A Factor Graph Nested Effects Model To Identify Networks from Genetic Perturbations

Complex phenotypes such as the transformation of a normal population of cells into cancerous tissue result from a series of molecular triggers gone awry. We describe a method that searches for a genetic network consistent with expression changes observed under the knock-down of a set of genes that share a common role in the cell, such as a disease phenotype. The method extends the Nested Effects Model of Markowetz et al. (2005) by using a probabilistic factor graph to search for a network representing interactions among these silenced genes. The method also expands the network by attaching new genes at specific downstream points, providing candidates for subsequent perturbations to further characterize the pathway. We investigated an extension provided by the factor graph approach in which the model distinguishes between inhibitory and stimulatory interactions. We found that the extension yielded significant improvements in recovering the structure of simulated and Saccharomyces cerevisae networks. We applied the approach to discover a signaling network among genes involved in a human colon cancer cell invasiveness pathway. The method predicts several genes with new roles in the invasiveness process. We knocked down two genes identified by our approach and found that both knock-downs produce loss of invasive potential in a colon cancer cell line. Nested effects models may be a powerful tool for inferring regulatory connections and genes that operate in normal and disease-related processes

Selecting Indicator Portfolios for Marine Species and Food Webs: A Puget Sound Case Study

Ecosystem-based management (EBM) has emerged as a promising approach for maintaining the benefits humans want and need from the ocean, yet concrete approaches for implementing EBM remain scarce. A key challenge lies in the development of indicators that can provide useful information on ecosystem status and trends, and assess progress towards management goals. In this paper, we describe a generalized framework for the methodical and transparent selection of ecosystem indicators. We apply the framework to the second largest estuary in the United States – Puget Sound, Washington – where one of the most advanced EBM processes is currently underway. Rather than introduce a new method, this paper integrates a variety of familiar approaches into one step-by-step approach that will lead to more consistent and reliable reporting on ecosystem condition. Importantly, we demonstrate how a framework linking indicators to policy goals, as well as a clearly defined indicator evaluation and scoring process, can result in a portfolio of useful and complementary indicators based on the needs of different users (e.g., policy makers and scientists). Although the set of indicators described in this paper is specific to marine species and food webs, we provide a general approach that could be applied to any set of management objectives or ecological system

Current and Future Patterns of Global Marine Mammal Biodiversity

Quantifying the spatial distribution of taxa is an important prerequisite for the preservation of biodiversity, and can provide a baseline against which to measure the impacts of climate change. Here we analyse patterns of marine mammal species richness based on predictions of global distributional ranges for 115 species, including all extant pinnipeds and cetaceans. We used an environmental suitability model specifically designed to address the paucity of distributional data for many marine mammal species. We generated richness patterns by overlaying predicted distributions for all species; these were then validated against sightings data from dedicated long-term surveys in the Eastern Tropical Pacific, the Northeast Atlantic and the Southern Ocean. Model outputs correlated well with empirically observed patterns of biodiversity in all three survey regions. Marine mammal richness was predicted to be highest in temperate waters of both hemispheres with distinct hotspots around New Zealand, Japan, Baja California, the Galapagos Islands, the Southeast Pacific, and the Southern Ocean. We then applied our model to explore potential changes in biodiversity under future perturbations of environmental conditions. Forward projections of biodiversity using an intermediate Intergovernmental Panel for Climate Change (IPCC) temperature scenario predicted that projected ocean warming and changes in sea ice cover until 2050 may have moderate effects on the spatial patterns of marine mammal richness. Increases in cetacean richness were predicted above 40° latitude in both hemispheres, while decreases in both pinniped and cetacean richness were expected at lower latitudes. Our results show how species distribution models can be applied to explore broad patterns of marine biodiversity worldwide for taxa for which limited distributional data are available

Patterns of Spatial Variation of Assemblages Associated with Intertidal Rocky Shores: A Global Perspective

Assemblages associated with intertidal rocky shores were examined for large scale distribution patterns with specific emphasis on identifying latitudinal trends of species richness and taxonomic distinctiveness. Seventy-two sites distributed around the globe were evaluated following the standardized sampling protocol of the Census of Marine Life NaGISA project (www.nagisa.coml.org). There were no clear patterns of standardized estimators of species richness along latitudinal gradients or among Large Marine Ecosystems (LMEs); however, a strong latitudinal gradient in taxonomic composition (i.e., proportion of different taxonomic groups in a given sample) was observed. Environmental variables related to natural influences were strongly related to the distribution patterns of the assemblages on the LME scale, particularly photoperiod, sea surface temperature (SST) and rainfall. In contrast, no environmental variables directly associated with human influences (with the exception of the inorganic pollution index) were related to assemblage patterns among LMEs. Correlations of the natural assemblages with either latitudinal gradients or environmental variables were equally strong suggesting that neither neutral models nor models based solely on environmental variables sufficiently explain spatial variation of these assemblages at a global scale. Despite the data shortcomings in this study (e.g., unbalanced sample distribution), we show the importance of generating biological global databases for the use in large-scale diversity comparisons of rocky intertidal assemblages to stimulate continued sampling and analyses

The feeding tube of cyst nematodes: characterisation of protein exclusion

Plant parasitic nematodes comprise several groups; the most economically damaging of these are the sedentary endoparasites. Sedentary endoparasitic nematodes are obligate biotrophs and modify host root tissue, using a suite of effector proteins, to create a feeding site that is their sole source of nutrition. They feed by withdrawing host cell assimilate from the feeding site though a structure known as the feeding tube. The function, composition and molecular characteristics of feeding tubes are poorly characterised. It is hypothesised that the feeding tube facilitates uptake of host cell assimilate by acting as a molecular sieve. Several studies, using molecular mass as the sole indicator of protein size, have given contradictory results about the exclusion limits of the cyst nematode feeding tube. In this study we propose a method to predict protein size, based on protein database coordinates in silico. We tested the validity of these predictions using travelling wave ion mobility spectrometry--mass spectrometry, where predictions and measured values were within approximately 6%. We used the predictions, coupled with mass spectrometry, analytical ultracentrifugation and protein electrophoresis, to resolve previous conflicts and define the exclusion characteristics of the cyst nematode feeding tube. Heterogeneity was tested in the liquid, solid and gas phase to provide a comprehensive evaluation of three proteins of particular interest to feeding tube size exclusion, GFP, mRFP and Dual PI. The data and procedures described here could be applied to the design of plant expressed defence compounds intended for uptake into cyst nematodes. We also highlight the need to assess protein heterogeneity when creating novel fusion proteins

Identifying modeled ship noise hotspots for marine mammals of Canada's Pacific region

RW was supported by a Marie Curie International Incoming Fellowship within the 7th European Community Framework Programme (Project CONCEAL, FP7, PIIF-GA-2009-253407). These analyses were funded by a grant to RW and EA from Marisla Foundation.The inshore, continental shelf waters of British Columbia (BC), Canada are busy with ship traffic. South coast waters are heavily trafficked by ships using the ports of Vancouver and Seattle. North coast waters are less busy, but expected to get busier based on proposals for container port and liquefied natural gas development and expansion. Abundance estimates and density surface maps are available for 10 commonly seen marine mammals, including northern resident killer whales, fin whales, humpback whales, and other species with at-risk status under Canadian legislation. Ship noise is the dominant anthropogenic contributor to the marine soundscape of BC, and it is chronic. Underwater noise is now being considered in habitat quality assessments in some countries and in marine spatial planning. We modeled the propagation of underwater noise from ships and weighted the received levels by species-specific audiograms. We overlaid the audiogram-weighted maps of ship audibility with animal density maps. The result is a series of so-called "hotspot'' maps of ship noise for all 10 marine mammal species, based on cumulative ship noise energy and average distribution in the boreal summer. South coast waters (Juan de Fuca and Haro Straits) are hotspots for all species that use the area, irrespective of their hearing sensitivity, simply due to ubiquitous ship traffic. Secondary hotspots were found on the central and north coasts (Johnstone Strait and the region around Prince Rupert). These maps can identify where anthropogenic noise is predicted to have above-average impact on species-specific habitat, and where mitigation measures may be most effective. This approach can guide effective mitigation without requiring fleet-wide modification in sites where no animals are present or where the area is used by species that are relatively insensitive to ship noise.Publisher PDFPeer reviewe

External stenting and disease progression in saphenous vein grafts two years after coronary artery bypass grafting: A multicenter randomized trial

Objectives Little data exist regarding the potential of external stents to mitigate long-term disease progression in saphenous vein grafts. We investigated the effect of external stents on the progression of saphenous vein graft disease. Methods A total of 184 patients undergoing isolated coronary artery bypass grafting, using an internal thoracic artery graft and at least 2 additional saphenous vein grafts, were enrolled in 14 European centers. One saphenous vein graft was randomized to an external stent, and 1 nonstented saphenous vein graft served as the control. The primary end point was the saphenous vein graft Fitzgibbon patency scale assessed by angiography, and the secondary end point was saphenous vein graft intimal hyperplasia assessed by intravascular ultrasound in a prespecified subgroup at 2 years. Results Angiography was completed in 128 patients and intravascular ultrasound in the entire prespecified cohort (n = 51) at 2 years. Overall patency rates were similar between stented and nonstented saphenous vein grafts (78.3% vs 82.2%, P = .43). However, the Fitzgibbon patency scale was significantly improved in stented versus nonstented saphenous vein grafts, with Fitzgibbon patency scale I, II, and III rates of 66.7% versus 54.9%, 27.8% versus 34.3%, and 5.5% versus 10.8%, respectively (odds ratio, 2.02; P = .03). Fitzgibbon patency scale was inversely related to saphenous vein graft minimal lumen diameter, with Fitzgibbon patency scale I, II, and III saphenous vein grafts having an average minimal lumen diameter of 2.62 mm, 1.98 mm, and 1.32 mm, respectively (P < .05). Externally stented saphenous vein grafts also showed significant reductions in mean intimal hyperplasia area (22.5%; P < .001) and thickness (23.5%; P < .001). Conclusions Two years after coronary artery bypass grafting, external stenting improves Fitzgibbon patency scales of saphenous vein grafts and significantly reduces intimal hyperplasia area and thickness. Whether this will eventually lead to improved long-term patency is still unknown