Pressing needs of biomedical text mining in biocuration and beyond: opportunities and challenges.

Text mining in the biomedical sciences is rapidly transitioning from small-scale evaluation to large-scale application. In this article, we argue that text-mining technologies have become essential tools in real-world biomedical research. We describe four large scale applications of text mining, as showcased during a recent panel discussion at the BioCreative V Challenge Workshop.

Training and evaluation corpora for the extraction of causal relationships encoded in biological expression language (BEL).

Success in extracting biological relationships is mainly dependent on the complexity of the task as well as the availability of high-quality training data. Here, we describe the new corpora in the systems biology modeling language BEL for training and testing biological relationship extraction systems that we prepared for the BioCreative V BEL track. BEL was designed to capture relationships not only between proteins or chemicals, but also complex events such as biological processes or disease states.

Reverse causal reasoning: applying qualitative causal knowledge to the interpretation of high-throughput data.

Background: Gene expression profiling and other genome-scale measurement technologies provide comprehensive information about molecular changes resulting from a chemical or genetic perturbation, or disease state. A critical challenge is the development of methods to interpret these large-scale data sets to identify specific biological mechanisms that can provide experimentally verifiable hypotheses and lead to the understanding of disease and drug action.

Results: We present a detailed description of Reverse Causal Reasoning (RCR), a reverse engineering methodology to infer mechanistic hypotheses from molecular profiling data.

Comparative transcriptional network modeling of three PPAR-α/γ co-agonists reveals distinct metabolic gene signatures in primary human hepatocytes.

Aims: To compare the molecular and biologic signatures of a balanced dual peroxisome proliferator-activated receptor (PPAR)-α/γ agonist, aleglitazar, with tesaglitazar (a dual PPAR-α/γ agonist) or a combination of pioglitazone (Pio; PPAR-γ agonist) and fenofibrate (Feno; PPAR-α agonist) in human hepatocytes.

Methods And Results: Gene expression microarray profiles were obtained from primary human hepatocytes treated with EC(50)-aligned low, medium and high concentrations of the three treatments. A systems biology approach, Causal Network Modeling, was used to model the data to infer upstream molecular mechanisms that may explain the observed changes in gene expression.

Early patient stratification and predictive biomarkers in drug discovery and development: a case study of ulcerative colitis anti-TNF therapy.

The current drug discovery paradigm is long, costly, and prone to failure. For projects in early development, lack of efficacy in Phase II is a major contributor to the overall failure rate. Efficacy failures often occur from one of two major reasons: either the investigational agent did not achieve the required pharmacology or the mechanism targeted by the investigational agent did not significantly contribute to the disease in the tested patient population.

A computable cellular stress network model for non-diseased pulmonary and cardiovascular tissue.

Background: Humans and other organisms are equipped with a set of responses that can prevent damage from exposure to a multitude of endogenous and environmental stressors. If these stress responses are overwhelmed, this can result in pathogenesis of diseases, which is reflected by an increased development of, e.g.

Construction of a computable cell proliferation network focused on non-diseased lung cells.

Background: Critical to advancing the systems-level evaluation of complex biological processes is the development of comprehensive networks and computational methods to apply to the analysis of systems biology data (transcriptomics, proteomics/phosphoproteomics, metabolomics, etc.). Ideally, these networks will be specifically designed to capture the normal, non-diseased biology of the tissue or cell types under investigation, and can be used with experimentally generated systems biology data to assess the biological impact of perturbations like xenobiotics and other cellular stresses.

A point mutation in the cargo-binding domain of myosin V affects its interaction with multiple cargoes.

Class V myosins move diverse intracellular cargoes, which attach via interaction of cargo-specific proteins to the myosin V globular tail. The globular tail of the yeast myosin V, Myo2p, contains two structural and functional subdomains. Subdomain I binds to the vacuole-specific protein, Vac17p, while subdomain II likely binds to an as yet unidentified secretory vesicle-specific protein.

Myosin V attachment to cargo requires the tight association of two functional subdomains.

The myosin V carboxyl-terminal globular tail domain is essential for the attachment of myosin V to all known cargoes. Previously, the globular tail was viewed as a single, functional entity. Here, we show that the globular tail of the yeast myosin Va homologue, Myo2p, contains two structural subdomains that have distinct functions, namely, vacuole-specific and secretory vesicle-specific movement.

Whole-genome analysis of two-component signal transduction genes in fungal pathogens.

Two-component phosphorelay systems are minimally comprised of a histidine kinase (HK) component, which autophosphorylates in response to an environmental stimulus, and a response regulator (RR) component, which transmits the signal, resulting in an output such as activation of transcription, or of a mitogen-activated protein kinase cascade. The genomes of the yeasts Saccharomyces cerevisiae, Schizosaccharomyces pombe, and Candida albicans encode one, three, and three HKs, respectively. In contrast, the genome sequences of the filamentous ascomycetes Neurospora crassa, Cochliobolus heterostrophus (Bipolaris maydis), Gibberella moniliformis (Fusarium verticillioides), and Botryotinia fuckeliana (Botrytis cinerea) encode an extensive family of two-component signaling proteins.

Identification of an organelle-specific myosin V receptor.

Class V myosins are widely distributed among diverse organisms and move cargo along actin filaments. Some myosin Vs move multiple types of cargo, where the timing of movement and the destinations of selected cargoes are unique. Here, we report the discovery of an organelle-specific myosin V receptor.

Regulated degradation of a class V myosin receptor directs movement of the yeast vacuole.

Normal cellular function requires that organelles be positioned in specific locations. The direction in which molecular motors move organelles is based in part on the polarity of microtubules and actin filaments. However, this alone does not determine the intracellular destination of organelles.