Activator-blocker model of transcriptional regulation by pioneer-like factors.

Zygotic genome activation (ZGA) in the development of flies, fish, frogs and mammals depends on pioneer-like transcription factors (TFs). Those TFs create open chromatin regions, promote histone acetylation on enhancers, and activate transcription. Here, we use the panel of single, double and triple mutants for zebrafish genome activators Pou5f3, Sox19b and Nanog, multi-omics and mathematical modeling to investigate the combinatorial mechanisms of genome activation.

Pluripotency factors determine gene expression repertoire at zygotic genome activation.

Awakening of zygotic transcription in animal embryos relies on maternal pioneer transcription factors. The interplay of global and specific functions of these proteins remains poorly understood. Here, we analyze chromatin accessibility and time-resolved transcription in single and double mutant zebrafish embryos lacking pluripotency factors Pou5f3 and Sox19b.

Extensions of ℓ regularization increase detection specificity for cell-type specific parameters in dynamic models.

Background: Ordinary differential equation systems are frequently utilized to model biological systems and to infer knowledge about underlying properties. For instance, the development of drugs requires the knowledge to which extent malign cells differ from healthy ones to provide a specific treatment with least side effects. As these cell-type specific properties may stem from any part of biochemical cell processes, systematic quantitative approaches are necessary to identify the relevant potential drug targets.

Benchmark problems for dynamic modeling of intracellular processes.

Motivation: Dynamic models are used in systems biology to study and understand cellular processes like gene regulation or signal transduction. Frequently, ordinary differential equation (ODE) models are used to model the time and dose dependency of the abundances of molecular compounds as well as interactions and translocations. A multitude of computational approaches, e.

Mathematical model of early Reelin-induced Src family kinase-mediated signaling.

Reelin is a large glycoprotein with a dual role in the mammalian brain. It regulates the positioning and differentiation of postmitotic neurons during brain development and modulates neurotransmission and memory formation in the adult brain. Alterations in the Reelin signaling pathway have been described in different psychiatric disorders.

Predicting ligand-dependent tumors from multi-dimensional signaling features.

Targeted therapies have shown significant patient benefit in about 5-10% of solid tumors that are addicted to a single oncogene. Here, we explore the idea of ligand addiction as a driver of tumor growth. High ligand levels in tumors have been shown to be associated with impaired patient survival, but targeted therapies have not yet shown great benefit in unselected patient populations.

Quantification of oxygen metabolic rates in Human brain with dynamic O MRI: Profile likelihood analysis.

Purpose: Parameter identifiability and confidence intervals were determined using a profile likelihood (PL) analysis method in a quantification model of the cerebral metabolic rate of oxygen consumption (CMRO ) with direct O MRI.

Methods: Three-dimensional dynamic O MRI datasets of the human brain were acquired after inhalation of O gas with the help of a rebreathing system, and CMRO was quantified with a pharmacokinetic model. To analyze the influence of the different model parameters on the identifiability of CMRO , PLs were calculated for different settings of the model parameters.

Driving the Model to Its Limit: Profile Likelihood Based Model Reduction.

In systems biology, one of the major tasks is to tailor model complexity to information content of the data. A useful model should describe the data and produce well-determined parameter estimates and predictions. Too small of a model will not be able to describe the data whereas a model which is too large tends to overfit measurement errors and does not provide precise predictions.

Identification of Cell Type-Specific Differences in Erythropoietin Receptor Signaling in Primary Erythroid and Lung Cancer Cells.

Lung cancer, with its most prevalent form non-small-cell lung carcinoma (NSCLC), is one of the leading causes of cancer-related deaths worldwide, and is commonly treated with chemotherapeutic drugs such as cisplatin. Lung cancer patients frequently suffer from chemotherapy-induced anemia, which can be treated with erythropoietin (EPO). However, studies have indicated that EPO not only promotes erythropoiesis in hematopoietic cells, but may also enhance survival of NSCLC cells.