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See detailA systems biology approach to identify niche determinants of cellular phenotypes
Ravichandran, Srikanth UL; Okawa, Satoshi UL; Martinez Arbas, Susana UL et al

in Stem Cell Research (2016)

Recent reports indicate a dominant role for cellular microenvironment or niche for stably maintaining cellular phenotypic states. Identification of key niche mediated signaling that maintains stem cells ... [more ▼]

Recent reports indicate a dominant role for cellular microenvironment or niche for stably maintaining cellular phenotypic states. Identification of key niche mediated signaling that maintains stem cells in specific phenotypic states remains a challenge, mainly due to the complex and dynamic nature of stem cell-niche interactions. In order to overcome this, we consider that stem cells maintain their phenotypic state by experiencing a constant effect created by the niche by integrating its signals via signaling pathways. Such a constant niche effect should induce sustained activation/inhibition of specific stem cell signaling pathways that controls the gene regulatory program defining the cellular phenotypic state. Based on this view, we propose a computational approach to identify the most likely receptor mediated signaling responsible for transmitting niche signals to the transcriptional regulatory network that maintain cell-specific gene expression patterns, termed as niche determinants. We demonstrate the utility of our method in different stem cell systems by identifying several known and novel niche determinants. Given the key role of niche in several degenerative diseases, identification of niche determinants can aid in developing strategies for potential applications in regenerative medicine. [less ▲]

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See detailA systems biology approach to studying the role of microbes in human health.
Thiele, Ines UL; Heinken, Almut Katrin UL; Fleming, Ronan MT UL

in Current Opinion in Biotechnology (2013), 24(1), 4-12

Host-microbe interactions play a crucial role in human health and disease. Of the various systems biology approaches, reconstruction of genome-scale metabolic networks combined with constraint-based ... [more ▼]

Host-microbe interactions play a crucial role in human health and disease. Of the various systems biology approaches, reconstruction of genome-scale metabolic networks combined with constraint-based modeling has been particularly successful at in silico predicting the phenotypic characteristics of single organisms. Here, we summarize recent studies, which have applied this approach to investigate microbe-microbe and host-microbe metabolic interactions. This approach can be also expanded to investigate the properties of an entire microbial community, as well as single organisms within the community. We illustrate that the constraint-based modeling approach is suitable to model host-microbe interactions at molecular resolution and will enable systematic investigation of metabolic links between the human host and its microbes. Such host-microbe models, combined with experimental data, will ultimately further our understanding of how microbes influence human health. [less ▲]

Detailed reference viewed: 182 (16 UL)
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See detailA systems biology approach towards understanding nuclear receptor interactions: Implications at the endocrine-xenobiotic signalling interface
Kolodkin, Alexey UL; Phillips, Anna; Hood, Steve et al

in Toxicology (2011), 290(2-3), 131-131

Detailed reference viewed: 85 (7 UL)
See detailSystems Biology Approaches for Identification of Molecular Mechanisms in Brain Disorders
Androsova, Ganna UL

Doctoral thesis (2018)

One out of four people are affected by a brain disorder at some stage in their life. Depending on the symptoms and the underlying molecular mechanisms, brain disorders can be classified into neurological ... [more ▼]

One out of four people are affected by a brain disorder at some stage in their life. Depending on the symptoms and the underlying molecular mechanisms, brain disorders can be classified into neurological and cognitive disorders. Complex disorders typically have a multifactorial pathogenesis. Epilepsy and postoperative delirium (POD) exemplifying neurological and cognitive disorders are no exception. Research efforts contributed to the understanding of molecular mechanisms of these diseases by discovering associations between clinical and genomic information and disease phenotypes. These findings, although necessary, are not sufficient to reconstruct the complete map of system-level interactions. To achieve a system-level understanding of a biological system, one can integrate diverse data sources by a network-based approach. Network analysis methods characterise interactions within and between molecular systems and can identify candidate biomarkers in various biological contexts. Specifically, correlation networks can reveal condition-dependent molecular patterns whose functional enrichment points to the altered molecular mechanisms of the phenotype. A molecular signature of a phenotype can be determined by machine learning algorithms for supervised classification as a set of molecules accurately discriminating between disease and healthy state. The primary aim of this dissertation is to identify altered biological pathways and functionally relevant molecules of epileptogenesis and postoperative delirium. This cumulative dissertation is composed of six chapters. Chapter 1provides the background information on brain disorders and the systems biology methods to study their molecular mechanisms. Chapter 2 was motivated by the fact that current anti-epilepsy treatments focus on minimisation of the symptoms and epileptic seizures, while no definitive cure exists. The understanding of molecular events triggering the development of epilepsy (also called epileptogenesis) can yield therapies halting the onset of epilepsy. We identified proteomic alterations in the animal model of epileptogenesis by a network-based method and validated our results by external data set and immunohistochemical staining. The functional annotation of molecular expression patterns revealed biological pathways not yet described in the context of epileptogenesis. Next, we identified the gap in a comparative analysis of available antiepileptic drugs for mesial temporal lobe epilepsy due to hippocampal sclerosis. Chapter 3 retrospectively compares retention, efficacy and tolerability of antiepileptic drugs in the large epilepsy pharmacogenomics database. Chapter 4 is focused on the identification of molecular alterations in postoperative delirium. Overlaying postmortem brain expression data with locations of functional networks disturbed in POD, we identified several gene expression patterns with relevant biological enrichment. Moreover, same biological functions were altered in the blood of POD patients. Previously described POD markers such as acetylcholinesterase, alpha-synuclein and protein C appeared in the identified clusters. In Chapter 5, I focused on the identification of a molecular signature discriminating POD patients before they undergo surgery. Having ranked preoperative expression levels of mRNAs and miRNAs by their ability to detect patients with POD, I identified a set of discriminatory features that achieved high accuracy, sensitivity and specificity in the training set. The trained model had a good generalisability on the unseen data set but its performance decreased on the test set not matched by age and gender. The final Chapter 6 summarises the main outcomes of the presented studies and concludes with an outlook. [less ▲]

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See detailSystems biology integration of proteomic data in rodent models of depression reveals involvement of the immune response and glutamatergic signalling
Carboni, Lucia; Nguyen, Thanh-Phuong UL; Caberlotto, Laura

in Proteomics. Clinical Applications (2016)

Purpose The pathophysiological basis of major depression is incompletely understood. Recently, numerous proteomic studies have been performed in rodent models of depression to investigate the molecular ... [more ▼]

Purpose The pathophysiological basis of major depression is incompletely understood. Recently, numerous proteomic studies have been performed in rodent models of depression to investigate the molecular underpinnings of depressive-like behaviours with an unbiased approach. The objective of the study was to integrate the results of these proteomic studies in depression models to shed light on the most relevant molecular pathways involved in the disease. Experimental design Network analysis was performed integrating pre-existing proteomic data from rodent models of depression. The IntAct mouse and the HRPD were used as reference protein-protein interaction databases. The functionality analyses of the networks were then performed by testing over-represented GO biological process terms and pathways. Results Functional enrichment analyses of the networks revealed an association with molecular processes related to depression in humans, such as those involved in the immune response. Pathways impacted by clinically effective antidepressants were modulated, including glutamatergic signalling and neurotrophic responses. Moreover, dysregulations of proteins regulating energy metabolism and circadian rhythms were implicated. The comparison with protein pathways modulated in depressive patients revealed significant overlapping. Conclusions and clinical relevance This systems biology study supports the notion that animal models could contribute to the research into the biology and therapeutics of depression. [less ▲]

Detailed reference viewed: 54 (3 UL)
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See detailA systems biology investigation of neurodegenerative dementia reveals a pivotal role of autophagy
Caberlotto, Laura; Nguyen, Thanh-Phuong UL

in BMC Systems Biology (2014), 8(1), 65

Detailed reference viewed: 62 (5 UL)
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See detailSystems Biology of Acidophile Biofilms for Efficient Metal Extraction
Christel, Stephan; Dopson, Mark; Vera, Mario et al

in Advanced Materials Research (2015), 1130

This European Union ERASysApp funded study will investigate one of the major drawbacks of bioleaching of the copper containing mineral chalcopyrite, namely the long lag phase between construction and ... [more ▼]

This European Union ERASysApp funded study will investigate one of the major drawbacks of bioleaching of the copper containing mineral chalcopyrite, namely the long lag phase between construction and inoculation of bioleaching heaps and the release of dissolved metals. In practice, this lag phase can be up to three years and the long time period adds to the operating expenses of bioheaps for chalcopyrite dissolution. One of the major time determining factors in bioleaching heaps is suggested to be the speed of mineral colonization by the acidophilic microorganisms present. By applying confocal microscopy, metatranscriptomics, metaproteomics, bioinformatics, and computer modeling the authors aim to investigate the processes leading up to, and influencing the attachment of three moderately thermophilic sulfur-and/or iron-oxidizing model species: Acidithiobacillus caldus, Leptospirillum ferriphilum, and Sulfobacillus thermosulfidooxidans. Stirred tank reactors containing chalcopyrite concentrate will be inoculated with these species in various orders and proportions and the effects on the lag phase and rates of metal release will be compared. Meanwhile, confocal microscopy studies of cell attachment to chalcopyrite mineral particles, as well as metatranscriptomics and metaproteomics of the formed biofilms will further increase understanding of the attachment process and help develop a model thereof. By fulfilling our goal to decrease the length of the lag phase of chalcopyrite bioleaching heaps we hope to increase their economic feasibility and therefore, industrial interest in bioleaching as a sustainable technology. [less ▲]

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See detailSystems biology of bacteria-host interactions
Heinken, Almut Katrin UL; Ravcheev, Dmitry UL; Thiele, Ines UL

in Nibali, Luigi; Henderson, Brian (Eds.) The Human Microbiota and Chronic Disease: Dysbiosis as a Cause of Human Pathology (2016)

The aim of systems biology is to use computational methods to gain a complete, systems-level understanding of a cell, organism, or ecosystem. This chapter describes computational systems biology ... [more ▼]

The aim of systems biology is to use computational methods to gain a complete, systems-level understanding of a cell, organism, or ecosystem. This chapter describes computational systems biology approaches and their applications to human gut microbiome research, with particular focus on constraint-based modeling. At heart of the Constraint-Based Modeling and Analysis (COBRA) approach are accurate, well-structured metabolic reconstructions based on the target organisms’ genome sequences. Such genome-scale reconstructions (GENREs) are constructed in a bottom-up manner and describe the target organism's metabolism. The availability of high-quality reconstructions of human metabolism and of other host organisms, enables the computational modeling of host-microbe interactions. Simulating host-microbe interactions is particularly valuable since it could be used to minimize the number of animal experiments. The discussed computational modeling approaches will be valuable tools for studying microbial dysbiosis and its impact on host metabolism. Common approaches for computational modeling include ordinary differential equation (ODE) and kinetic modeling [less ▲]

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See detailSystems biology of host-microbe metabolomics
Heinken, Almut Katrin UL; Thiele, Ines UL

in Wiley Interdisciplinary Reviews. Systems Biology and Medicine (2015)

The human gut microbiota performs essential functions for host and wellbeing, but has also been linked to a variety of disease states, e.g., obesity and type 2 diabetes. The mammalian body fluid and ... [more ▼]

The human gut microbiota performs essential functions for host and wellbeing, but has also been linked to a variety of disease states, e.g., obesity and type 2 diabetes. The mammalian body fluid and tissue metabolomes are greatly influenced by the microbiota, with many health-relevant metabolites being considered “mammalian-microbial co-metabolites”. To systematically investigate this complex host-microbial co-metabolism, a systems biology approach integrating high-throughput data and computational network models is required. Here, we review established top-down and bottom-up systems biology approaches that have successfully elucidated relationships between gut microbiota-derived metabolites and host health and disease. We particularly focus on the constraint-based modeling and analysis approach, which enables the prediction of mechanisms behind metabolic host-microbe interactions on the molecular level. We illustrate that constraint-based models are a useful tool for the contextualization of metabolomic measurements and can further our insight into host-microbe interactions, yielding, e.g., in potential novel drugs and biomarkers. [less ▲]

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See detailSystems Biology of Microbiomes
Wilmes, Paul UL

Scientific Conference (2016, September)

Detailed reference viewed: 23 (0 UL)
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See detailSystems biology towards life in silico: mathematics of the control of living cells.
Westerhoff, Hans V.; Kolodkin, Alexey UL; Conradie, Riaan et al

in Journal of Mathematical Biology (2009), 58(1-2), 7-34

Systems Biology is the science that aims to understand how biological function absent from macromolecules in isolation, arises when they are components of their system. Dedicated to the memory of Reinhart ... [more ▼]

Systems Biology is the science that aims to understand how biological function absent from macromolecules in isolation, arises when they are components of their system. Dedicated to the memory of Reinhart Heinrich, this paper discusses the origin and evolution of the new part of systems biology that relates to metabolic and signal-transduction pathways and extends mathematical biology so as to address postgenomic experimental reality. Various approaches to modeling the dynamics generated by metabolic and signal-transduction pathways are compared. The silicon cell approach aims to describe the intracellular network of interest precisely, by numerically integrating the precise rate equations that characterize the ways macromolecules' interact with each other. The non-equilibrium thermodynamic or 'lin-log' approach approximates the enzyme rate equations in terms of linear functions of the logarithms of the concentrations. Biochemical Systems Analysis approximates in terms of power laws. Importantly all these approaches link system behavior to molecular interaction properties. The latter two do this less precisely but enable analytical solutions. By limiting the questions asked, to optimal flux patterns, or to control of fluxes and concentrations around the (patho)physiological state, Flux Balance Analysis and Metabolic/Hierarchical Control Analysis again enable analytical solutions. Both the silicon cell approach and Metabolic/Hierarchical Control Analysis are able to highlight where and how system function derives from molecular interactions. The latter approach has also discovered a set of fundamental principles underlying the control of biological systems. The new law that relates concentration control to control by time is illustrated for an important signal transduction pathway, i.e. nuclear hormone receptor signaling such as relevant to bone formation. It is envisaged that there is much more Mathematical Biology to be discovered in the area between molecules and Life. [less ▲]

Detailed reference viewed: 80 (3 UL)
See detailSystems ecology of human-microbe interactions
Wilmes, Paul UL

Scientific Conference (2016, June)

Detailed reference viewed: 16 (0 UL)
See detailSystems ecology of microbial pioneers in the gut
Wilmes, Paul UL

Presentation (2017, October)

Detailed reference viewed: 25 (3 UL)
See detailSystems ecology of microbiome-human interactions: identifying which functions are key
Wilmes, Paul UL

Scientific Conference (2018, April)

Detailed reference viewed: 20 (0 UL)
See detailSystems ecology of microbiomes
Wilmes, Paul UL

Scientific Conference (2018, December)

Detailed reference viewed: 53 (9 UL)
See detailSystems ecology of microbiomes
Wilmes, Paul UL

Scientific Conference (2018, May)

Detailed reference viewed: 35 (0 UL)
See detailSystems ecology of microbiomes: a new frontier of discovery in microbiology
Wilmes, Paul UL

Presentation (2017, August)

Detailed reference viewed: 19 (0 UL)
See detailSystems Ecology of Microbiomes: A New Frontier of Discovery in Microbiology
Wilmes, Paul UL

Scientific Conference (2017, May)

Detailed reference viewed: 25 (0 UL)
See detailSystems ecology of microbiomes: a new frontier of discovery in microbiology
Wilmes, Paul UL

Presentation (2017, August)

Detailed reference viewed: 16 (0 UL)
See detailSystems ecology of microbiomes: a new frontier of discovery in microbiology
Wilmes, Paul UL

Scientific Conference (2017, September)

Detailed reference viewed: 23 (1 UL)