EndoNet: an information resource about regulatory networks of cell-to-cell communication†

EndoNet is an information resource about intercellular regulatory communication. It provides information about hormones, hormone receptors, the sources (i.e. cells, tissues and organs) where the hormones are synthesized and secreted, and where the respective receptors are expressed. The database focuses on the regulatory relations between them. An elementary communication is displayed as a causal link from a cell that secretes a particular hormone to those cells which express the corresponding hormone receptor and respond to the hormone. Whenever expression, synthesis and/or secretion of another hormone are part of this response, it renders the corresponding cell an internal node of the resulting network. This intercellular communication network coordinates the function of different organs. Therefore, the database covers the hierarchy of cellular organization of tissues and organs as it has been modeled in the Cytomer ontology, which has now been directly embedded into EndoNet. The user can query the database; the results can be used to visualize the intercellular information flow. A newly implemented hormone classification enables to browse the database and may be used as alternative entry point. EndoNet is accessible at: http://endonet.bioinf.med.uni-goettingen.de

Integration of gene expression data with prior knowledge for network analysis and validation

<p>Abstract</p> <p>Background</p> <p>Reconstruction of protein-protein interaction or metabolic networks based on expression data often involves in silico predictions, while on the other hand, there are unspecific networks of in vivo interactions derived from knowledge bases.</p> <p>We analyze networks designed to come as close as possible to data measured in vivo, both with respect to the set of nodes which were taken to be expressed in experiment as well as with respect to the interactions between them which were taken from manually curated databases</p> <p>Results</p> <p>A signaling network derived from the TRANSPATH database and a metabolic network derived from KEGG LIGAND are each filtered onto expression data from breast cancer (SAGE) considering different levels of restrictiveness in edge and vertex selection.</p> <p>We perform several validation steps, in particular we define pathway over-representation tests based on refined null models to recover functional modules. The prominent role of the spindle checkpoint-related pathways in breast cancer is exhibited. High-ranking key nodes cluster in functional groups retrieved from literature. Results are consistent between several functional and topological analyses and between signaling and metabolic aspects.</p> <p>Conclusions</p> <p>This construction involved as a crucial step the passage to a mammalian protein identifier format as well as to a reaction-based semantics of metabolism. This yielded good connectivity but also led to the need to perform benchmark tests to exclude loss of essential information. Such validation, albeit tedious due to limitations of existing methods, turned out to be informative, and in particular provided biological insights as well as information on the degrees of coherence of the networks despite fragmentation of experimental data.</p> <p>Key node analysis exploited the networks for potentially interesting proteins in view of drug target prediction.</p

The pairwise disconnectivity index as a new metric for the topological analysis of regulatory networks

<p>Abstract</p> <p>Background</p> <p>Currently, there is a gap between purely theoretical studies of the topology of large bioregulatory networks and the practical traditions and interests of experimentalists. While the theoretical approaches emphasize the global characterization of regulatory systems, the practical approaches focus on the role of distinct molecules and genes in regulation. To bridge the gap between these opposite approaches, one needs to combine 'general' with 'particular' properties and translate abstract topological features of large systems into testable functional characteristics of individual components. Here, we propose a new topological parameter – the pairwise disconnectivity index of a network's element – that is capable of such bridging.</p> <p>Results</p> <p>The pairwise disconnectivity index quantifies how crucial an individual element is for sustaining the communication ability between connected pairs of vertices in a network that is displayed as a directed graph. Such an element might be a vertex (i.e., molecules, genes), an edge (i.e., reactions, interactions), as well as a group of vertices and/or edges. The index can be viewed as a measure of topological redundancy of regulatory paths which connect different parts of a given network and as a measure of sensitivity (robustness) of this network to the presence (absence) of each individual element. Accordingly, we introduce the notion of a path-degree of a vertex in terms of its corresponding incoming, outgoing and mediated paths, respectively. The pairwise disconnectivity index has been applied to the analysis of several regulatory networks from various organisms. The importance of an individual vertex or edge for the coherence of the network is determined by the particular position of the given element in the whole network.</p> <p>Conclusion</p> <p>Our approach enables to evaluate the effect of removing each element (i.e., vertex, edge, or their combinations) from a network. The greatest potential value of this approach is its ability to systematically analyze the role of every element, as well as groups of elements, in a regulatory network.</p

Nature of alkali-carbonate fluids in the sub-continental lithospheric mantle

Mantle xenoliths sampled by kimberlite and alkali basalt magmas show a range of metasomatic styles, but direct evidence for the nature of the metasomatising fl uids is often elusive. It has been suggested that carbonate-rich melts produced by partial melting of carbonated peridotites and eclogites play an important role in modifying the composition of the lithospheric mantle. These mantle-derived carbonate melts are often inferred to be enriched in alkali elements; however, alkali-rich carbonate fl uids have only been reported as micro-inclusions in diamonds and as unique melts involved in the formation of the Udachnaya-East kimberlite (Yakutia, Russia). In this paper we present the fi rst direct evidence for alkali-carbonate melts in the shallow lithospheric mantle (~110-115 km), above the diamond stability fi eld. These alkali-carbonate melts are preserved in primary multiphase inclusions hosted by large metasomatic ilmenite grains contained in a polymict mantle xenolith from the Bultfontein kimberlite (Kimberley, South Africa). The inclusions host abundant carbonates (magnesite, dolomite, and K-Na-Ca carbonates), kalsilite, phlogopite, K-Na titanates, and phosphates, with lesser amounts of olivine, chlorides, and alkali sulfates. Textural and chemical observations indicate that the alkali-carbonate melt likely derived from primary or precursor kimberlite magmas. Our fi ndings extend the evidence for alkali-carbonate melts/fl uids permeating the Earth mantle outside the diamond stability fi eld and provide new insights into the chemical features of previously hypothesized melts. As metasomatism by alkali-rich carbonate melts is often reported to affect mantle xenoliths, and predicted from experimental studies, the fl uid type documented here likely represent a major metasomatising agent in the Earth's lithospheric mantle

Evidence for an intrabasinal source and multiple concentration processes in the formation of the carbon leader reef, Witwatersrand Supergroup, South Africa

Laser ablation-inductively coupled plasma-mass spectrometer (LA-ICP-MS) trace element maps of pyrite and gold from the Carbon Leader Reef in the Witwatersrand basin provide new evidence that a significant proportion of the pyrite and gold was intrabasinal, derived from the West Rand Group or equivalent shales stratigraphically below this reef. Rounded detrital pyrite grains in the Carbon Leader Reef vary from compact to porous to sooty, with similar textures and composition to diagenetic pyrites reported from sedimentary rocks in the West Rand Group. Detrital porous and sooty pyrites contain 0.4 to 11.3 ppm solid-solution gold, sulfur isotope δ34S values from −17 to +16%, and high levels of As and Te, plus a wide range of other trace elements (in decreasing order: Ni, Co, Sb, Cr, Cu, U, Pb, Bi, Mo, Zn and Ag). The sooty pyrite is the most Au, Te, and Mo rich and is intergrown with alumino-silicates and organic matter. The detrital pyrite textures, S-isotopes and geochemistry resemble diagenetic pyrite developed under suboxic to anoxic bottom water conditions. The LA-ICP-MS maps also show that the detrital pyrite grains have euhedral hydrothermal pyrite overgrowths containing micro-inclusions of gold, brannerite, and Ni-As sulfides. The pyrite overgrowths are also enriched in solid-solution gold, tellurium, and other trace elements including, in decreasing order, As, Co, Ni, Cr, Cu, Mn, Pb, Bi, and Ag. Fractured and brecciated pyrite associated with brittle bedding-parallel fracture zones in the Carbon Leader Reef are also enriched in these elements due to alteration of pyrite surrounding the fractures. Laser ICP-MS Pb isotope determinations on the cores of detrital pyrite indicate an age between 2750 and 2950 Ma with hydrothermal overgrowths originating between 2100 and 2020 Ma incorporating highly radiogenic Pb. This study demonstrates that both of the two competing theories for the origin of the Witwatersrand gold reefs are likely to be correct. We suggest that the hydrothermal event was widespread (kilometer scale) and involved basinal fluids that scavenged gold, tellurium, arsenic, and trace elements (Co, Ni, Cr, Cu, Mn, Pb, Bi, Ag) from gold-bearing sedimentary units in the Central Rand Group.GeoRef Subject: clastic rocks conglomerate Africa lead mineral deposits, genesis Pb-207/Pb-204 Pb-207/Pb-206 metasomatism gold ores isotope ratios isotopes Witwatersrand Witwatersrand Supergroup metal ores metals Pb-206/Pb-204 sedimentary rocks S-34/S-32 sulfur Precambrian pyrite radioactive isotopes South Africa Southern Africa sulfides stable isotopes.Ross R. Large, Sebastien Meffre, Rob Burnett, Bradley Guy, Stuart Bull, Sarah Gilbert ... et al

Novel Methods to Manipulate Autolysis in Sparkling Wine: Effects on Yeast

Sparkling wine made by the traditional method (Méthode Traditionelle) develops a distinct and desirable flavour and aroma profile attributed to proteolytic processes during prolonged ageing on lees. Microwave, ultrasound and addition of β-glucanase enzymes were applied to accelerate the disruption of Saccharomyces cerevisiae, and added to the tirage solution for secondary fermentation in traditional sparkling winemaking. Scanning electron microscopy and flow cytometry analyses were used to observe and describe yeast whole-cell anatomy, and cell integrity and structure via propidium iodide (PI) permeability after 6-, 12- and 18-months post-tirage. Treatments applied produced features on lees that were distinct from that of the untreated control yeast. Whilst control yeast displayed budding cells (growth features) with smooth, cavitated and flat external cell appearances; microwave treated yeast cells exhibited modifications like ‘doughnut’ shapes immediately after treatment (time 0). Similar ‘doughnut’-shaped and ‘pitted/porous’ cell features were observed on progressively older lees from the control. Flow cytometry was used to discriminate yeast populations; features consistent with cell disruption were observed in the microwave, ultrasound and enzyme treatments, as evidenced by up to 4-fold increase in PI signal in the microwave treatment. Forward and side scatter signals reflected changes in size and structure of yeast cells, in all treatments applied. When flow cytometry was interpreted alongside the scanning electron microscopy images, bimodal populations of yeast cells with low and high PI intensities were revealed and distinctive ‘doughnut’-shaped cell features observed in association with the microwave treatment only at tirage, that were not observed until 12 months wine ageing in older lees from the control. This work offers both a rapid approach to visualise alterations to yeast cell surfaces and a better understanding of the mechanisms of yeast lysis. Microwave, ultrasound or β-glucanase enzymes are tools that could potentially initiate the release of yeast cell compounds into wine. Further investigation into the impact of such treatments on the flavour and aroma profiles of the wines through sensory evaluation is warranted

Induction of Immunity to Prostate Cancer Antigens: Results of a Clinical Trial of Vaccination with Irradiated Autologous Prostate Tumor Cells engineered to Secrete Granulocyte-Macrophage Colony-Stimulating Factor Using ex vivo Gene Transfer.

Vaccination with irradiated granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting gene-transduced cancer vaccines induces tumoricidal immune responses. In a Phase I human gene therapy trial, eight immunocompetent prostate cancer (PCA) patients were treated with autologous, GM-CSF-secreting, irradiated tumor vaccines prepared from ex vivo retroviral transduction of surgically harvested cells. Expansion of primary cultures of autologous vaccine cells was successful to meet trial specifications in 8 of 11 cases (73%); the yields of the primary culture cell limited the number of courses of vaccination. Side effects were pruritus, erythema, and swelling at vaccination sites. Vaccine site biopsies manifested infiltrates of dendritic cells and macrophages among prostate tumor vaccine cells. Vaccination activated new T-cell and B-cell immune responses against PCA antigens. T-cell responses, evaluated by assessing delayed-type hypersensitivity (DTH) reactions against untransduced autologous tumor cells, were evident in two of eight patients before vaccination and in seven of eight patients after treatment. Reactive DTH site biopsies manifested infiltrates of effector cells consisting of CD45RO+ T-cells, and degranulating eosinophils consistent with activation of both Th1 and Th2 T-cell responses. A distinctive eosinophilic vasculitis was evident near autologous tumor cells at vaccine sites, and at DTH sites. B-cell responses were also induced. Sera from three of eight vaccinated men contained new antibodies recognizing polypeptides of 26, 31, and 150 kDa in protein extracts from prostate cells. The 150-kDa polypeptide was expressed by LNCaP and PC-3 PCA cells, as well as by normal prostate epithelial cells, but not by prostate stromal cells. No antibodies against prostate-specific antigen were detected. These data suggest that both T-cell and B-cell immune responses to human PCA can be generated by treatment with irradiated, GM-CSF gene-transduced PCA vaccines