Search

Transcriptomic data from an in vitro model is used to predict candidate drug targets for Parkinson’s disease, which are further validated using a drug repurposing approach.

Alterations in brain metabolism are closely associated with the molecular hallmarks of Parkinson’s disease (PD). A clear understanding of the main metabolic perturbations in PD is therefore important. Here, we retrospectively analysed the expression of metabolic genes from 34 PD-control post-mortem human brain transcriptome data from literature, spanning multiple brain regions, and found significant metabolic correlations between the Substantia nigra (SN) and cerebral cortical tissues with high perturbations in protein modification, transport, nucleotide and inositol phosphate metabolic pathways. Moreover, three main metabolic clusters of SN tissues were identified from patient cohort studies, each characterised by perturbations in (a) pyruvate, amino acid, neurotransmitter, and complex lipid metabolisms (b) inflammation-related metabolism, and (c) lipid breakdown for energy metabolism. Finally, we analysed 58 PD-control transcriptome data from in vivo/in vitro disease models and identified experimental PD models with significant correlations to matched human brain regions. Collectively, our findings are based on 47 PD transcriptome datasets covering 92 PD-control comparisons spanning more than 1000 samples in total, and they suggest metabolic alterations in several brain regions, heterogeneity in metabolic alterations between study cohorts for the SN tissues and suggest the need to optimize current experimental models to advance research on metabolic aspects of PD.

Transcriptome-integrated human genome-scale metabolic models (GEMs) have been used widely to assess alterations in metabolism in response to disease. Transcriptome integration leads to identification of metabolic reactions that are differentially inactivated in the tissue of interest. Among the methods available for mapping transcriptome data on GEMs, we focus here on an Integrative Metabolic Analysis Tool (iMAT), which we have recently applied to the analysis of Alzheimer's disease (AD). We provide a detailed protocol for applying iMAT to create models of personalized metabolic networks, which can be further processed to identify reactions associated with abnormal metabolism.

Primary cancer cells exert unique capacity to disseminate and nestle in distant organs. Once seeded in secondary sites, cancer cells may enter a dormant state, becoming resistant to current treatment approaches, and they remain silent until they reactivate and cause overt metastases. To illuminate the complex mechanisms of cancer dormancy, 10 transcriptomic datasets from the literature enabling 21 dormancy-cancer comparisons were mapped on protein-protein interaction networks and gene-regulatory networks to extract subnetworks that are enriched in significantly deregulated genes. The genes appearing in the subnetworks and significantly upregulated in dormancy with respect to proliferative state were scored and filtered across all comparisons, leading to a dormancy-interaction network for the first time in the literature, which includes 139 genes and 1974 interactions. The dormancy interaction network will contribute to the elucidation of cellular mechanisms orchestrating cancer dormancy, paving the way for improvements in the diagnosis and treatment of metastatic cancer., Scientific and Technological Research Council of Turkey (TÜBİTAK)

High conservation of the disease-associated genes between fly and human facilitates the common use of Drosophila melanogaster to study metabolic disorders under controlled laboratory conditions. However, metabolic modeling studies are highly limited for this organism. We here report a comprehensively curated genome-scale metabolic network model of Drosophila using an orthology-based approach. The gene coverage and metabolic information of the orthology-based draft model were expanded via Drosophila-specific KEGG and MetaCyc databases, with several curation steps to avoid metabolic redundancy and stoichiometric inconsistency. Further, we performed literature-based curations to improve gene-reaction associations, subcellular metabolite locations, and updated various metabolic pathways including cholesterol metabolism. The performance of the resulting Drosophila model, termed iDrosophila1 (8,230 reactions, 6,990 metabolites, and 2,388 genes), was assessed using flux balance analysis in comparison with the other currently available fly models leading to superior or comparable results. We also evaluated transcriptome-based prediction capacity of the iDrosophila1, where differential metabolic pathways during Parkinson’s disease could be successfully elucidated. Overall, iDrosophila1 is promising to investigate systems-level metabolic alterations in response to genetic and environmental perturbations.

The role of brain cholesterol metabolism in Alzheimer’s disease (AD) remains unclear. Peripheral and brain cholesterol levels are largely independent due to the impermeability of the blood brain barrier (BBB), highlighting the importance of studying the role of brain cholesterol homeostasis in AD. We first tested whether metabolite markers of brain cholesterol biosynthesis and catabolism were altered in AD and associated with AD pathology using linear mixed-effects models in two brain autopsy samples from the Baltimore Longitudinal Study of Aging (BLSA) and the Religious Orders Study (ROS). We next tested whether genetic regulators of brain cholesterol biosynthesis and catabolism were altered in AD using the ANOVA test in publicly available brain tissue transcriptomic datasets. Finally, using regional brain transcriptomic data, we performed genome-scale metabolic network modeling to assess alterations in cholesterol biosynthesis and catabolism reactions in AD. We show that AD is associated with pervasive abnormalities in cholesterol biosynthesis and catabolism. Using transcriptomic data from Parkinson’s disease (PD) brain tissue samples, we found that gene expression alterations identified in AD were not observed in PD, suggesting that these changes may be specific to AD. Our results suggest that reduced de novo cholesterol biosynthesis may occur in response to impaired enzymatic cholesterol catabolism and efflux to maintain brain cholesterol levels in AD. This is accompanied by the accumulation of nonenzymatically generated cytotoxic oxysterols. Our results set the stage for experimental studies to address whether abnormalities in cholesterol metabolism are plausible therapeutic targets in AD.

In this study, we have investigated the cheese starter culture as a microbial community through a question: can the metabolic behaviour of a co‐culture be explained by the characterized individual organism that constituted the co‐culture? To address this question, the dairy‐origin lactic acid bacteria Lactococcus lactis subsp. cremoris, Lactococcus lactis subsp. lactis, Streptococcus thermophilus and Leuconostoc mesenteroides, commonly used in cheese starter cultures, were grown in pure and four different co‐cultures. We used a dynamic metabolic modelling approach based on the integration of the genome‐scale metabolic networks of the involved organisms to simulate the co‐cultures. The strain‐specific kinetic parameters of dynamic models were estimated using the pure culture experiments and they were subsequently applied to co‐culture models. Biomass, carbon source, lactic acid and most of the amino acid concentration profiles simulated by the co‐culture models fit closely to the experimental results and the co‐culture models explained the mechanisms behind the dynamic microbial abundance. We then applied the co‐culture models to estimate further information on the co‐cultures that could not be obtained by the experimental method used. This includes estimation of the profile of various metabolites in the co‐culture medium such as flavour compounds produced and the individual organism level metabolic exchange flux profiles, which revealed the potential metabolic interactions between organisms in the co‐cultures., Co‐cultures of lactic acid bacteria were investigated using dynamic genome‐scale metabolic modelling techniques. Özcan and co‐workers estimated the metabolic capacity, microbial abundance, potential of flavour compounds production and metabolic interactions of the co‐cultures using the features of individual organisms that constituted the co‐cultures.

A major problem in medicine and oncology is cancer recurrence through the activation of dormant cancer cells. A system scale examination of metabolic dysregulations associated with the cancer dormancy offers promise for the discovery of novel molecular targets for cancer precision medicine, and importantly, for the prevention of cancer recurrence. In this study, we mapped the total mRNA sequencing-based transcriptomic data from dormant cancer cell lines and nondormant cancer controls onto a human genome-scale metabolic network by using a graph-based approach, and two mass balance-based approaches with one based on reaction activity/inactivity and the other one on flux changes. The gene expression datasets were accessed from Gene Expression Omnibus (GSE83142 and GSE114012). This analysis included two diverse cancer types, a liquid and a solid cancer, namely, acute lymphoblastic leukemia and colorectal cancer. For the dormant cancer state, we observed changes in major adenosine triphosphate-producing pathways, including the citric acid cycle, oxidative phosphorylation, and glycolysis/gluconeogenesis, indicating a reprogramming in the metabolism of dormant cells away from Warburg-based energy metabolism. All three computational approaches unanimously predicted that folate metabolism, pyruvate metabolism, and glutamate metabolism, as well as valine/leucine/isoleucine metabolism are likely dysregulated in cancer dormancy. These findings provide new insights and molecular pathway targets on cancer dormancy, comprehensively catalog dormancy-associated metabolic pathways, and inform future research aimed at prevention of cancer recurrence in particular.

In this study, FeSO4 supplementation ranging from 0 to 4.5 mM, and MgSO4 supplementation ranging from 0 to 5.1 mM were investigated to observe the effect on the population dynamics, biochemical composition and fatty acid content of mixed microalgae grown in Anaerobic Liquid Digestate (ALD). Overall, 3.1 mM FeSO4 addition into ALD increased the total protein content 60% and led to highest biomass (1.56 g L−1) and chlorophyll-a amount (18.7 mg L−1) produced. Meanwhile, 0.4 mM MgSO4 addition increased the total carotenoid amount 2.2 folds and slightly increased the biomass amount. According to the microbial community analysis, Diphylleia rotans, Synechocystis PCC-6803 and Chlorella sorokiniana were identified as mostly detected species after confirmation with 4 different markers. The abundance of Chlorella sorokiniana and Synechocystis PCC-6803 increased almost 2 folds both in iron and magnesium addition. On the other hand, the dominancy of Diphylleia rotans was not affected by iron addition while drastically decreased (95%) with magnesium addition. This study helps to understand how the dynamics of symbiotic life changes if macro elements are added to the ALD and reveal that microalgae can adapt to adverse environmental conditions by fostering the diversity with a positive effect on high value product.

Genome-scale metabolic networks enable systemic investigation of metabolic alterations caused by diseases by providing interpretation of omics data. Although Mus musculus (mouse) is one of the most commonly used model organisms for neurodegenerative diseases, a brain-specific metabolic network model of mice has not yet been reconstructed. Here we reconstructed the first brain-specific metabolic network model of mice, iBrain674-Mm, by a homology-based approach, which consisted of 992 reactions controlled by 674 genes and distributed over 48 pathways. We validated the newly reconstructed network model by showing that it predicts healthy resting-state metabolic phenotypes of mouse brain compatible with the literature. We later used iBrain674-Mm to interpret various experimental mouse models of Parkinson's Disease (PD) at the transcriptome level. To this end, we applied a constraint-based modelling based biomarker prediction method called TIMBR (Transcriptionally Inferred Metabolic Biomarker Response) to predict altered metabolite production from transcriptomic data. Systemic analysis of seven different PD mouse models by TIMBR showed that the neuronal levels of glutamate, lactate, creatine phosphate, neuronal acetylcholine, bilirubin and formate increased in most of the PD mouse models, whereas the levels of melatonin, epinephrine, astrocytic formate and astrocytic bilirubin decreased. Although most of the predictions were consistent with the literature, there were some inconsistencies among different PD mouse models, signifying that there is no perfect experimental model to reflect PD metabolism. The newly reconstructed brain-specific genome-scale metabolic network model of mice can make important contributions to the interpretation and development of experimental mouse models of PD and other neurodegenerative diseases.

Leuconostoc mesenteroides subsp. cremoris is an obligate heterolactic fermentative lactic acid bacterium that is mostly used in industrial dairy fermentations. The phosphoketolase pathway (PKP) is a unique feature of the obligate heterolactic fermentation, which leads to the production of lactate, ethanol, and/or acetate, and the final product profile of PKP highly depends on the energetics and redox state of the organism. Another characteristic of the L. mesenteroides subsp. cremoris is the production of aroma compounds in dairy fermentation, such as in cheese production, through the utilization of citrate. Considering its importance in dairy fermentation, a detailed metabolic characterization of the organism is necessary for its more efficient use in the industry. To this aim, a genome-scale metabolic model of dairy-origin L. mesenteroides subsp. cremoris ATCC 19254 (iLM.c559) was reconstructed to explain the energetics and redox state mechanisms of the organism in full detail. The model includes 559 genes governing 1088 reactions between 1129 metabolites, and the reactions cover citrate utilization and citrate-related flavor metabolism. The model was validated by simulating co-metabolism of glucose and citrate and comparing the in silico results to our experimental results. Model simulations further showed that, in co-metabolism of citrate and glucose, no flavor compounds were produced when citrate could stimulate the formation of biomass. Significant amounts of flavor metabolites (e.g., diacetyl and acetoin) were only produced when citrate could not enhance growth, which suggests that flavor formation only occurs under carbon and ATP excess. The effects of aerobic conditions and different carbon sources on product profiles and growth were also investigated using the reconstructed model. The analyses provided further insights for the growth stimulation and flavor formation mechanisms of the organism. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature. FEN-C-DRP-091116-0498 2214-A Türkiye Bilimsel ve Teknolojik Araştirma Kurumu Funding information This work received financial support from The Scientific and Technological Research Council of Turkey through TUBITAK 2214-A program and the Marmara University Scientific Research Project Fund through Project No: FEN-C-DRP-091116-0498.

Aging is an inevitable process that negatively affects all living organisms and their vital functions. The brain is one of the most important organs in living beings and is primarily impacted by aging. The molecular mechanisms of learning, memory and cognition are altered over time, and the impairment in these mechanisms can lead to neurodegenerative diseases. Transcriptomics can be used to study these impairments to acquire more detailed information on the affected molecular mechanisms. Here we analyzed learning- and memory-related transcriptome data by mapping it on the organism-specific protein-protein interactome network. Subnetwork discovery algorithms were applied to discover highly dysregulated subnetworks, which were complemented with co-expression-based interactions. The functional analysis shows that the identified subnetworks are enriched with genes having roles in synaptic plasticity, gliogenesis, neurogenesis and cognition, which are reported to be related to memory and learning. With a detailed analysis, we show that the results from different subnetwork discovery algorithms or from different transcriptomic datasets can be successfully reconciled, leading to a memory-learning network that sheds light on the molecular mechanisms behind aging and memory-related impairments.

Plant-derived compounds as natural products have attracted a lot of attention in the treatment of complex diseases, especially cancers, primarily due to their poly-pharmacologic mechanisms of action. However, methodological limitations have impeded gaining complete knowledge of their molecular targets. While most of the current understanding of these compounds is based on reductive methods, it is increasingly becoming clear that holistic techniques, leveraging current improvements in omic data collection and bioinformatics methods, are better suited for elucidating their systemic effects. Here, to provide an explanation to the mechanisms of action of plant-derived natural products in breast cancer, we applied a data integration approach to comprehensively study oncogenic signaling pathways targeted by withaferin A, actein, compound kushen injection and indole-3-carbinol. Specifically, we mapped the transcriptome-level response of cancer cell lines to these molecules on a human protein-protein interaction network and constructed the underlying active subnetworks. We used these subnetworks to define the perturbed signaling pathways and validated their relevance in carcinogenesis. The similarity of each identified oncogenic signaling pathway in terms of overlapping genes was subsequently used to construct pathway-pathway interaction networks, which were used to reduce pathway redundancy and to identify pathway crosstalk. Filtered pathways were then mapped on three major carcinogenesis processes. The results showed that the pleiotropic effects of plant-derived drugs at the gene expression level can be used to predict targeted pathways. Thus, from such pathways, it is possible to infer a systemic mechanism of action of such natural products.

Pathogenic microorganisms exploit host metabolism for sustained survival by rewiring its metabolic interactions. Therefore, several metabolic changes are induced in both pathogen and host cells in the course of infection. A systems-based approach to elucidate those changes includes the integrative use of genome-scale metabolic networks and molecular omics data, with the overall goal of better characterizing infection mechanisms for novel treatment strategies. This review focuses on novel aspects of metabolism-oriented systems-based investigation of pathogen-human interactions. The reviewed approaches are the generation of dual-omics data for the characterization of metabolic signatures of pathogen-host interactions, the reconstruction of pathogen-host integrated genome-scale metabolic networks, which has a high potential to be applied to pathogen-gut microbiota interactions, and the structure-based analysis of enzymes playing role in those interactions. The integrative use of those approaches will pave the way for the identification of novel biomarkers and drug targets for the prediction and prevention of infectious diseases.

Klebsiella pneumoniae is an opportunistic bacterial pathogen leading to life-threatening nosocomial infections. Emergence of highly resistant strains poses a major challenge in the management of the infections by healthcare-associated K. pneumoniae isolates. Thus, despite intensive efforts, the current treatment strategies remain insufficient to eradicate such infections. Failure of the conventional infection-prevention and treatment efforts explicitly indicates the requirement of new therapeutic approaches. This prompted us to systematically analyze the K. pneumoniae metabolism to investigate drug targets. Genome-scale metabolic networks (GMNs) facilitating the systematic analysis of the metabolism are promising platforms. Thus, we used a GMN of K. pneumoniae MGH 78578 to determine putative targets through gene- and metabolite-centric approaches. To develop more realistic infection models, we performed the bacterial growth simulations within different host-mimicking media, using an improved biomass formation reaction. We selected more suitable targets based on several property-based prioritization procedures. KdsA was identified as the high-ranked putative target satisfying most of the target prioritization criteria specified under the gene-centric approach. Through a structure-based virtual screening protocol, we identified potential KdsA inhibitors. In addition, the metabolite-centric approach extended the drug target list based on synthetic lethality. This revealed the importance of combined metabolic analyses for a better understanding of the metabolism. To our knowledge, this is the first comprehensive effort on the investigation of the K. pneumoniae metabolism for drug target prediction through the constraint-based analysis of its GMN in conjunction with several bioinformatic approaches. This study can guide the researchers for the future drug designs by providing initial findings regarding crucial components of the Klebsiella metabolism.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Genome-scale modelling in eukaryotes has been pioneered by the yeast Saccharomyces cerevisiae. Early metabolic networks have been reconstructed based on genome sequence and information accumulated in the literature on biochemical reactions. Protein-protein interaction networks have been constructed based on experimental observations such as yeast-2-hybrid method. Gene regulatory networks were based on a variety of data types, including information on TF-promoter binding and gene coexpression. The aforementioned networks have been improved gradually, and methods for their integration were developed. Incorporation of omics data including genomics, metabolomics, transcriptomics, fluxome, and phosphoproteome led to next-generation genome-scale models. The methods tested on yeast have later been implemented in human, further, cellular components found to be important in yeast physiology under (ab)normal conditions, and (dis)regulation mechanisms in yeast shed light to the healthy and disease states in human. This chapter provides a historical perspective on next-generation genome-scale models incorporating multilevel 'omics data, from yeast to human.

Klebsiella pneumoniae is an opportunistic bacterial pathogen leading to life-threatening nosocomial infections. Emergence of highly resistant strains poses a major challenge in the management of the infections by healthcare-associated K. pneumoniae isolates. Thus, despite intensive efforts, the current treatment strategies remain insufficient to eradicate such infections. Failure of the conventional infection-prevention and treatment efforts explicitly indicates the requirement of new therapeutic approaches. This prompted us to systematically analyze the K. pneumoniae metabolism to investigate drug targets. Genome-scale metabolic networks (GMNs) facilitating the systematic analysis of the metabolism are promising platforms. Thus, we used a GMN of K. pneumoniae MGH 78578 to determine putative targets through gene- and metabolite-centric approaches. To develop more realistic infection models, we performed the bacterial growth simulations within different host-mimicking media, using an improved biomass formation reaction. We selected more suitable targets based on several property-based prioritization procedures. KdsA was identified as the high-ranked putative target satisfying most of the target prioritization criteria specified under the gene-centric approach. Through a structure-based virtual screening protocol, we identified potential KdsA inhibitors. In addition, the metabolite-centric approach extended the drug target list based on synthetic lethality. This revealed the importance of combined metabolic analyses for a better understanding of the metabolism. To our knowledge, this is the first comprehensive effort on the investigation of the K. pneumoniae metabolism for drug target prediction through the constraint-based analysis of its GMN in conjunction with several bioinformatic approaches. This study can guide the researchers for the future drug designs by providing initial findings regarding crucial components of the Klebsiella metabolism.

Genome-scale modelling in eukaryotes has been pioneered by the yeast Saccharomyces cerevisiae. Early metabolic networks have been reconstructed based on genome sequence and information accumulated in the literature on biochemical reactions. Protein-protein interaction networks have been constructed based on experimental observations such as yeast-2-hybrid method. Gene regulatory networks were based on a variety of data types, including information on TF-promoter binding and gene coexpression. The aforementioned networks have been improved gradually, and methods for their integration were developed. Incorporation of omics data including genomics, metabolomics, transcriptomics, fluxome, and phosphoproteome led to next-generation genome-scale models. The methods tested on yeast have later been implemented in human, further, cellular components found to be important in yeast physiology under (ab)normal conditions, and (dis)regulation mechanisms in yeast shed light to the healthy and disease states in human. This chapter provides a historical perspective on next-generation genome-scale models incorporating multilevel 'omics data, from yeast to human.

Through its metabolic network, a cell distributes the available carbon flux into several pathways. The pathway activity information for a cell is crucial to deduce underlying molecular mechanisms and to monitor the effect of perturbations such as diseases. The constraint-based modeling approach to organism- and tissue-specific metabolic networks has therefore become a popular focus in the computational system’s biology field. The approach uses reaction stoichiometries and the reversibility information for the reactions as well as few literature-based flux measurements to calculate flux distributions through all covered pathways in a metabolic network. Therefore, the effect of phenomena such as hypoxia, hyperglycemia, and neurodegenerative diseases on brain metabolism can be computationally documented to enlighten molecular mechanisms and to design new hypotheses. This chapter covers the basics of constraint-based modeling via a toy metabolic network example and gives an overview of the application of the approach to couple neuronal and astrocytic metabolisms. It further utilizes a recently developed genome-scale metabolic network of the brain to calculate fluxes for the resting state and for hypoxia in and between astrocytes and neurons. Finally, the chapter shortly discusses the use of transcriptome data to obtain condition-specific flux distributions.

Systems-based investigation of diseases requires integrated analysis of cellular networks and high-throughput data of gene products. The use of genome-scale metabolic networks for such integration has led to the elucidation of cellular mechanisms for several cell types from microorganisms to plants. It has become easier and cheaper to generate high-throughput data over years in the form of transcriptome, proteome and metabolome. This has tremendously improved the quality and quantity of information extracted from such data enabling the documentation of active pathways and reactions in cell metabolism. A number of omics-based datasets for several neurodegenerative diseases are now available in public repositories. This increases the potential of using genome-scale brain metabolic networks as a scaffold for this type of data to map metabolic alterations for the purpose of elucidating disease mechanisms and for the diagnosis and treatment of such disorders. This chapter first reviews omics data collected for neurodegenerative diseases to map their effect on metabolism. Later, the potential for genome-scale metabolic modeling of such data is reviewed and discussed in light of recently reconstructed brain metabolic networks at genome-scale.

A systems approach to elucidate the effect of infection on cell metabolism provides several opportunities from a better understanding of molecular mechanisms to the identification of potential biomarkers and drug targets. This is obvious from the fact that we have witnessed the accelerated use of computational systems biology in the last five years to study metabolic changes in pathogen and/or host cells in response to infection. In this chapter, we aim to present a comprehensive review of the recent research by focusing on genome-scale metabolic network models of pathogen-host systems and genome-wide metabolomics and fluxomics analysis of infected cells.

Systems-based investigation of diseases requires integrated analysis of cellular networks and high-throughput data of gene products. The use of genome-scale metabolic networks for such integration has led to the elucidation of cellular mechanisms for several cell types from microorganisms to plants. It has become easier and cheaper to generate high-throughput data over years in the form of transcriptome, proteome and metabolome. This has tremendously improved the quality and quantity of information extracted from such data enabling the documentation of active pathways and reactions in cell metabolism. A number of omics-based datasets for several neurodegenerative diseases are now available in public repositories. This increases the potential of using genome-scale brain metabolic networks as a scaffold for this type of data to map metabolic alterations for the purpose of elucidating disease mechanisms and for the diagnosis and treatment of such disorders. This chapter first reviews omics data collected for neurodegenerative diseases to map their effect on metabolism. Later, the potential for genome-scale metabolic modeling of such data is reviewed and discussed in light of recently reconstructed brain metabolic networks at genome-scale.

Reverse engineering metabolome data to infer metabolic interactions is a challenging research topic. Here we introduce JacLy, a Jacobian-based method to infer metabolic interactions of small networks (in silico small-scale metabolome datasets. The power of JacLy lies on the use of steady-state metabolome data to predict the Jacobian matrix of the system, which is a source of information on structure and dynamic characteristics of the system. Besides its advantage of inferring directed interactions, its superiority over correlation-based network inference was especially clear in terms of the required number of replicates and the effect of the use of priori knowledge in the inference. Additionally, we showed the use of standard deviation of the replicate data as a suitable approximation for the magnitudes of metabolite fluctuations inherent in the system.

Highlights • A novel brain-specific metabolic model was reconstructed, covering 570 genes. • The model, iMS570, correctly predicts major metabolic fluxes. • It is used as a scaffold to map transcriptome data for neurodegenerative diseases. • Identified reporter metabolites are potential biomarkers for the disease pathology. • Pathway-specific effect of the diseases on brain metabolism is revealed., Network-oriented analysis is essential to identify those parts of a cell affected by a given perturbation. The effect of neurodegenerative perturbations in the form of diseases of brain metabolism was investigated by using a newly reconstructed brain-specific metabolic network. The developed stoichiometric model correctly represents healthy brain metabolism, and includes 630 metabolic reactions in and between astrocytes and neurons, which are controlled by 570 genes. The integration of transcriptome data of six neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, multiple sclerosis, schizophrenia) with the model was performed to identify reporter features specific and common for these diseases, which revealed metabolites and pathways around which the most significant changes occur. The identified metabolites are potential biomarkers for the pathology of the related diseases. Our model indicated perturbations in oxidative stress, energy metabolism including TCA cycle and lipid metabolism as well as several amino acid related pathways, in agreement with the role of these pathways in the studied diseases. The computational prediction of transcription factors that commonly regulate the reporter metabolites was achieved through binding-site analysis. Literature support for the identified transcription factors such as USF1, SP1 and those from FOX families are known from the literature to have regulatory roles in the identified reporter metabolic pathways as well as in the neurodegenerative diseases. In essence, the reconstructed brain model enables the elucidation of effects of a perturbation on brain metabolism and the illumination of possible machineries in which a specific metabolite or pathway acts as a regulatory spot for cellular reorganization.

In the emerging field of systems biology of fungal infection, one of the central roles belongs to the modeling of gene regulatory networks (GRNs). Utilizing omics-data, GRNs can be predicted by mathematical modeling. Here, we review current advances of data-based reconstruction of both small-scale and large-scale GRNs for human pathogenic fungi. The advantage of large-scale genome-wide modeling is the possibility to predict central (hub) genes and thereby indicate potential biomarkers and drug targets. In contrast, small-scale GRN models provide hypotheses on the mode of gene regulatory interactions, which have to be validated experimentally. Due to the lack of sufficient quantity and quality of both experimental data and prior knowledge about regulator–target gene relations, the genome-wide modeling still remains problematic for fungal pathogens. While a first genome-wide GRN model has already been published for Candida albicans, the feasibility of such modeling for Aspergillus fumigatus is evaluated in the present article. Based on this evaluation, opinions are drawn on future directions of GRN modeling of fungal pathogens. The crucial point of genome-wide GRN modeling is the experimental evidence, both used for inferring the networks (omics ‘first-hand’ data as well as literature data used as prior knowledge) and for validation and evaluation of the inferred network models.

Developments in genome scale metabolic modeling techniques and omics technologies have enabled the reconstruction of context-specific metabolic models. In this study, glioblastoma multiforme (GBM), one of the most common and aggressive malignant brain tumors, is investigated by mapping GBM gene expression data on the growth-implemented brain specific genome-scale metabolic network, and GBM-specific models are generated. The models are used to calculate metabolic flux distributions in the tumor cells. Metabolic phenotypes predicted by the GBM-specific metabolic models reconstructed in this work reflect the general metabolic reprogramming of GBM, reported both in in-vitro and in-vivo experiments. The computed flux profiles quantitatively predict that major sources of the acetyl-CoA and oxaloacetic acid pool used in TCA cycle are pyruvate dehydrogenase from glycolysis and anaplerotic flux from glutaminolysis, respectively. Also, our results, in accordance with recent studies, predict a contribution of oxidative phosphorylation to ATP pool via a slightly active TCA cycle in addition to the major contributor aerobic glycolysis. We verified our results by using different computational methods that incorporate transcriptome data with genome-scale models and by using different transcriptome datasets. Correct predictions of flux distributions in glycolysis, glutaminolysis, TCA cycle and lipid precursor metabolism validate the reconstructed models for further use in future to simulate more specific metabolic patterns for GBM.

Pathogen-Host Interactions (PHIs) play a significant role in the mechanisms of infections. Therefore, the investigation of infection mechanisms through PHIs is a crucial step to develop novel and more effective solutions against drug-resistance and for personalized therapy. To this aim, systems biology approach considers the whole PHI system instead of focusing hosts or pathogens individually. Computational modeling and analysis has a vital place within the whole systems biology workflow (Cyclic operation of experimental and modeling work). Multi-scale modeling provides the holistic view needed in the investigation of pathogen-host molecular interactions. However, it is usually very difficult to identify the model structure and parameters for complex multi-scale models. On the other hand, focused modeling types require more stringent and advanced feature selection approaches. This research topic aims to provide examples from the current picture of the research on computational systems biology of PHIs. The papers included here review recent studies or present original research on computational inference of PHI networks, computational prediction of PHIs, text mining of PHI data from the literature, and mathematical modeling and computational analysis of PHI networks. This research topic presents three review papers, 10 original research articles, and one technology report. Opening this research topic, we provide a comprehensive review of the studies on computational systems biology of PHIs (Durmus et al.). We focus on the computational methods for the inference of molecular interaction networks of PHI systems, bioinformatic analysis of PHI networks, the Web-based PHI databases, and text-mining efforts to extract PHI data hidden in the literature. In this sense, this review provides a systems perspective on which the other articles covered in this research topic are based.

Reverse engineering of high-throughput omics data to infer underlying biological networks is one of the challenges in systems biology. However, applications in the field of metabolomics are rather limited. We have focused on a systematic analysis of metabolic network inference from in silico metabolome data based on statistical similarity measures. Three different data types based on biological/environmental variability around steady state were analyzed to compare the relative information content of the data types for inferring the network. Comparing the inference power of different similarity scores indicated the clear superiority of conditioning or pruning based scores as they have the ability to eliminate indirect interactions. We also show that a mathematical measure based on the Fisher information matrix gives clues on the information quality of different data types to better represent the underlying metabolic network topology. Results on several datasets of increasing complexity consistently show that metabolic variations observed at steady state, the simplest experimental analysis, are already informative to reveal the connectivity of the underlying metabolic network with a low false-positive rate when proper similarity-score approaches are employed. For experimental situations this implies that a single organism under slightly varying conditions may already generate more than enough information to rightly infer networks. Detailed examination of the strengths of interactions of the underlying metabolic networks demonstrates that the edges that cannot be captured by similarity scores mainly belong to metabolites connected with weak interaction strength. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11306-009-0156-4) contains supplementary material, which is available to authorized users.

A systems-based investigation of the effect of perturbations on metabolic machinery is crucial to elucidate the mechanism behind perturbations. One way to investigate the perturbation-induced changes within the cell metabolism is to focus on pathway-level effects. In this study, three different perturbation types (genetic, environmental and disease-based) are analyzed to compute a list of reporter pathways, metabolic pathways which are significantly affected from a perturbation. The most common omics data type, transcriptome, is used as an input to the bioinformatic analysis. The pathways are scored by two alternative approaches: by averaging the changes in the expression levels of the genes controlling the associated reactions (reaction-centric) and by averaging the changes in the associated metabolites which were scored based on the associated genes (metabolite-centric). The analysis reveals the superiority of the novel metabolite-centric approach over the commonly used reaction-centric approach since it is based on metabolites which better represent the cross-talk among different pathways, enabling a more global and realistic cataloguing of network-wide perturbation effects.