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See detailModelling gender-specific regulation of tau in Alzheimer’s disease
Glaab, Enrico UL

Presentation (2016)

Public transcriptomic studies have shown that several genes display pronounced gender differences in their expression in the human brain, which may influence the manifestations and risk for neuronal ... [more ▼]

Public transcriptomic studies have shown that several genes display pronounced gender differences in their expression in the human brain, which may influence the manifestations and risk for neuronal disorders. Here, we apply a transcriptome-wide analysis to discover genes with gender-specific expression and significant alterations in public postmortem brain tissue from Alzheimer’s disease (AD) patients compared to controls. We identify the sex-linked ubiquitin-specific peptidase 9 (USP9) as an outstanding candidate gene with highly significant expression differences between the genders and male-specific underexpression in AD. Since previous studies have shown that USP9 can modulate the phosphorylation of the AD-associated protein MAPT, we investigate functional associations between USP9 and MAPT in further detail. After observing a high positive correlation between the expression of USP9 and MAPT in the public transcriptomics data, we show that USP9 knockdown results in significantly decreased MAPT expression in a DU145 cell culture model and a concentration-dependent decrease for the MAPT orthologs mapta and maptb in a zebrafish model. From the analysis of microarray and qRT-PCR experiments for the knockdown in DU145 cells and prior knowledge from the literature, we derive a data-congruent model for a USP9-dependent regulatory mechanism modulating MAPT expression via BACH1 and SMAD4. Overall, the analyses suggest USP9 may contribute to molecular gender differences observed in tauopathies and provide a new target for intervention strategies to modulate MAPT expression. [less ▲]

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See detailToward Omics-Based, Systems Biomedicine, and Path and Drug Discovery Methodologies for Depression-Inflammation Research
Maes; Nowak, Gabriel; Caso, Javier et al

in Molecular Neurobiology (2016), 53(5), 2927-2935

Meta-analyses confirm that depression is accompanied by signs of inflammation including increased levels of acute phase proteins, e.g., C-reactive protein, and pro-inflammatory cytokines, e.g ... [more ▼]

Meta-analyses confirm that depression is accompanied by signs of inflammation including increased levels of acute phase proteins, e.g., C-reactive protein, and pro-inflammatory cytokines, e.g., interleukin-6. Supporting the translational significance of this, a meta-analysis showed that anti-inflammatory drugs may have antidepressant effects. Here, we argue that inflammation and depression research needs to get onto a new track. Firstly, the choice of inflammatory biomarkers in depression research was often too selective and did not consider the broader pathways. Secondly, although mild inflammatory responses are present in depression, other immune-related pathways cannot be disregarded as new drug targets, e.g., activation of cell-mediated immunity, oxidative and nitrosative stress (O&NS) pathways, autoimmune responses, bacterial translocation, and activation of the toll-like receptor and neuroprogressive pathways. Thirdly, anti-inflammatory treatments are sometimes used without full understanding of their effects on the broader pathways underpinning depression. Since many of the activated immune-inflammatory pathways in depression actually confer protection against an overzealous inflammatory response, targeting these pathways may result in unpredictable and unwanted results. Furthermore, this paper discusses the required improvements in research strategy, i.e., path and drug discovery processes, omics-based techniques, and systems biomedicine methodologies. Firstly, novel methods should be employed to examine the intracellular networks that control and modulate the immune, O&NS and neuroprogressive pathways using omics-based assays, including genomics, transcriptomics, proteomics, metabolomics, epigenomics, immunoproteomics and metagenomics. Secondly, systems biomedicine analyses are essential to unravel the complex interactions between these cellular networks, pathways, and the multifactorial trigger factors and to delineate new drug targets in the cellular networks or pathways. Drug discovery processes should delineate new drugs targeting the intracellular networks and immune-related pathways. [less ▲]

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See detailExploring therapeutic viability of a non-dopaminergic target for Parkinson’s disease
Ashrafi, Amer; Buttini, Manuel UL; Garcia, Pierre UL et al

in Movement Disorders (2016), 31(2), 630

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See detailTranscriptomic analyses of primary astrocytes under TNFα treatment
Birck, Cindy UL; Koncina, Eric UL; Heurtaux, Tony UL et al

in Genomics Data (2015), 7

Astrocytes, the most abundant glial cell population in the central nervous system, have important functional roles in the brain as blood brain barrier maintenance, synaptic transmission or intercellular ... [more ▼]

Astrocytes, the most abundant glial cell population in the central nervous system, have important functional roles in the brain as blood brain barrier maintenance, synaptic transmission or intercellular communications. Numerous studies suggested that astrocytes exhibit a functional and morphological high degree of plasticity. For example, following any brain injury, astrocytes become reactive and hypertrophic. This phenomenon, also called reactive gliosis, is characterized by a set of progressive gene expression and cellular changes. Interestingly, in this context, astrocytes can re-acquire neurogenic properties. It has been shown that astrocytes can undergo dedifferentiation upon injury and inflammation, and may re-acquire the potentiality of neural progenitors. To assess the effect of inflammation on astrocytes, primary mouse astrocytes were treated with tumor necrosis factor α (TNFα), one of the main pro-inflammatory cytokines. The strength of this study is that pure primary astrocytes were used. As microglia are highly reactive immune cells, we used a magnetic cell sorting separation (MACS) method to further obtain highly pure astrocyte cultures devoid of microglia. Here, we provide details of the microarray data, which have been deposited in the Gene Expression Omnibus (GEO) under the series accession number GSE73022. The analysis and interpretation of these data are included in Gabel et al. (2015). Analysis of gene expression indicated that the NFκB pathway-associated genes were induced after a TNFα treatment. We have shown that primary astrocytes devoid of microglia can respond to a TNFα treatment with the re-expression of genes implicated in the glial cell development. [less ▲]

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See detailInflammation Promotes a Conversion of Astrocytes into Neural Progenitor Cells via NF-κB Activation
Gabel, Sebastien; Koncina, Eric UL; Dorban, Gauthier et al

in Molecular Neurobiology (2015), 53(8), 5041-5055

Brain inflammation, a common feature in neurodegenerative diseases, is a complex series of events, which can be detrimental and even lead to neuronal death. Nonetheless, several studies suggest that ... [more ▼]

Brain inflammation, a common feature in neurodegenerative diseases, is a complex series of events, which can be detrimental and even lead to neuronal death. Nonetheless, several studies suggest that inflammatory signals are also positively influencing neural cell proliferation, survival, migration, and differentiation. Recently, correlative studies suggested that astrocytes are able to dedifferentiate upon injury and may thereby re-acquire neural stem cell (NSC) potential. However, the mechanism underlying this dedifferentiation process upon injury remains unclear. Here, we report that during the early response of reactive gliosis, inflammation induces a conversion of mature astrocytes into neural progenitors. A TNF treatment induces the decrease of specific astrocyte markers, such as glial fibrillary acidic protein (GFAP) or genes related to glycogen metabolism, while a subset of these cells re-expresses immaturity markers, such as CD44, Musashi-1, and Oct4. Thus, TNF treatment results in the appearance of cells that exhibit a neural progenitor phenotype and are able to proliferate and differentiate into neurons and/or astrocytes. This dedifferentiation process is maintained as long as TNF is present in the culture medium. In addition, we highlight a role for Oct4 in this process, since the TNF-induced dedifferentiation can be prevented by inhibiting Oct4 expression. Our results show that activation of the NF-κB pathway through TNF plays an important role in the dedifferentiation of astrocytes via the re-expression of Oct4. These findings indicate that the first step of reactive gliosis is in fact a dedifferentiation process of resident astrocytes mediated by the NF-κB pathway. [less ▲]

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See detailUsing prior knowledge from cellular pathways and molecular networks for diagnostic specimen classification
Glaab, Enrico UL

in Briefings in Bioinformatics (2015)

For many complex diseases, an earlier and more reliable diagnosis is considered a key prerequisite for developing more effective therapies to prevent or delay disease progression. Classical statistical ... [more ▼]

For many complex diseases, an earlier and more reliable diagnosis is considered a key prerequisite for developing more effective therapies to prevent or delay disease progression. Classical statistical learning approaches for specimen classification using omics data, however, often cannot provide diagnostic models with sufficient accuracy and robustness for heterogeneous diseases like cancers or neurodegenerative disorders. In recent years, new approaches for building multivariate biomarker models on omics data have been proposed, which exploit prior biological knowledge from molecular networks and cellular pathways to address these limitations. This survey provides an overview of these recent developments and compares pathway- and network-based specimen classification approaches in terms of their utility for improving model robustness, accuracy and biological interpretability. Different routes to translate omics-based multifactorial biomarker models into clinical diagnostic tests are discussed, and a previous study is presented as example. [less ▲]

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See detailBuilding a virtual ligand screening pipeline using free software: a survey
Glaab, Enrico UL

in Briefings in Bioinformatics (2015)

Virtual screening, the search for bioactive compounds via computational methods, provides a wide range of opportunities to speed up drug development and reduce the associated risks and costs. While ... [more ▼]

Virtual screening, the search for bioactive compounds via computational methods, provides a wide range of opportunities to speed up drug development and reduce the associated risks and costs. While virtual screening is already a standard practice in pharmaceutical companies, its applications in preclinical academic research still remain under-exploited, in spite of an increasing availability of dedicated free databases and software tools. In this survey, an overview of recent developments in this field is presented, focusing on free software and data repositories for screening as alternatives to their commercial counterparts, and outlining how available resources can be interlinked into a comprehensive virtual screening pipeline using typical academic computing facilities. Finally, to facilitate the set-up of corresponding pipelines, a downloadable software system is provided, using platform virtualization to integrate pre-installed screening tools and scripts for reproducible application across different operating systems. [less ▲]

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See detailShared alterations in the human brain transcriptome during adult aging and in Parkinson's disease
Glaab, Enrico UL; Schneider, Reinhard UL

Poster (2015, June 15)

Aging-related biomolecular changes in the human brain are thought to be associated with an increased risk for neurodegenerative diseases. In particular, aging and Parkinson’s disease (PD) share various ... [more ▼]

Aging-related biomolecular changes in the human brain are thought to be associated with an increased risk for neurodegenerative diseases. In particular, aging and Parkinson’s disease (PD) share various molecular hallmarks, including a gradual decline in dopamine synthesis and increased levels of deleted mitochondrial DNA. While some specific mechanistic links between brain aging and PD have been proposed and investigated previously, systematic analyses of shared molecular alterations at a genome-scale level are required to obtain a better understanding of the affected cellular processes and their interrelations. We present a joint analysis of high-throughput brain transcriptomics data from PD patients and unaffected individuals from different adult age groups using a statistical meta-analysis and a recently published pathway and network analysis approach. Our analyses provide statistical evidence for specific functional associations between molecular network changes in PD and aging, identify new significant joint pathway deregulations and suggest mechanistic explanations for the observed age-dependence of PD risk. [less ▲]

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See detailComparative pathway and network analysis of brain transcriptome changes during adult aging and in Parkinson's disease
Glaab, Enrico UL; Schneider, Reinhard UL

in Neurobiology of Disease (2015), 74

Aging is considered as one of the main factors promoting the risk for Parkinson's disease (PD) and common mechanisms of dopamine neuron degeneration in aging and PD have been proposed in recent years ... [more ▼]

Aging is considered as one of the main factors promoting the risk for Parkinson's disease (PD) and common mechanisms of dopamine neuron degeneration in aging and PD have been proposed in recent years. Here, we use a statistical meta-analysis of human brain transcriptomics data to investigate potential mechanistic relationships between adult brain aging and PD pathogenesis at the pathway and network level. The analyses identify statistically significant shared pathway and network alterations in aging and PD and an enrichment in PD-associated sequence variants from genome-wide association studies among the jointly deregulated genes. We find robust discriminative patterns for groups of functionally related genes with potential applications as combined risk biomarkers to detect aging- and PD-linked oxidative stress, e.g. a consistent over-expression of metallothioneins matching with findings in previous independent studies. Interestingly, analyzing the regulatory network and mouse knockout expression data for the transcription factor NR4A2, previously associated with rare mutations in PD and here found as the most significantly under-expressed gene in PD among the jointly altered genes, suggests that aging-related NR4A2 expression changes may increase PD risk by producing downstream effects similar to disease-linked mutations and to expression changes observed in sporadic PD. Overall, the analyses suggest mechanistic explanations for the age-dependence of PD risk, reveal significant and robust shared process alterations in aging and PD, and examine their potential for biomarker applications in pre-symptomatic risk assessment or early-stage diagnosis. [less ▲]

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See detailRepExplore: Addressing technical replicate variance in proteomics and metabolomics data analysis
Glaab, Enrico UL; Schneider, Reinhard UL

in Bioinformatics (2015), 31(13), 2235

High-throughput omics datasets often contain technical replicates, included to account for technical sources of noise in the measurement process. Although summarizing these replicate measurements by using ... [more ▼]

High-throughput omics datasets often contain technical replicates, included to account for technical sources of noise in the measurement process. Although summarizing these replicate measurements by using robust averages may help to reduce the influence of noise on downstream data analysis, the information on the variance across the replicate measurements is lost in the averaging process and therefore typically disregarded in subsequent statistical analyses. We introduce RepExplore, a web-service dedicated to exploit the information captured in the technical replicate variance to provide more reliable and informative differential expression and abundance statistics for omics datasets. The software builds on previously published statistical methods, which have been applied successfully to biomedical omics data but are difficult to use without prior experience in programming or scripting. RepExplore facilitates the analysis by providing a fully automated data processing and interactive ran- king tables, whisker plot, heat map and principal component analysis visualizations to interpret omics data and derived statistics. [less ▲]

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See detailInference of longevity-related genes from a robust co-expression network of seed maturation identifies new regulators linking seed storability to biotic defense-related pathways
Righetti, Karima; Vu, Joseph Ly; Pelletier, Sandra et al

in Plant Cell (2015), 27(10), 2692-2708

Seed longevity, the maintenance of viability during storage is a crucial factor to preserve genetic resources and to ensure proper seedling establishment and high crop yield. A systems biology approach ... [more ▼]

Seed longevity, the maintenance of viability during storage is a crucial factor to preserve genetic resources and to ensure proper seedling establishment and high crop yield. A systems biology approach was used to identify key genes regulating the acquisition of longevity during seed maturation of Medicago truncatula. Using 104 transcriptomes of seed developmental time courses obtained under five growth environments, a robust, stable co-expression network (MatNet) was generated, thereby capturing the conserved backbone of maturation. Using a trait-based gene significance measure, a co-expression module related to the acquisition of longevity was inferred from MatNet. Comparative analysis between maturation processes in Medicago and A. thaliana seeds and mining Arabidopsis interaction databases revealed conserved connectivity for 87% of longevity module nodes between both species. Arabidopsis mutant screening for longevity and maturation phenotypes demonstrated high predictive power of the longevity cross-species network. Overrepresentation analysis of the network nodes indicated biological functions related to defense, light and auxin. Characterization of defense-related wrky3 and nfxl1 mutants demonstrated that these genes regulate part of the network nodes and exhibit impaired longevity acquisition during maturation. These data suggest that seed longevity evolved by co-opting existing genetic pathways regulating activation of defense against pathogens. [less ▲]

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See detailThe Mouse Brain Metabolome: Region-Specific Signatures and Response to Excitotoxic Neuronal Injury
Jäger, Christian UL; Glaab, Enrico UL; Michelucci, Alessandro UL et al

in American Journal of Pathology (2015), 185(6), 1699-1712

Neurodegeneration is a multistep process characterized by a multitude of molecular entities and their interactions. Systems' analyses, or omics approaches, have become an important tool in characterizing ... [more ▼]

Neurodegeneration is a multistep process characterized by a multitude of molecular entities and their interactions. Systems' analyses, or omics approaches, have become an important tool in characterizing this process. Although RNA and protein profiling made their entry into this field a couple of decades ago, metabolite profiling is a more recent addition. The metabolome represents a large part or all metabolites in a tissue, and gives a snapshot of its physiology. By using gas chromatography coupled to mass spectrometry, we analyzed the metabolic profile of brain regions of the mouse, and found that each region is characterized by its own metabolic signature. We then analyzed the metabolic profile of the mouse brain after excitotoxic injury, a mechanism of neurodegeneration implicated in numerous neurological diseases. More important, we validated our findings by measuring, histologically and molecularly, actual neurodegeneration and glial response. We found that a specific global metabolic signature, best revealed by machine learning algorithms, rather than individual metabolites, was the most robust correlate of neuronal injury and the accompanying gliosis, and this signature could serve as a global biomarker for neurodegeneration. We also observed that brain lesioning induced several metabolites with neuroprotective properties. Our results deepen the understanding of metabolic changes accompanying neurodegeneration in disease models, and could help rapidly evaluate these changes in preclinical drug studies. [less ▲]

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See detailGenePEN: analysis of network activity alterations in complex diseases via the pairwise elastic net
Vlassis, Nikos UL; Glaab, Enrico UL

in Statistical Applications in Genetics and Molecular Biology (2015), 14(2), 221-224

Complex diseases are often characterized by coordinated expression alterations of genes and proteins which are grouped together in a molecular network. Identifying such interconnected and jointly altered ... [more ▼]

Complex diseases are often characterized by coordinated expression alterations of genes and proteins which are grouped together in a molecular network. Identifying such interconnected and jointly altered gene/protein groups from functional omics data and a given molecular interaction network is a key challenge in bioinformatics. <br />We describe GenePEN, a penalized logistic regression approach for sample classification via convex optimization, using a newly designed Pairwise Elastic Net penalty that favors the selection of discriminative genes/proteins according to their connectedness in a molecular interaction graph. An efficient implementation of the method finds provably optimal solutions on high-dimensional omics data in a few seconds and is freely available at http://lcsb-portal.uni.lu/bioinformatics.Complex diseases are often characterized by coordinated expression alterations of genes and proteins which are grouped together in a molecular network. Identifying such interconnected and jointly altered gene/protein groups from functional omics data and a given molecular interaction network is a key challenge in bioinformatics. <br />We describe GenePEN, a penalized logistic regression approach for sample classification via convex optimization, using a newly designed Pairwise Elastic Net penalty that favors the selection of discriminative genes/proteins according to their connectedness in a molecular interaction graph. An efficient implementation of the method finds provably optimal solutions on high-dimensional omics data in a few seconds and is freely available at http://lcsb-portal.uni.lu/bioinformatics. [less ▲]

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See detailDynamic modelling of ROS management and ROS-induced mitophagy
Kolodkin, Alexey UL; Ignatenko, Andrew UL; Sangar, Vineet et al

Poster (2014, June)

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See detailAddressing Technical Replicate Variance in Omics Data Analysis
Glaab, Enrico UL; Schneider, Reinhard UL

Poster (2014)

High-throughput omics datasets often contain technical replicates, included to account for technical sources of noise in the measurement process. Although summarizing these replicate measurements by using ... [more ▼]

High-throughput omics datasets often contain technical replicates, included to account for technical sources of noise in the measurement process. Although summarizing these replicate measurements by using robust averages may help to reduce the influence of noise on downstream data analysis, the information on the variance across the replicate measurements is lost in the averaging process and therefore typically disregarded in subsequent statistical analyses. We introduce RepExplore, a web-service dedicated to exploit the information captured in the technical replicate variance to provide more reliable and informative differential expression and abundance statistics for omics datasets. The software builds on previously published statistical methods, which have been applied successfully to biomedical omics data but are difficult to use without prior experience in programming or scripting. RepExplore facilitates the analysis by providing a fully automated data processing and interactive ranking tables, whisker plot, heat map and principal component analysis visualizations to interpret omics data and derived statistics. The web-based software is freely available at http://www.repexplore.tk. [less ▲]

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See detailIntegrating Pathways of Parkinson's Disease in a Molecular Interaction Map
Fujita, Kazuhiro A.; Ostaszewski, Marek UL; Matsuoka, Yukiko et al

in Molecular Neurobiology (2014)

Parkinson's disease (PD) is a major neurodegenerative chronic disease, most likely caused by a complex interplay of genetic and environmental factors. Information on various aspects of PD pathogenesis is ... [more ▼]

Parkinson's disease (PD) is a major neurodegenerative chronic disease, most likely caused by a complex interplay of genetic and environmental factors. Information on various aspects of PD pathogenesis is rapidly increasing and needs to be efficiently organized, so that the resulting data is available for exploration and analysis. Here we introduce a computationally tractable, comprehensive molecular interaction map of PD. This map integrates pathways implicated in PD pathogenesis such as synaptic and mitochondrial dysfunction, impaired protein degradation, alpha-synuclein pathobiology and neuroinflammation. We also present bioinformatics tools for the analysis, enrichment and annotation of the map, allowing the research community to open new avenues in PD research. The PD map is accessible at http://minerva.uni.lu/pd_map . [less ▲]

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See detailThe Parkinson's Disease Map: A Framework for Integration, Curation and Exploration of Disease-related Pathways
Ostaszewski, Marek UL; Fujita, Kazuhiro; Matsuoka, Yukiko et al

Poster (2013, March 09)

Objectives: The pathogenesis of Parkinson's Disease (PD) is multi-factorial and age-related, implicating various genetic and environmental factors. It becomes increasingly important to develop new ... [more ▼]

Objectives: The pathogenesis of Parkinson's Disease (PD) is multi-factorial and age-related, implicating various genetic and environmental factors. It becomes increasingly important to develop new approaches to organize and explore the exploding knowledge of this field. Methods: The published knowledge on pathways implicated in PD, such as synaptic and mitochondrial dysfunction, alpha-synuclein pathobiology, failure of protein degradation systems and neuroinflammation has been organized and represented using CellDesigner. This repository has been linked to a framework of bioinformatics tools including text mining, database annotation, large-scale data integration and network analysis. The interface for online curation of the repository has been established using Payao tool. Results: We present the PD map, a computer-based knowledge repository, which includes molecular mechanisms of PD in a visually structured and standardized way. A bioinformatics framework that facilitates in-depth knowledge exploration, extraction and curation supports the map. We discuss the insights gained from PD map-driven text mining of a corpus of over 50 thousands full text PD-related papers, integration and visualization of gene expression in post mortem brain tissue of PD patients with the map, as well as results of network analysis. Conclusions: The knowledge repository of disease-related mechanisms provides a global insight into relationships between different pathways and allows considering a given pathology in a broad context. Enrichment with available text and bioinformatics databases as well as integration of experimental data supports better understanding of complex mechanisms of PD and formulation of novel research hypotheses. [less ▲]

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