Modeling system states in liver cells: survival, apoptosis and their modifications in response to viral infection.

Background: The decision pro- or contra apoptosis is complex, involves a number of different inputs, and is central for the homeostasis of an individual cell as well as for the maintenance and regeneration of the complete organism.

Results: This study centers on Fas ligand (FasL)-mediated apoptosis, and a complex and internally strongly linked network is assembled around the central FasL-mediated apoptosis cascade. Different bioinformatical techniques are employed and different crosstalk possibilities including the integrin pathway are considered.

Structural and kinetic determinants of protease substrates.

Two fundamental questions with regard to proteolytic networks and pathways concern the structural repertoire and kinetic threshold that distinguish legitimate signaling substrates. We used N-terminal proteomics to address these issues by identifying cleavage sites within the Escherichia coli proteome that are driven by the apoptotic signaling protease caspase-3 and the bacterial protease glutamyl endopeptidase (GluC). Defying the dogma that proteases cleave primarily in natively unstructured loops, we found that both caspase-3 and GluC cleave in alpha-helices nearly as frequently as in extended loops.

Inferring direct directed-information flow from multivariate nonlinear time series.

Estimating the functional topology of a network from multivariate observations is an important task in nonlinear dynamics. We introduce the nonparametric partial directed coherence that allows disentanglement of direct and indirect connections and their directions. We illustrate the performance of the nonparametric partial directed coherence by means of a simulation with data from synchronized nonlinear oscillators and apply it to real-world data from a patient suffering from essential tremor.

Time-variant estimation of directed influences during Parkinsonian tremor.

The inference of interaction structures in multidimensional time series is a major challenge not only in neuroscience but in many fields of research. To gather information about the connectivity in a network from measured data, several parametric as well as non-parametric approaches have been proposed and widely examined. Today a lot of interest is focused on the evolution of the network connectivity in time which might contain information about ongoing tasks in the brain or possible dynamic dysfunctions.

High functional connectivity of tremor related subthalamic neurons in Parkinson's disease.

Objective: Tremor is a core symptom of Parkinson's disease (PD). The subthalamic nucleus (STN) seems to be crucial for tremor pathophysiology considering that deep brain stimulation (DBS) of the STN leads to an effective reduction of Parkinsonian tremor. Here, we investigate the functional connectivity between STN neurons in patients with Parkinsonian tremor.

Hemostatic resuscitation during surgery improves survival in patients with traumatic-induced coagulopathy.

Background: Although hemostatic resuscitation with a 1:1 ratio of fresh-frozen plasma (FFP) to packed red blood cells (PRBC) after severe hemorrhage has been shown to improve survival, its benefit in patients with traumatic-induced coagulopathy (TIC) after >10 units of PRBC during operation has not been elucidated. We hypothesized that a survival benefit would occur when early hemostatic resuscitation was used intraoperatively after injury in patients with TIC.

Methods: A 7-year retrospective study of patients with emergency department diagnosis of TIC after transfusion of >10 units of PRBC in the operating room.

Estimation of gene induction enables a relevance-based ranking of gene sets.

In order to handle and interpret the vast amounts of data produced by microarray experiments, the analysis of sets of genes with a common biological functionality has been shown to be advantageous compared to single gene analyses. Some statistical methods have been proposed to analyse the differential gene expression of gene sets in microarray experiments. However, most of these methods either require threshhold values to be chosen for the analysis, or they need some reference set for the determination of significance.

Spleen tyrosine kinase is overexpressed and represents a potential therapeutic target in chronic lymphocytic leukemia.

B-cell receptor signaling contributes to apoptosis resistance in chronic lymphocytic leukemia (CLL), limiting the efficacy of current therapeutic approaches. In this study, we investigated the expression of spleen tyrosine kinase (SYK), a key component of the B-cell receptor signaling pathway, in CLL and its role in apoptosis. Gene expression profiling identified enhanced expression of SYK and downstream pathways in CLL compared with healthy B cells.

Signatures of gene expression noise in cellular systems.

Noise in gene expression, either due to inherent stochasticity or to varying inter- and intracellular environment, can generate significant cell-to-cell variability of protein levels in clonal populations. To quantify the different sources of gene expression noise, several theoretical studies have been performed using either a quasi-stationary approximation for the emerging master equation or employing a time-dependent description, when cell division is taken explicitly into account. Here, we give an overview of the different origins of gene expression noise which were found experimentally and introduce the basic stochastic modeling approaches.

Structural and practical identifiability analysis of partially observed dynamical models by exploiting the profile likelihood.

Motivation: Mathematical description of biological reaction networks by differential equations leads to large models whose parameters are calibrated in order to optimally explain experimental data. Often only parts of the model can be observed directly. Given a model that sufficiently describes the measured data, it is important to infer how well model parameters are determined by the amount and quality of experimental data.

Parametric versus nonparametric transfer function estimation of cerebral autoregulation from spontaneous blood-pressure oscillations.

Cerebral autoregulation (CAR) is a control mechanism of the brain keeping cerebral blood flow constant albeit the arterial blood pressure varies. Impaired CAR may be associated with an increased risk of cerebral ischemic events in patients with obstructive cerebrovascular disease. Spontaneous blood pressure oscillations are analyzed using a nonparametric and two parametric transfer function estimators, i.

Assessing the strength of directed influences among neural signals using renormalized partial directed coherence.

Partial directed coherence is a powerful tool used to analyze interdependencies in multivariate systems based on vector autoregressive modeling. This frequency domain measure for Granger-causality is designed such that it is normalized to [0,1]. This normalization induces several pitfalls for the interpretability of the ordinary partial directed coherence, which will be discussed in some detail in this paper.

Systems-level interactions between insulin-EGF networks amplify mitogenic signaling.

Crosstalk mechanisms have not been studied as thoroughly as individual signaling pathways. We exploit experimental and computational approaches to reveal how a concordant interplay between the insulin and epidermal growth factor (EGF) signaling networks can potentiate mitogenic signaling. In HEK293 cells, insulin is a poor activator of the Ras/ERK (extracellular signal-regulated kinase) cascade, yet it enhances ERK activation by low EGF doses.

Functional diversity of R3 single-repeat genes in trichome development.

Trichome and root hair patterning are governed by a conserved cassette of bHLH and MYB factors, the WD40 protein TTG1, and six single-repeat MYB R3 factors that are thought to counteract them. In this work we focus on the single-repeat R3 factor ETC3 and show that its major role is in the regulation of trichome density in a redundant manner. Diversification of the ETC3 gene has occurred at the promoter level, as etc3 mutants can be rescued by expressing ETC3 under the control of the TRY or CPC promoter.

Noisy signaling through promoter logic gates.

We study the influence of noisy transcription factor signals on cis-regulatory promoter elements. These elements process the probability of binary binding events analogous to computer logic gates. At equilibrium, this probability is given by the so-called input function.

Combination of immunosuppressive drugs leaves specific "fingerprint" on gene expression in vitro.

Following organ transplantation many patients suffer from drug-related side effects, or receive more immunosuppression than necessary to prevent rejection. Hence, parameters are needed to tailor the immunosuppressive therapy to the individual needs of an organ recipient. The aim of this study was to determine whether drug combinations provoke specific gene expression patterns in a simple assay system in vitro.

Systems biology: experimental design.

Experimental design has a long tradition in statistics, engineering and life sciences, dating back to the beginning of the last century when optimal designs for industrial and agricultural trials were considered. In cell biology, the use of mathematical modeling approaches raises new demands on experimental planning. A maximum informative investigation of the dynamic behavior of cellular systems is achieved by an optimal combination of stimulations and observations over time.

A longitudinal study of tremor frequencies in Parkinson's disease and essential tremor.

Objective: There is evidence that the tremor frequency in essential tremor (ET) decreases with time. Longitudinal studies on the evolution of tremor frequencies in Parkinson's disease (PD) have so far not been published. Here, we present a longitudinal analysis of tremor frequencies in PD and ET.

A novel approach for reliable microarray analysis of microdissected tumor cells from formalin-fixed and paraffin-embedded colorectal cancer resection specimens.

We present a novel approach for microarray analysis of RNA derived from microdissected cells of routinely formalin-fixed and paraffin-embedded (FFPE) cancer resection specimens. Subsequent to RNA sample preparation and hybridization to standard GeneChips (Affymetrix), RNA samples yielded 36.43 +/- 9.

Notochord-derived BMP antagonists inhibit endothelial cell generation and network formation.

Embryonic blood vessel formation is initially mediated through the sequential differentiation, migration, and assembly of endothelial cells (ECs). While many molecular signals that promote vascular development have been identified, little is known about suppressors of this process. In higher vertebrates, including birds and mammals, the vascular network forms throughout the embryonic disk with the exception of a region along the midline.

Streptolysin O promotes group A Streptococcus immune evasion by accelerated macrophage apoptosis.

Group A Streptococcus (GAS) is a leading human bacterial pathogen capable of producing invasive infections even in previously healthy individuals. As frontline components of host innate defense, macrophages play a key role in control and clearance of GAS infections. We find GAS induces rapid, dose-dependent apoptosis of primary and cultured macrophages and neutrophils.

A quantitative and dynamic model for plant stem cell regulation.

Plants maintain pools of totipotent stem cells throughout their entire life. These stem cells are embedded within specialized tissues called meristems, which form the growing points of the organism. The shoot apical meristem of the reference plant Arabidopsis thaliana is subdivided into several distinct domains, which execute diverse biological functions, such as tissue organization, cell-proliferation and differentiation.

Systems biology of JAK/STAT signalling.

Signalling in multicellular organisms is mediated by complex networks that integrate extracellular and intracellular signals to generate appropriate responses regulating cell proliferation, differentiation and survival. Downstream of many cytokine and growth hormone receptors, receptor-associated JAKs (Janus kinases) activate transcription factors of the STAT (signal transducer and activator of transcription) protein family and thereby mediate signal transduction from the plasma membrane to the nucleus. The JAK/STAT pathway has been shown to be constitutively activated in a wide array of human malignancies.

A competitive complex formation mechanism underlies trichome patterning on Arabidopsis leaves.

Trichome patterning in Arabidopsis serves as a model system for de novo pattern formation in plants. It is thought to typify the theoretical activator-inhibitor mechanism, although this hypothesis has never been challenged by a combined experimental and theoretical approach. By integrating the key genetic and molecular data of the trichome patterning system, we developed a new theoretical model that allows the direct testing of the effect of experimental interventions and in the prediction of patterning phenotypes.

Genome-wide analysis of genetic alterations in Barrett's adenocarcinoma using single nucleotide polymorphism arrays.

We performed genome-wide analysis of copy-number changes and loss of heterozygosity (LOH) in Barrett's esophageal adenocarcinoma by single nucleotide polymorphism (SNP) microarrays to identify associated genomic alterations. DNA from 27 esophageal adenocarcinomas and 14 matching normal tissues was subjected to SNP microarrays. The data were analyzed using dChipSNP software.