CONET: copy number event tree model of evolutionary tumor history for single-cell data.

Copy number alterations constitute important phenomena in tumor evolution. Whole genome single-cell sequencing gives insight into copy number profiles of individual cells, but is highly noisy. Here, we propose CONET, a probabilistic model for joint inference of the evolutionary tree on copy number events and copy number calling.

RosettaSX: Reliable gene expression signature scoring of cancer models and patients.

Gene expression signatures have proven their potential to characterize important cancer phenomena like oncogenic signaling pathway activities, cellular origins of tumors, or immune cell infiltration into tumor tissues. Large collections of expression signatures provide the basis for their application to data sets, but the applicability of each signature in a new experimental context must be reassessed. We apply a methodology that utilizes the previously developed concept of coherent expression of genes in signatures to identify translatable signatures before scoring their activity in single tumors.

Feature selection strategies for drug sensitivity prediction.

Drug sensitivity prediction constitutes one of the main challenges in personalized medicine. Critically, the sensitivity of cancer cells to treatment depends on an unknown subset of a large number of biological features. Here, we compare standard, data-driven feature selection approaches to feature selection driven by prior knowledge of drug targets, target pathways, and gene expression signatures.

Genetic Interactions and Tissue Specificity Modulate the Association of Mutations with Drug Response.

In oncology, biomarkers are widely used to predict subgroups of patients that respond to a given drug. Although clinical decisions often rely on single gene biomarkers, machine learning approaches tend to generate complex multi-gene biomarkers that are hard to interpret. Models predicting drug response based on multiple altered genes often assume that the effects of single alterations are independent.

Expressional analysis of disease-relevant signalling-pathways in primary tumours and metastasis of head and neck cancers.

Head and neck squamous cell carcinoma (HNSCC) often metastasize to lymph nodes resulting in poor prognosis for patients. Unfortunately, the underlying molecular mechanisms contributing to tumour aggressiveness, recurrences, and metastasis are still not fully understood. However, such knowledge is key to identify biomarkers and drug targets to improve prognosis and treatments.

Dissolution and dissolution/permeation experiments for predicting systemic exposure following oral administration of the BCS class II drug clarithromycin.

In order to save time and resources in early drug development, in vitro methods that correctly predict the formulation effect on oral drug absorption are necessary. The aim of this study was to 1) evaluate various BCS class II drug formulations with in vitro methods and in vivo in order to 2) determine which in vitro method best correlates with the in vivo results. Clarithromycin served as model compound in formulations with different particle sizes and content of excipients.

Comparison of HapMap and 1000 Genomes Reference Panels in a Large-Scale Genome-Wide Association Study.

An increasing number of genome-wide association (GWA) studies are now using the higher resolution 1000 Genomes Project reference panel (1000G) for imputation, with the expectation that 1000G imputation will lead to the discovery of additional associated loci when compared to HapMap imputation. In order to assess the improvement of 1000G over HapMap imputation in identifying associated loci, we compared the results of GWA studies of circulating fibrinogen based on the two reference panels. Using both HapMap and 1000G imputation we performed a meta-analysis of 22 studies comprising the same 91,953 individuals.

Optimization of the Ussing chamber setup with excised rat intestinal segments for dissolution/permeation experiments of poorly soluble drugs.

Context: Prediction of the in vivo absorption of poorly soluble drugs may require simultaneous dissolution/permeation experiments. In vivo predictive media have been modified for permeation experiments with Caco-2 cells, but not for excised rat intestinal segments.

Objective: The present study aimed at improving the setup of dissolution/permeation experiments with excised rat intestinal segments by assessing suitable donor and receiver media.

Meta-analysis of gene-environment-wide association scans accounting for education level identifies additional loci for refractive error.

Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry.

Kinome Profiling of Regulatory T Cells: A Closer Look into a Complex Intracellular Network.

Regulatory T cells (Treg) are essential for T cell homeostasis and maintenance of peripheral tolerance. They prevent activation of auto-reactive T effector cells (Teff) in the context of autoimmunity and allergy. Otherwise, Treg also inhibit effective immune responses against tumors.

Gene expression patterns underlying parasite-induced alterations in host behaviour and life history.

Many parasites manipulate their hosts' phenotype. In particular, parasites with complex life cycles take control of their intermediate hosts' behaviour and life history to increase transmission to their definitive host. The proximate mechanisms underlying these parasite-induced alterations are poorly understood.

A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration.

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels.

Systemic PaO2 Oscillations Cause Mild Brain Injury in a Pig Model.

Objective: Systemic PaO2 oscillations occur during cyclic recruitment and derecruitment of atelectasis in acute respiratory failure and might harm brain tissue integrity.

Design: Controlled animal study.

Setting: University research laboratory.

Systematically evaluating interfaces for RNA-seq analysis from a life scientist perspective.

RNA-sequencing (RNA-seq) has become an established way for measuring gene expression in model organisms and humans. While methods development for refining the corresponding data processing and analysis pipeline is ongoing, protocols for typical steps have been proposed and are widely used. Several user interfaces have been developed for making such analysis steps accessible to life scientists without extensive knowledge of command line tools.

Distribution, genetic and cardiovascular determinants of FVIII:c - Data from the population-based Gutenberg Health Study.

Background: Elevated levels of

Fviii: c are associated with risk for both venous and arterial thromboembolism. However, no population-based study on the sex-specific distribution and reference ranges of plasma

Fviii: c and its cardiovascular determinants is available.

Fviii: c was analyzed in a randomly selected sample of 2533 males and 2440 females from the Gutenberg Health Study in Germany.

A systems level analysis reveals transcriptomic and proteomic complexity in Ixodes ricinus midgut and salivary glands during early attachment and feeding.

Although pathogens are usually transmitted within the first 24-48 h of attachment of the castor bean tick Ixodes ricinus, little is known about the tick's biological responses at these earliest phases of attachment. Tick midgut and salivary glands are the main tissues involved in tick blood feeding and pathogen transmission but the limited genomic information for I. ricinus delays the application of high-throughput methods to study their physiology.

Dynamic oscillation of translation and stress granule formation mark the cellular response to virus infection.

Virus infection-induced global protein synthesis suppression is linked to assembly of stress granules (SGs), cytosolic aggregates of stalled translation preinitiation complexes. To study long-term stress responses, we developed an imaging approach for extended observation and analysis of SG dynamics during persistent hepatitis C virus (HCV) infection. In combination with type 1 interferon, HCV infection induces highly dynamic assembly/disassembly of cytoplasmic SGs, concomitant with phases of active and stalled translation, delayed cell division, and prolonged cell survival.

Identification of type I and type II interferon-induced effectors controlling hepatitis C virus replication.

Unlabelled: Persistent infection with hepatitis C virus (HCV) can lead to chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. All current therapies of hepatitis C include interferon-alpha (IFN-α). Moreover, IFN-gamma (IFN-γ), the only type II IFN, strongly inhibits HCV replication in vitro and is the primary mediator of HCV-specific antiviral T-cell responses.

Reconstructing nonlinear dynamic models of gene regulation using stochastic sampling.

Background: The reconstruction of gene regulatory networks from time series gene expression data is one of the most difficult problems in systems biology. This is due to several reasons, among them the combinatorial explosion of possible network topologies, limited information content of the experimental data with high levels of noise, and the complexity of gene regulation at the transcriptional, translational and post-translational levels. At the same time, quantitative, dynamic models, ideally with probability distributions over model topologies and parameters, are highly desirable.