A Regularized Graph Layout Framework for Dynamic Network Visualization

Many real-world networks, including social and information networks, are dynamic structures that evolve over time. Such dynamic networks are typically visualized using a sequence of static graph layouts. In addition to providing a visual representation of the network structure at each time step, the sequence should preserve the mental map between layouts of consecutive time steps to allow a human to interpret the temporal evolution of the network. In this paper, we propose a framework for dynamic network visualization in the on-line setting where only present and past graph snapshots are available to create the present layout. The proposed framework creates regularized graph layouts by augmenting the cost function of a static graph layout algorithm with a grouping penalty, which discourages nodes from deviating too far from other nodes belonging to the same group, and a temporal penalty, which discourages large node movements between consecutive time steps. The penalties increase the stability of the layout sequence, thus preserving the mental map. We introduce two dynamic layout algorithms within the proposed framework, namely dynamic multidimensional scaling (DMDS) and dynamic graph Laplacian layout (DGLL). We apply these algorithms on several data sets to illustrate the importance of both grouping and temporal regularization for producing interpretable visualizations of dynamic networks.Comment: To appear in Data Mining and Knowledge Discovery, supporting material (animations and MATLAB toolbox) available at http://tbayes.eecs.umich.edu/xukevin/visualization_dmkd_201

Virtual pathway explorer (viPEr) and pathway enrichment analysis tool (PEANuT): creating and analyzing focus networks to identify cross-talk between molecules and pathways

BACKGROUND: Interpreting large-scale studies from microarrays or next-generation sequencing for further experimental testing remains one of the major challenges in quantitative biology. Combining expression with physical or genetic interaction data has already been successfully applied to enhance knowledge from all types of high-throughput studies. Yet, toolboxes for navigating and understanding even small gene or protein networks are poorly developed. RESULTS: We introduce two Cytoscape plug-ins, which support the generation and interpretation of experiment-based interaction networks. The virtual pathway explorer viPEr creates so-called focus networks by joining a list of experimentally determined genes with the interactome of a specific organism. viPEr calculates all paths between two or more user-selected nodes, or explores the neighborhood of a single selected node. Numerical values from expression studies assigned to the nodes serve to score identified paths. The pathway enrichment analysis tool PEANuT annotates networks with pathway information from various sources and calculates enriched pathways between a focus and a background network. Using time series expression data of atorvastatin treated primary hepatocytes from six patients, we demonstrate the handling and applicability of viPEr and PEANuT. Based on our investigations using viPEr and PEANuT, we suggest a role of the FoxA1/A2/A3 transcriptional network in the cellular response to atorvastatin treatment. Moreover, we find an enrichment of metabolic and cancer pathways in the Fox transcriptional network and demonstrate a patient-specific reaction to the drug. CONCLUSIONS: The Cytoscape plug-in viPEr integrates –omics data with interactome data. It supports the interpretation and navigation of large-scale datasets by creating focus networks, facilitating mechanistic predictions from –omics studies. PEANuT provides an up-front method to identify underlying biological principles by calculating enriched pathways in focus networks. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12864-015-2017-z) contains supplementary material, which is available to authorized users

Targeting of EGFR by a combination of antibodies mediates unconventional EGFR trafficking and degradation

Antibody combinations targeting cell surface receptors are a new modality of cancer therapy. The trafficking and signalling mechanisms regulated by such therapeutics are not fully understood but could underlie differential tumour responses. We explored EGFR trafficking upon treatment with the antibody combination Sym004 which has shown promise clinically. Sym004 promoted EGFR endocytosis distinctly from EGF: it was asynchronous, not accompanied by canonical signalling events and involved EGFR clustering within detergent-insoluble plasma mebrane-associated tubules. Sym004 induced lysosomal degradation independently of EGFR ubiquitylation but dependent upon Hrs/Tsg101 that are required for the formation of intraluminal vesicles (ILVs) within late endosomes. We propose Sym004 cross-links EGFR physically triggering EGFR endocytosis and incorporation onto ILVs and so Sym004 sensitivity correlates with EGFR numbers available for binding, rather than specific signalling events. Consistently Sym004 efficacy and potentiation of cisplatin responses correlated with EGFR surface expression in head and neck cancer cells. These findings will have implications in understanding the mode of action of this new class of cancer therapeutics

A nanoscale investigation of Carlin-type gold deposits: an atom-scale elemental and isotopic perspective

Carlin-type gold deposits are one of the most important gold mineralization styles in the world. Despite their economic importance and the large volume of work that has been published, there remain crucial questions regarding their metallogenesis. Much of this uncertainty is due to the cryptic nature of the gold occurrence, with gold occurring as dispersed nanoscale inclusions within host pyrite rims that formed on earlier formed barren pyrite cores. The small size of the gold inclusions has made determining their nature within the host sulfides and the mechanisms by which they precipitated from the ore fluids particularly problematic. This study combines high-resolution electron probe microanalysis (EPMA) with atom probe tomography (APT) to constrain whether the gold occurs as nanospheres or is dispersed within the Carlin pyrites. APT offers the unique capability of obtaining major, minor, trace, and isotopic chemical information at near-atomic spatial resolution. We use this capability to investigate the atomic-scale distribution of trace elements within Carlin-type pyrite rims, as well as the relative differences of sulfur isotopes within the rim and core of gold-hosting pyrite.Funding from the United Kingdom Engineering and Physical Sciences Research Council (EPSRC) under grants EP/K029770/1 and EP/M022803/1, as well as from the United Kingdom Environmental Research Council (NERC) under grant NE/K009540/

A nanoscale investigation of Carlin-type gold deposits: an atom-scale elemental and isotopic perspective

Carlin-type gold deposits are one of the most important gold mineralization styles in the world. Despite their economic importance and the large volume of work that has been published, there remain crucial questions regarding their metallogenesis. Much of this uncertainty is due to the cryptic nature of the gold occurrence, with gold occurring as dispersed nanoscale inclusions within host pyrite rims that formed on earlier formed barren pyrite cores. The small size of the gold inclusions has made determining their nature within the host sulfides and the mechanisms by which they precipitated from the ore fluids particularly problematic. This study combines high-resolution electron probe microanalysis (EPMA) with atom probe tomography (APT) to constrain whether the gold occurs as nanospheres or is dispersed within the Carlin pyrites. APT offers the unique capability of obtaining major, minor, trace, and isotopic chemical information at near-atomic spatial resolution. We use this capability to investigate the atomic-scale distribution of trace elements within Carlintype pyrite rims, as well as the relative differences of sulfur isotopes within the rim and core of gold-hosting pyrite. We show that gold within a sample from the Turquoise Ridge deposit (Nevada) occurs within arsenian pyrite overgrowth (rims) that formed on a pyrite core. Furthermore, this As-rich rim does not contain nanonuggets of gold and instead contains dispersed lattice-bound Au within the pyrite crystal structure. The spatial correlation of gold and arsenic within our samples is consistent with increased local arsenic concentrations that enhanced the ability of arsenian pyrite to host dispersed gold (Kusebauch et al., 2019). We hypothesize that point defects in the lattice induced by the addition of arsenic to the pyrite structure facilitate the dissemination of gold. The lack of gold nanospheres in our study is consistent with previous work showing that dispersed gold in arsenian pyrite can occur in concentrations up to ~1:200 (gold/arsenic). We also report a method for determining the sulfur isotope ratios from atom probe data sets of pyrite (±As) that illustrates a relative change between the pyrite core and its Au and arsenian pyrite rim. This spatial variation confirms that the observed pyrite core-rim structure is due to two-stage growth involving a sedimentary core and hydrothermal rim, as opposed to precipitation from an evolving hydrothermal fluid

A nanoscale investigation of Carlin-type gold deposits: an atom-scale elemental and isotopic perspective

Carlin-type gold deposits are one of the most important gold mineralization styles in the world. Despite their economic importance and the large volume of work that has been published, there remain crucial questions regarding their metallogenesis. Much of this uncertainty is due to the cryptic nature of the gold occurrence, with gold occurring as dispersed nanoscale inclusions within host pyrite rims that formed on earlier formed barren pyrite cores. The small size of the gold inclusions has made determining their nature within the host sulfides and the mechanisms by which they precipitated from the ore fluids particularly problematic. This study combines high-resolution electron probe microanalysis (EPMA) with atom probe tomography (APT) to constrain whether the gold occurs as nanospheres or is dispersed within the Carlin pyrites. APT offers the unique capability of obtaining major, minor, trace, and isotopic chemical information at near-atomic spatial resolution. We use this capability to investigate the atomic-scale distribution of trace elements within Carlintype pyrite rims, as well as the relative differences of sulfur isotopes within the rim and core of gold-hosting pyrite. We show that gold within a sample from the Turquoise Ridge deposit (Nevada) occurs within arsenian pyrite overgrowth (rims) that formed on a pyrite core. Furthermore, this As-rich rim does not contain nanonuggets of gold and instead contains dispersed lattice-bound Au within the pyrite crystal structure. The spatial correlation of gold and arsenic within our samples is consistent with increased local arsenic concentrations that enhanced the ability of arsenian pyrite to host dispersed gold (Kusebauch et al., 2019). We hypothesize that point defects in the lattice induced by the addition of arsenic to the pyrite structure facilitate the dissemination of gold. The lack of gold nanospheres in our study is consistent with previous work showing that dispersed gold in arsenian pyrite can occur in concentrations up to ~1:200 (gold/arsenic). We also report a method for determining the sulfur isotope ratios from atom probe data sets of pyrite (±As) that illustrates a relative change between the pyrite core and its Au and arsenian pyrite rim. This spatial variation confirms that the observed pyrite core-rim structure is due to two-stage growth involving a sedimentary core and hydrothermal rim, as opposed to precipitation from an evolving hydrothermal fluid