1  - Dandekar, Thomas
T1  - ‘Isotopo’ a database application for facile analysis and management of mass isotopomer data
JF  - Database
N2  - 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.
KW  - stable-isotope
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120102
VL  - 2014
IS  - bau077
ER  - 
TY  - JOUR
A1  - Kern, Selina
A1  - Agarwal, Shruti
A1  - Huber, Kilian
A1  - Gehring, Andre P.
A1  - Strödke, Benjamin
A1  - Wirth, Christine C.
A1  - Brügl, Thomas
A1  - Abodo, Liane Onambele
A1  - Dandekar, Thomas
A1  - Doerig, Christian
A1  - Fischer, Rainer
A1  - Tobin, Andrew B.
A1  - Alam, Mahmood M.
A1  - Bracher, Franz
A1  - Pradel, Gabriele
T1  - Inhibition of the SR Protein-Phosphorylating CLK Kinases of Plasmodium falciparum Impairs Blood Stage Replication and Malaria Transmission
JF  - PLOS ONE
N2  - 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.
KW  - parasite
KW  - expression
KW  - mosquito
KW  - splicing factors
KW  - lactate dehydrogenase
KW  - xanthurenic acid
KW  - in-vitro
KW  - RNA-SEQ
KW  - identification
KW  - culture
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-115405
SN  - 1932-6203
VL  - 9
IS  - 9
ER  -