Petri Net computational modelling of Langerhans cell Interferon Regulatory Factor Network predicts their role in T cell activation

Langerhans cells (LCs) are able to orchestrate adaptive immune responses in the skin by interpreting the microenvironmental context in which they encounter foreign substances, but the regulatory basis for this has not been established. Utilising systems immunology approaches combining in silico modelling of a reconstructed gene regulatory network (GRN) with in vitro validation of the predictions, we sought to determine the mechanisms of regulation of immune responses in human primary LCs. The key role of Interferon regulatory factors (IRFs) as controllers of the human Langerhans cell response to epidermal cytokines was revealed by whole transcriptome analysis. Applying Boolean logic we assembled a Petri net-based model of the IRF-GRN which provides molecular pathway predictions for the induction of different transcriptional programmes in LCs. In silico simulations performed after model parameterisation with transcription factor expression values predicted that human LC activation of antigen-specific CD8 T cells would be differentially regulated by epidermal cytokine induction of specific IRF-controlled pathways. This was confirmed by in vitro measurement of IFN-g production by activated T cells. As a proof of concept, this approach shows that stochastic modelling of a specific immune networks renders transcriptome data valuable for the prediction of functional outcomes of immune responses

Current Challenges in Modeling Cellular Metabolism

Mathematical and computational models play an essential role in understanding the cellular metabolism. They are used as platforms to integrate current knowledge on a biological system and to systematically test and predict the effect of manipulations to such systems. The recent advances in genome sequencing techniques have facilitated the reconstruction of genome-scale metabolic networks for a wide variety of organisms from microbes to human cells. These models have been successfully used in multiple biotechnological applications. Despite these advancements, modeling cellular metabolism still presents many challenges. The aim of this Research Topic is not only to expose and consolidate the state-of-the-art in metabolic modeling approaches, but also to push this frontier beyond the current edge through the introduction of innovative solutions. The articles presented in this e-book address some of the main challenges in the field, including the integration of different modeling formalisms, the integration of heterogeneous data sources into metabolic models, explicit representation of other biological processes during phenotype simulation, and standardization efforts in the representation of metabolic models and simulation results

A systems biology approach reveals major metabolic changes in the thermoacidophilic archaeon Sulfolobus solfataricus in response to the carbon source L-fucose versus D-glucose

Archaea are characterised by a complex metabolism with many unique enzymes that differ from their bacterial and eukaryotic counterparts. The thermoacidophilic archaeon Sulfolobus solfataricus is known for its metabolic versatility and is able to utilize a great variety of different carbon sources. However, the underlying degradation pathways and their regulation are often unknown. In this work, we analyse growth on different carbon sources using an integrated systems biology approach. The comparison of growth on L-fucose and D-glucose allows first insights into the genome-wide changes in response to the two carbon sources and revealed a new pathway for L-fucose degradation in S. solfataricus. During growth on L-fucose we observed major changes in the central carbon metabolic network, as well as an increased activity of the glyoxylate bypass and the 3-hydroxypropionate/4-hydroxybutyrate cycle. Within the newly discovered pathway for L-fucose degradation the following key reactions were identified: (i) L-fucose oxidation to L-fuconate via a dehydrogenase, (ii) dehydration to 2-keto-3-deoxy-L-fuconate via dehydratase, (iii) 2-keto-3-deoxy-L-fuconate cleavage to pyruvate and L-lactaldehyde via aldolase and (iv) L-lactaldehyde conversion to L-lactate via aldehyde dehydrogenase. This pathway as well as L-fucose transport shows interesting overlaps to the D-arabinose pathway, representing another example for pathway promiscuity in Sulfolobus species

Methods in Computational Biology

Modern biology is rapidly becoming a study of large sets of data. Understanding these data sets is a major challenge for most life sciences, including the medical, environmental, and bioprocess fields. Computational biology approaches are essential for leveraging this ongoing revolution in omics data. A primary goal of this Special Issue, entitled “Methods in Computational Biology”, is the communication of computational biology methods, which can extract biological design principles from complex data sets, described in enough detail to permit the reproduction of the results. This issue integrates interdisciplinary researchers such as biologists, computer scientists, engineers, and mathematicians to advance biological systems analysis. The Special Issue contains the following sections:•Reviews of Computational Methods•Computational Analysis of Biological Dynamics: From Molecular to Cellular to Tissue/Consortia Levels•The Interface of Biotic and Abiotic Processes•Processing of Large Data Sets for Enhanced Analysis•Parameter Optimization and Measuremen

Regulatory role of small RNAs and RNA-binding proteins in carbon metabolism and collective behaviour of Vibrio cholerae

The importance of small regulatory RNAs (sRNAs) has been recognized across all domains of life. Originally considered “non-coding RNAs,” several bacterial sRNAs have been found to encode functional proteins that are under 50 amino acids long. This group of regulators are called dual-function regulators. To date, only five such regulators have been characterized in bacteria. In the primary study, the first dual-function RNA of Vibrio cholerae was discovered and characterized. The pathogen colonizes and infects the upper intestines by producing two key virulence determinants – toxin co-regulated pilus (TCP) and cholera toxin (CT). While all the known sRNAs of V. cholerae act directly or indirectly to regulate the production of TCP, the sRNA VqmR is the only known direct repressor of CT production to date. Therefore, a forward genetic screen was employed to score for CT repression. This screen identified another promising candidate called Vcr082. Interestingly, Vcr082 also encodes 29 amino acids long ORF and hence was re-named VcdRP, for V. cholerae dual RNA regulator and protein, eponymous to their roles. The dual regulator is controlled by the global transcription factor of carbon utilization, cAMP-CRP. The riboregulatory component is conserved at the 3’ end of the dual regulator. By employing a conserved stretch of four cytosines, VcdR base-pairs with and represses mRNAs that encode for transporters that import PTS sugars. Additionally, VcdR also downregulates the phosphor-carrier proteins PtsH and PtsI that are involved in the phospho-relay during glycolysis. The small protein, VcdP exerts its regulatory role by interacting with and accelerating the activity of citrate synthase enzyme, opening the gateway into the TCA cycle. This way, both VcdR and VcdP act to block sugar uptake and modulate the flux through the TCA cycle, thereby striking a balance to maintain overall carbon metabolism in V. cholerae. The diverse environments that V. cholerae inhabits necessitates that the organism rapidly perceives changes in its external environment and appropriately tailors its gene expression paradigm. To achieve this, the bacteria employ quorum sensing (QS) to communicate and coordinate a suitable response. While this mechanism of census taking has been well-documented early on in several marine bacteria, more recent studies have identified additional QS systems in V. cholerae. Similarly, while biofilm formation has been extensively studied, the transition into and subsequent dispersal was only documented recently. These incomplete underpinnings thereby prompted further investigation of the QS pathway. Therefore, in the second study, a forward genetic screen in a V. cholerae mutant library was employed to score for an altered QS phenotypic transition. This screen identified a novel RNA-binding protein called MbrA (membrane-bound RNA-binding protein A). This protein localizes to the membrane and contains two trans-membrane domains at the N-terminus and a conserved RNA recognition motif-type RNA-binding domain located towards the C-terminus. MbrA is activated by the global transcription factor cAMP-CRP and a subsequent transcriptome analysis revealed its role in the regulation of motility genes and flagellar assembly complex in V. cholerae

27th Fungal Genetics Conference

Program and abstracts from the 27th Fungal Genetics Conference Asilomar, March 12-17, 2013

27th Fungal Genetics Conference

Program and abstracts from the 27th Fungal Genetics Conference Asilomar, March 12-17, 2013

28th Fungal Genetics Conference

Full abstracts from the 28th Fungal Genetics Conference Asilomar, March 17-22, 2015