Systemic network analysis identifies XIAP and IkappaBalpha as potential drug targets in TRAIL resistant BRAF mutated melanoma.

in NPJ systems biology and applications (2018), 4

Metastatic melanoma remains a life-threatening disease because most tumors develop resistance to targeted kinase inhibitors thereby regaining tumorigenic capacity. We show the 2nd generation hexavalent ... [more ▼]

Metastatic melanoma remains a life-threatening disease because most tumors develop resistance to targeted kinase inhibitors thereby regaining tumorigenic capacity. We show the 2nd generation hexavalent TRAIL receptor-targeted agonist IZI1551 to induce pronounced apoptotic cell death in mutBRAF melanoma cells. Aiming to identify molecular changes that may confer IZI1551 resistance we combined Dynamic Bayesian Network modelling with a sophisticated regularization strategy resulting in sparse and context-sensitive networks and show the performance of this strategy in the detection of cell line-specific deregulations of a signalling network. Comparing IZI1551-sensitive to IZI1551-resistant melanoma cells the model accurately and correctly predicted activation of NFkappaB in concert with upregulation of the anti-apoptotic protein XIAP as the key mediator of IZI1551 resistance. Thus, the incorporation of multiple regularization functions in logical network optimization may provide a promising avenue to assess the effects of drug combinations and to identify responders to selected combination therapies. [less ▲]

Systemic Risk and the Solvency-Liquidity Nexus of Banks

in International Journal of Central Banking (2015), (40),

This paper highlights the empirical interaction between solvency and liquidity risks of banks that make them particularly vulnerable to an aggregate crisis. In line with the literature explaining bank ... [more ▼]

This paper highlights the empirical interaction between solvency and liquidity risks of banks that make them particularly vulnerable to an aggregate crisis. In line with the literature explaining bank runs based on the quality of the bank’s fundamentals, I find that banks lose their access to short-term funding when markets expect they will be insolvent in a crisis. This solvency-liquidity nexus is found to be strong under many robustness checks and to contain useful information for forecasting the short-term balance sheet of banks. The results suggest that capital not only acts as a loss-absorbing buffer, but it also ensures the confidence of creditors to continue to provide funding to the banks in a crisis. [less ▲]

A systemic transcriptome analysis reveals the regulation of neural stem cell maintenance by an E2F1-miRNA feedback loop.

in Nucleic Acids Research (2013), 41(6), 3699-712

Stem cell fate decisions are controlled by a molecular network in which transcription factors and miRNAs are of key importance. To systemically investigate their impact on neural stem cell (NSC ... [more ▼]

Stem cell fate decisions are controlled by a molecular network in which transcription factors and miRNAs are of key importance. To systemically investigate their impact on neural stem cell (NSC) maintenance and neuronal commitment, we performed a high-throughput mRNA and miRNA profiling and isolated functional interaction networks of involved mechanisms. Thereby, we identified an E2F1-miRNA feedback loop as important regulator of NSC fate decisions. Although E2F1 supports NSC proliferation and represses transcription of miRNAs from the miR-17 approximately 92 and miR-106a approximately 363 clusters, these miRNAs are transiently up-regulated at early stages of neuronal differentiation. In these early committed cells, increased miRNAs expression levels directly repress E2F1 mRNA levels and inhibit cellular proliferation. In mice, we demonstrated that these miRNAs are expressed in the neurogenic areas and that E2F1 inhibition represses NSC proliferation. The here presented data suggest a novel interaction mechanism between E2F1 and miR-17 approximately 92 / miR-106a approximately 363 miRNAs in controlling NSC proliferation and neuronal differentiation. [less ▲]

Systemisches und räumliches Denken in der geographischen Bildung. Erste Ergebnisse zur Überprüfung eines Modells der Geographischen Systemkompetenz

in Hüttermann, A.; Kirchner, P.; Schuler, S. (Eds.) et al Räumliche Orientierung: Räumliche Orientierung, Karten und Geoinformation im Unterricht (2012)

Systems analysis of transcription factor activities in environments with stable and dynamic oxygen concentrations

in Open Biology (2012), 2(7), 120091

Understanding gene regulation requires knowledge of changes in transcription factor (TF) activities. Simultaneous direct measurement of numerous TF activities is currently impossible. Nevertheless ... [more ▼]

Understanding gene regulation requires knowledge of changes in transcription factor (TF) activities. Simultaneous direct measurement of numerous TF activities is currently impossible. Nevertheless, statistical approaches to infer TF activities have yielded non-trivial and verifiable predictions for individual TFs. Here, global statistical modelling identifies changes in TF activities from transcript profiles of Escherichia coli growing in stable (fixed oxygen availabilities) and dynamic (changing oxygen availability) environments. A core oxygen-responsive TF network, supplemented by additional TFs acting under specific conditions, was identified. The activities of the cytoplasmic oxygen-responsive TF, FNR, and the membrane-bound terminal oxidases implied that, even on the scale of the bacterial cell, spatial effects significantly influence oxygen-sensing. Several transcripts exhibited asymmetrical patterns of abundance in aerobic to anaerobic and anaerobic to aerobic transitions. One of these transcripts, ndh, encodes a major component of the aerobic respiratory chain and is regulated by oxygen-responsive TFs ArcA and FNR. Kinetic modelling indicated that ArcA and FNR behaviour could not explain the ndh transcript profile, leading to the identification of another TF, PdhR, as the source of the asymmetry. Thus, this approach illustrates how systematic examination of regulatory responses in stable and dynamic environments yields new mechanistic insights into adaptive processes. [less ▲]

Systems approaches for transforming social practice: Design requirements

in König, Ariane (Ed.) Sustainability Science: Key issues (2018)

A systems biology approach to analyse leaf carbohydrate metabolism in Arabidopsis thaliana.

in EURASIP Journal on Bioinformatics and Systems Biology (2011), 2011(1), 2

Plant carbohydrate metabolism comprises numerous metabolite interconversions, some of which form cycles of metabolite degradation and re-synthesis and are thus referred to as futile cycles. In this study ... [more ▼]

Plant carbohydrate metabolism comprises numerous metabolite interconversions, some of which form cycles of metabolite degradation and re-synthesis and are thus referred to as futile cycles. In this study, we present a systems biology approach to analyse any possible regulatory principle that operates such futile cycles based on experimental data for sucrose (Scr) cycling in photosynthetically active leaves of the model plant Arabidopsis thaliana. Kinetic parameters of enzymatic steps in Scr cycling were identified by fitting model simulations to experimental data. A statistical analysis of the kinetic parameters and calculated flux rates allowed for estimation of the variability and supported the predictability of the model. A principal component analysis of the parameter results revealed the identifiability of the model parameters. We investigated the stability properties of Scr cycling and found that feedback inhibition of enzymes catalysing metabolite interconversions at different steps of the cycle have differential influence on stability. Applying this observation to futile cycling of Scr in leaf cells points to the enzyme hexokinase as an important regulator, while the step of Scr degradation by invertases appears subordinate. [less ▲]

A Systems biology approach to elucidate the contribution of alpha-synuclein to early in vitro phenotypes of Parkinson’s disease

Doctoral thesis (2020)

Although Parkinson's disease (PD was first described more than two hundred years ago, the clinical treatment options remain limited to symptom alleviation. Consequently, understanding the underlying ... [more ▼]

Although Parkinson's disease (PD was first described more than two hundred years ago, the clinical treatment options remain limited to symptom alleviation. Consequently, understanding the underlying molecular mechanisms is vital for the development of new therapeutic strategies. Most cases of PD are associated with toxic aggregations of the alpha-synuclein (α-syn) protein. However, the physiological and pathological mechanisms of α-syn aggregation are not entirely understood. One main reason for this knowledge gap is the lack of models that properly recapitulate the pathology in a human-midbrain-like context. Organoid models have emerged as an attractive model system that covers key aspects of in vivo tissue and organ complexity. Here, we present an optimized organoid protocol, which recapitulates features of the human midbrain. These human midbrain organoids (hMOs) present reduced levels of cell death in the core, while exhibiting reduced variability and increased viability. Their smaller size also allowed the implementation of a time-efficient image analysis technique. By using the protocol mentioned above, we generated hMOs from patient-derived induced pluripotent stem cells (iPSCs harboring a triplication of the SNCA gene (3xSNCA. 3xSNCAexhibited twice the levels of α-syn protein compared to wild type (WT) hMOs. Transcriptionalanalysis of 3xSNCA hMOs showed upregulation of PD- and SNCA-associated genes, as wellas transcriptional deregulations in neurogenesis, cell death, proliferation, and synapse formation. The analysis of cellular phenotypes in patient-specific hMOs supported these genetic observations. 3xSNCA hMOs presented reduced proliferation, cell death and reduced synapse count in mature organoids. Furthermore, 3xSNCA hMOs showed a reduced total number of neurons and impaired astrocytic differentiation. In addition, analysis of transcriptional and metabolomic data showed deregulation in metabolic pathways. To further analyze and explain our results, we used the latest human metabolic reconstruction (Recon3D) to generate an in silico model. The results presented here are a systematic analysis of patient-specific phenotypes in midbrain organoids from individuals with a triplication in the SNCA gene, which represent a starting point for further approaches to develop therapies. [less ▲]

A systems biology approach to studying the role of microbes in human health.

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 ▲]

Systems Biology Approaches for Identification of Molecular Mechanisms in Brain Disorders

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 ▲]