COVID19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms.

in Molecular systems biology (2021), 17(10), 10387

We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets ... [more ▼]

We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective. [less ▲]

Do Genome-scale Models Need Exact Solvers or Clearer Standards?

in Molecular Systems Biology (2015), 11(10), 1

PLAU inferred from a correlation network is critical for suppressor function of regulatory T cells.

in Molecular Systems Biology (2012), 8

Human FOXP3(+)CD25(+)CD4(+) regulatory T cells (Tregs) are essential to the maintenance of immune homeostasis. Several genes are known to be important for murine Tregs, but for human Tregs the genes and ... [more ▼]

Human FOXP3(+)CD25(+)CD4(+) regulatory T cells (Tregs) are essential to the maintenance of immune homeostasis. Several genes are known to be important for murine Tregs, but for human Tregs the genes and underlying molecular networks controlling the suppressor function still largely remain unclear. Here, we describe a strategy to identify the key genes directly from an undirected correlation network which we reconstruct from a very high time-resolution (HTR) transcriptome during the activation of human Tregs/CD4(+) T-effector cells. We show that a predicted top-ranked new key gene PLAU (the plasminogen activator urokinase) is important for the suppressor function of both human and murine Tregs. Further analysis unveils that PLAU is particularly important for memory Tregs and that PLAU mediates Treg suppressor function via STAT5 and ERK signaling pathways. Our study demonstrates the potential for identifying novel key genes for complex dynamic biological processes using a network strategy based on HTR data, and reveals a critical role for PLAU in Treg suppressor function. [less ▲]

Carbohydrate-active enzymes exemplify entropic principles in metabolism

in Molecular Systems Biology (2011), 7(542),

Glycans comprise ubiquitous and essential biopolymers, which usually occur as highly diverse mixtures. The myriad different structures are generated by a limited number of carbohydrate-active enzymes ... [more ▼]

Glycans comprise ubiquitous and essential biopolymers, which usually occur as highly diverse mixtures. The myriad different structures are generated by a limited number of carbohydrate-active enzymes (CAZymes), which are unusual in that they catalyze multiple reactions by being relatively unspecific with respect to substrate size. Existing experimental and theoretical descriptions of CAZyme-mediated reaction systems neither comprehensively explain observed action patterns nor suggest biological functions of polydisperse pools in metabolism. Here, we overcome these limitations with a novel theoretical description of this important class of biological systems in which the mixing entropy of polydisperse pools emerges as an important system variable. In vitro assays of three CAZymes essential for central carbon metabolism confirm the power of our approach to predict equilibrium distributions and non-equilibrium dynamics. A computational study of the turnover of the soluble heteroglycan pool exemplifies how entropy-driven reactions establish a metabolic buffer in vivo that attenuates fluctuations in carbohydrate availability. We argue that this interplay between energy- and entropy-driven processes represents an important regulatory design principle of metabolic systems. [less ▲]

Design principles of nuclear receptor signaling: how complex networking improves signal transduction.

in Molecular Systems Biology (2010), 6

The topology of nuclear receptor (NR) signaling is captured in a systems biological graphical notation. This enables us to identify a number of 'design' aspects of the topology of these networks that ... [more ▼]

The topology of nuclear receptor (NR) signaling is captured in a systems biological graphical notation. This enables us to identify a number of 'design' aspects of the topology of these networks that might appear unnecessarily complex or even functionally paradoxical. In realistic kinetic models of increasing complexity, calculations show how these features correspond to potentially important design principles, e.g.: (i) cytosolic 'nuclear' receptor may shuttle signal molecules to the nucleus, (ii) the active export of NRs may ensure that there is sufficient receptor protein to capture ligand at the cytoplasmic membrane, (iii) a three conveyor belts design dissipating GTP-free energy, greatly aids response, (iv) the active export of importins may prevent sequestration of NRs by importins in the nucleus and (v) the unspecific nature of the nuclear pore may ensure signal-flux robustness. In addition, the models developed are suitable for implementation in specific cases of NR-mediated signaling, to predict individual receptor functions and differential sensitivity toward physiological and pharmacological ligands. [less ▲]

Residues crucial for maintaining short paths in network communication mediate signaling in proteins

in Molecular Systems Biology (2009), 2

Here, we represent protein structures as residue interacting networks, which are assumed to involve a permanent flowof information between amino acids. By removal of nodes from the protein network, we ... [more ▼]

Here, we represent protein structures as residue interacting networks, which are assumed to involve a permanent flowof information between amino acids. By removal of nodes from the protein network, we identify fold centrally conserved residues, which are crucial for sustaining the shortest pathways and thus play key roles in long-range interactions. Analysis of seven protein families (myoglobins, G-protein-coupled receptors, the trypsin class of serine proteases, hemoglobins, oligosaccharide phosphorylases, nuclear receptor ligand-binding domains and retroviral proteases) confirms that experimentally many of these residues are important for allosteric communication. The agreement between the centrally conserved residues, which are key in preserving short path lengths, and residues experimentally suggested to mediate signaling further illustrates that topology plays an important role in network communication. Protein folds have evolved under constraints imposed by function. To maintain function, protein structures need to be robust to mutational events. On the other hand, robustness is accompanied by an extreme sensitivity at some crucial sites. Thus, here we propose that centrally conserved residues, whose removal increases the characteristic path length in protein networks, may relate to the system fragility. [less ▲]