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The epicardium and its derivatives provide trophic and structural support for the developing and adult heart. Here we tested the ability of human embryonic stem cell (hESC)-derived epicardium to augment the structure and function of engineered heart tissue in vitro and to improve efficacy of hESC-cardiomyocyte grafts in infarcted athymic rat hearts. Epicardial cells markedly enhanced the contractility, myofibril structure and calcium handling of human engineered heart tissues, while reducing passive stiffness compared with mesenchymal stromal cells. Transplanted epicardial cells formed persistent fibroblast grafts in infarcted hearts. Cotransplantation of hESC-derived epicardial cells and cardiomyocytes doubled graft cardiomyocyte proliferation rates in vivo, resulting in 2.6-fold greater cardiac graft size and simultaneously augmenting graft and host vascularization. Notably, cotransplantation improved systolic function compared with hearts receiving either cardiomyocytes alone, epicardial cells alone or vehicle. The ability of epicardial cells to enhance cardiac graft size and function makes them a promising adjuvant therapeutic for cardiac repair. Cell therapy in a rat model of heart attack is enhanced by stem-cell-derived epicardium. [ABSTRACT FROM AUTHOR]

Post-transcriptional regulation of cellular mRNA is essential for protein synthesis. Here we describe the importance of mRNA translational repression and mRNA subcellular location for protein expression during B lymphocyte activation and the DNA damage response. Cytoplasmic RNA granules are formed upon cell activation with mitogens, including stress granules that contain the RNA binding protein Tia1. Tia1 binds to a subset of transcripts involved in cell stress, including p53 mRNA, and controls translational silencing and RNA granule localization. DNA damage promotes mRNA relocation and translation in part due to dissociation of Tia1 from its mRNA targets. Upon DNA damage, p53 mRNA is released from stress granules and associates with polyribosomes to increase protein synthesis in a CAPindependent manner. Global analysis of cellular mRNA abundance and translation indicates that this is an extended ATM-dependent mechanism to increase protein expression of key modulators of the DNA damage response. [ABSTRACT FROM AUTHOR]

Behaviours of complex biomolecular systems are often irreducible to the elementary properties of their individual components. Explanatory and predictive mathematical models are therefore useful for fully understanding and precisely engineering cellular functions. The development and analyses of these models require their adaptation to the problems that need to be solved and the type and amount of available genetic or molecular data. Quantitative and logic modelling are among the main methods currently used to model molecular and gene networks. Each approach comes with inherent advantages and weaknesses. Recent developments show that hybrid approaches will become essential for further progress in synthetic biology and in the development of virtual organisms. [ABSTRACT FROM AUTHOR]

Genomic data allow the large-scale manual or semi-automated assembly of metabolic network reconstructions, which provide highly curated organism-specific knowledge bases. Although several genome-scale network reconstructions describe Saccharomyces cerevisiae metabolism, they differ in scope and content, and use different terminologies to describe the same chemical entities. This makes comparisons between them difficult and underscores the desirability of a consolidated metabolic network that collects and formalizes the 'community knowledge' of yeast metabolism. We describe how we have produced a consensus metabolic network reconstruction for S. cerevisiae. In drafting it, we placed special emphasis on referencing molecules to persistent databases or using database-independent forms, such as SMILES or InChI strings, as this permits their chemical structure to be represented unambiguously and in a manner that permits automated reasoning. The reconstruction is readily available via a publicly accessible database and in the Systems Biology Markup Language (http://www.comp-sys-bio.org/yeastnet). It can be maintained as a resource that serves as a common denominator for studying the systems biology of yeast. Similar strategies should benefit communities studying genome-scale metabolic networks of other organisms. [ABSTRACT FROM AUTHOR]

Coliform bacteria detect chemical attractants by means of a membrane-associated cluster of receptors and signalling molecules. We have used recently determined molecular structures, in conjunction with plastic models generated by three-dimensional printer technology, to predict how the proteins of the complex are arranged in relation to the plasma membrane. The proposed structure is a regular two-dimensional lattice in which the cytoplasmic ends of chemotactic-receptor dimers are inserted into a hexagonal array of CheA and CheW molecules. This structure creates separate compartments for adaptation and downstream signalling, and indicates a possible basis for the spread of activity within the cluster. [ABSTRACT FROM AUTHOR]

Neurulation is a complex process of histogenesis involving the precise temporal and spatial organization of gene expression. Genes influencing neurulation include proneural genes determining primary cell fate, neurogenic genes involved in lateral inhibition pathways and genes controlling the frequency of mitotic events. This is reflected in the aetiology and genetics of human and mouse neural tube defects, which are of both multifactorial and multigenic origin. The X-linked gene Nap1/2, specifically expressed in neurons, encodes a protein that is highly similar to the nucleosome assembly (NAP) and SET proteins. We inactivated Nap1l2 in mice by gene targeting, leading to embryonic lethality from mid-gestation onwards. Surviving mutant chimaeric embryos showed extensive surface ectoderm defects as well as the presence of open neural tubes and exposed brains similar to those observed in human spina bifida and anencephaly. These defects correlated with an overproduction of neuronal precursor cells. Protein expression studies showed that the Nap1/2 protein binds to condensing chromatin during S phase and in apoptotic cells, but remained cytoplasmic during G1 phase. Nap1/2 therefore likely represents a class of tissue-specific factors interacting with chromatin to regulate neuronal cell proliferation. [ABSTRACT FROM AUTHOR]

Presents research which showed that the alpha-4 nAChR subunit is crucial for nicotine-elicited antinociception. How nicotine exerts antinociceptive effects; Methods used to identify the subunits involved in these effects in mice; Traits of homozygous alpha-4 mice; Use of the hot-plate test and the tail-flick test; Patch-clamp recordings.

The development of computational approaches in systems biology has reached a state of maturity that allows their transition to systems medicine. Despite this progress, intuitive visualisation and context-dependent knowledge representation still present a major bottleneck. In this paper, we describe the Disease Maps Project, an effort towards a community-driven computationally readable comprehensive representation of disease mechanisms. We outline the key principles and the framework required for the success of this initiative, including use of best practices, standards and protocols. We apply a modular approach to ensure efficient sharing and reuse of resources for projects dedicated to specific diseases. Community-wide use of disease maps will accelerate the conduct of biomedical research and lead to new disease ontologies defined from mechanism-based disease endotypes rather than phenotypes. [ABSTRACT FROM AUTHOR]

A correction to the article "The Systems Biology Graphical Notation" in the August 7, 2009 issue that was published online is presented.