Data- and knowledge-based modeling of gene regulatory networks: an update

Gene regulatory network inference is a systems biology approach which predicts interactions between genes with the help of high-throughput data. In this review, we present current and updated network inference methods focusing on novel techniques for data acquisition, network inference assessment, network inference for interacting species and the integration of prior knowledge. After the advance of Next-Generation-Sequencing of cDNAs derived from RNA samples (RNA-Seq) we discuss in detail its application to network inference. Furthermore, we present progress for large-scale or even full-genomic network inference as well as for small-scale condensed network inference and review advances in the evaluation of network inference methods by crowdsourcing. Finally, we reflect the current availability of data and prior knowledge sources and give an outlook for the inference of gene regulatory networks that reflect interacting species, in particular pathogen-host interactions

How to Predict Molecular Interactions between Species?

Organisms constantly interact with other species through physical contact which leads to chan-ges on the molecular level, for example the transcriptome. These changes can be monitored forall genes, with the help of high-throughput experiments such as RNA-seq or microarrays. Theadaptation of the gene expression to environmental changes within cells is mediated throughcomplex gene regulatory networks. Often, our knowledge of these networks is incomplete. Netw-ork inference predicts gene regulatory interactions based on transcriptome data. An emergingapplication of high-throughput transcriptome studies are dual transcriptomics experiments. Here,the transcriptome of two or more interacting species is measured simultaneously. Based ona dual RNA-seq data set of murine dendritic cells infected with the fungal pathogen Candidaalbicans, the software tool NetGenerator was applied to predict an inter-species gene regulatorynetwork. To promote further investigations of molecular inter-species interactions, we recentlydiscussed dual RNA-seq experiments for host-pathogen interactions and extended the appliedtool NetGenerator (Schulze et al., 2015). The updated version of NetGenerator makes use ofmeasurement variances in the algorithmic procedure and accepts gene expression time seriesdata with missing values. Additionally, we tested multiple modeling scenarios regarding the stimulifunctions of the gene regulatory network. Here, we summarize the work by Schulze et al. (2015)and put it into a broader context. We review various studies making use of the dual transcriptomicsapproach to investigate the molecular basis of interacting species. Besides the application tohost-pathogen interactions, dual transcriptomics data are also utilized to study mutualistic andcommensalistic interactions. Furthermore, we give a short introduction into additional approachesfor the prediction of gene regulatory networks and discuss their application to dual transcriptomicsdata. We conclude that the application of network inference on dual-transcriptomics data is apromising approach to predict molecular inter-species interactions

Novel application of multi-stimuli network inference to synovial fibroblasts of rheumatoid arthritis patients

BACKGROUND: Network inference of gene expression data is an important challenge in systems biology. Novel algorithms may provide more detailed gene regulatory networks (GRN) for complex, chronic inflammatory diseases such as rheumatoid arthritis (RA), in which activated synovial fibroblasts (SFBs) play a major role. Since the detailed mechanisms underlying this activation are still unclear, simultaneous investigation of multi-stimuli activation of SFBs offers the possibility to elucidate the regulatory effects of multiple mediators and to gain new insights into disease pathogenesis. METHODS: A GRN was therefore inferred from RA-SFBs treated with 4 different stimuli (IL-1 β, TNF- α, TGF- β, and PDGF-D). Data from time series microarray experiments (0, 1, 2, 4, 12 h; Affymetrix HG-U133 Plus 2.0) were batch-corrected applying ‘ComBat’, analyzed for differentially expressed genes over time with ‘Limma’, and used for the inference of a robust GRN with NetGenerator V2.0, a heuristic ordinary differential equation-based method with soft integration of prior knowledge. RESULTS: Using all genes differentially expressed over time in RA-SFBs for any stimulus, and selecting the genes belonging to the most significant gene ontology (GO) term, i.e., ‘cartilage development’, a dynamic, robust, moderately complex multi-stimuli GRN was generated with 24 genes and 57 edges in total, 31 of which were gene-to-gene edges. Prior literature-based knowledge derived from Pathway Studio or manual searches was reflected in the final network by 25/57 confirmed edges (44%). The model contained known network motifs crucial for dynamic cellular behavior, e.g., cross-talk among pathways, positive feed-back loops, and positive feed-forward motifs (including suppression of the transcriptional repressor OSR2 by all 4 stimuli. CONCLUSION: A multi-stimuli GRN highly concordant with literature data was successfully generated by network inference from the gene expression of stimulated RA-SFBs. The GRN showed high reliability, since 10 predicted edges were independently validated by literature findings post network inference. The selected GO term ‘cartilage development’ contained a number of differentiation markers, growth factors, and transcription factors with potential relevance for RA. Finally, the model provided new insight into the response of RA-SFBs to multiple stimuli implicated in the pathogenesis of RA, in particular to the ‘novel’ potent growth factor PDGF-D

Microbial Cell Factories / Monitoring the Dynamics of Transcription and Translation Within the Time Course of Recombinant E. coli Cultivations

Oral presentation from The 4th Recombinant Protein Production Meeting: a comparative view on host physiology, Barcelona, Spain. 21\u201323 September 200

Exploring the Interior: Essays on Literary and Cultural History

In this fascinating collection of essays Harvard Emeritus Professor Karl S. Guthke examines the ways in which, for European scholars and writers of the eighteenth and early nineteenth century, world-wide geographical exploration led to an exploration of the self. Guthke explains how in the age of Enlightenment and beyond intellectual developments were fuelled by excitement about what Ulrich Im Hof called "the grand opening-up of the wide world”, especially of the interior of the non-European continents. This outward turn was complemented by a fascination with "the world within” as anthropology and ethnology focused on the humanity of the indigenous populations of far-away lands – an interest in human nature that suggested a way for Europeans to understand themselves, encapsulated in Gauguin’s Tahitian rumination "What are we?” The essays in the first half of the book discuss first- or second-hand, physical or mental encounters with the exotic lands and populations beyond the supposed cradle of civilisation. The works of literature and documents of cultural life featured in these essays bear testimony to the crossing not only of geographical, ethnological, and cultural borders but also of borders of a variety of intellectual activities and interests. The second section examines the growing interest in astronomy and the engagement with imagined worlds in the universe, again with a view to understanding homo sapiens, as compared now to the extra-terrestrials that were confidently assumed to exist. The final group of essays focuses on the exploration of the landscape of what was called "the universe within”; featuring, among a variety of other texts, Schiller’s plays The Maid of Orleans and William Tell, these essays observe and analyse what Erich Heller termed "The Artist’s Journey into the Interior.” This collection, which travels from the interior of continents to the interior of the mind, is itself a set of explorations that revel in the discovery of what was half-hidden in language. Written by a scholar of international repute, it is eye-opening reading for all those with an interest in the literary and cultural history of (and since) the Enlightenment

Exploring the Interior

"In this fascinating collection of essays Harvard Emeritus Professor Karl S. Guthke examines the ways in which, for European scholars and writers of the eighteenth and early nineteenth century, world-wide geographical exploration led to an exploration of the self. Guthke explains how in the age of Enlightenment and beyond intellectual developments were fuelled by excitement about what Ulrich Im Hof called ""the grand opening-up of the wide world”, especially of the interior of the non-European continents. This outward turn was complemented by a fascination with ""the world within” as anthropology and ethnology focused on the humanity of the indigenous populations of far-away lands – an interest in human nature that suggested a way for Europeans to understand themselves, encapsulated in Gauguin’s Tahitian rumination ""What are we?” The essays in the first half of the book discuss first- or second-hand, physical or mental encounters with the exotic lands and populations beyond the supposed cradle of civilisation. The works of literature and documents of cultural life featured in these essays bear testimony to the crossing not only of geographical, ethnological, and cultural borders but also of borders of a variety of intellectual activities and interests. The second section examines the growing interest in astronomy and the engagement with imagined worlds in the universe, again with a view to understanding homo sapiens, as compared now to the extra-terrestrials that were confidently assumed to exist. The final group of essays focuses on the exploration of the landscape of what was called ""the universe within”; featuring, among a variety of other texts, Schiller’s plays The Maid of Orleans and William Tell, these essays observe and analyse what Erich Heller termed ""The Artist’s Journey into the Interior.” This collection, which travels from the interior of continents to the interior of the mind, is itself a set of explorations that revel in the discovery of what was half-hidden in language. Written by a scholar of international repute, it is eye-opening reading for all those with an interest in the literary and cultural history of (and since) the Enlightenment.

Beyond static assessment of children's receptive vocabulary: the dynamic assessment of word learning (DAWL)

Background: Children's low scores on vocabulary tests are often erroneously interpreted as reflecting poor cognitive and/or language skills. It may be necessary to incorporate the measurement of word-learning ability in estimating children's lexical abilities. Aims: To explore the reliability and validity of the Dynamic Assessment of Word Learning (DAWL), a new dynamic assessment of receptive vocabulary. Methods & Procedures: A dynamic assessment (DA) of word learning ability was developed and adopted within a nursery school setting with 15 children aged between 3;07 and 4;03, ten of whom had been referred to speech and language therapy. Outcomes & Results: A number of quantitative measures were derived from the DA procedure, including measures of children's ability to identify the targeted items and to generalize to a second exemplar, as well as measures of children's ability to retain the targeted items. Internal, inter-rater and test–retest reliability of the DAWL was established as well as correlational measures of concurrent and predictive validity. Conclusions & Implications: The DAWL was found to provide both quantitative and qualitative information which could be used to improve the accuracy of differential diagnosis and the understanding of processes underlying the child's performance. The latter can be used for the purpose of designing more individualized interventions

Dynamic Assessment of Narrative Competence

In Developmental Education, language plays an essential role as a tool for communication (and thinking). Learning to produce coherent messages (“narratives”) with both cultural and personal value in the context of meaningful socio-cultural practices is considered as an important goal of Developmental Education. Narratives are essential for human action as they function as a tool for giving meaning to reality. Therefore, close observation and assessment of children’s narratives is essential in the context of Developmental Education. Over the past years we have developed a Dynamic Assessment (DA) instrument for assessing children’s narrative competence. This instrument combines two common approaches to DA, namely standardised interventionist DA and interactionist DA. With the help of this instrument, teachers are able to gain insight into children’s actual narrative competence as well as their developmental potential and their receptivity to certain forms of assistance to reach this potential. Our experience up to now shows that it is possible to assess children’s narrative competence in a valid and reliable manner

Integrative analysis of the heat shock response in Aspergillus fumigatus

<p>Abstract</p> <p>Background</p> <p><it>Aspergillus fumigatus </it>is a thermotolerant human-pathogenic mold and the most common cause of invasive aspergillosis (IA) in immunocompromised patients. Its predominance is based on several factors most of which are still unknown. The thermotolerance of <it>A. fumigatus </it>is one of the traits which have been assigned to pathogenicity. It allows the fungus to grow at temperatures up to and above that of a fevered human host. To elucidate the mechanisms of heat resistance, we analyzed the change of the <it>A. fumigatus </it>proteome during a temperature shift from 30°C to 48°C by 2D-fluorescence difference gel electrophoresis (DIGE). To improve 2D gel image analysis results, protein spot quantitation was optimized by missing value imputation and normalization. Differentially regulated proteins were compared to previously published transcriptome data of <it>A. fumigatus</it>. The study was augmented by bioinformatical analysis of transcription factor binding sites (TFBSs) in the promoter region of genes whose corresponding proteins were differentially regulated upon heat shock.</p> <p>Results</p> <p>91 differentially regulated protein spots, representing 64 different proteins, were identified by mass spectrometry (MS). They showed a continuous up-, down- or an oscillating regulation. Many of the identified proteins were involved in protein folding (chaperones), oxidative stress response, signal transduction, transcription, translation, carbohydrate and nitrogen metabolism. A correlation between alteration of transcript levels and corresponding proteins was detected for half of the differentially regulated proteins. Interestingly, some previously undescribed putative targets for the heat shock regulator Hsf1 were identified. This provides evidence for Hsf1-dependent regulation of mannitol biosynthesis, translation, cytoskeletal dynamics and cell division in <it>A. fumigatus</it>. Furthermore, computational analysis of promoters revealed putative binding sites for an AP-2alpha-like transcription factor upstream of some heat shock induced genes. Until now, this factor has only been found in vertebrates.</p> <p>Conclusions</p> <p>Our newly established DIGE data analysis workflow yields improved data quality and is widely applicable for other DIGE datasets. Our findings suggest that the heat shock response in <it>A. fumigatus </it>differs from already well-studied yeasts and other filamentous fungi.</p