Adding metabolic tasks to human GEM models to improve the study of gene targets and their associated toxicities.

Genetic minimal cut sets (gMCS) are genes that must be deactivated simultaneously to avoid unwanted states in a metabolic model. The concept of gMCS can be applied to two different scenarios. First, it can be used to identify potential gene toxicities in generic or healthy cell models. Second, it can be used to develop genetic strategies to target cancer cells and prevent their proliferation. Up to now, gMCS have been evaluated using the traditional procedure of preventing biomass production. This paper proposes an additional way: using essential metabolic tasks, which any human cell should perform, to enlarge the set of unwanted states. Including this addition can significantly improve the study of toxicities and reveal targets that can be used to treat unhealthy cells. Excluding metabolic tasks can cause important information to be overlooked, which could impact the study's success. Regarding toxicities, using the generic Human model, the number of detected generic toxicities with metabolic tasks increases from 106 to 281 (136 gMCSs of length 1 and 49 of length 2). We have used the following context-specific models to evaluate specific toxicities in different healthy tissues: blood, pancreas, liver, heart, and kidney. Again, considering metabolic tasks, we have found new toxicities (lengths 1 and 2) whose inactivation could damage these healthy tissues.Our research strategy has been applied to identify new cancer drug targets in two myeloma cell lines. We obtained new therapeutic targets of lengths 1 and 2 for each cell line. After analyzing the data, we conclude that incorporating metabolic tasks into cancer models can reveal important therapeutic targets previously disregarded by the conventional method of inhibiting biomass production. This approach also improves the evaluation of potential drug toxicities.

On the representativeness and stability of a set of EFMs.

MOTIVATION: Elementary flux modes are a well-known tool for analyzing metabolic networks. The whole set of elementary flux modes (EFMs) cannot be computed in most genome-scale networks due to their large cardinality. Therefore, different methods have been proposed to compute a smaller subset of EFMs that can be used for studying the structure of the network. These latter methods pose the problem of studying the representativeness of the calculated subset. In this article, we present a methodology to tackle this problem. RESULTS: We have introduced the concept of stability for a particular network parameter and its relation to the representativeness of the EFM extraction method studied. We have also defined several metrics to study and compare the EFM biases. We have applied these techniques to compare the relative behavior of previously proposed methods in two case studies. Furthermore, we have presented a new method for the EFM computation (PiEFM), which is more stable (less biased) than previous ones, has suitable representativeness measures, and exhibits better variability in the extracted EFMs. AVAILABILITY AND IMPLEMENTATION: Software and additional material are freely available at https://github.com/biogacop/PiEFM.

Staphylococcus epidermidis RP62A's Metabolic Network: Validation and Intervention Strategies.

Increasingly, systems biology is gaining relevance in basic and applied research. The combination of computational biology with wet laboratory methods produces synergy that results in an exponential increase in knowledge of biological systems. The study of microorganisms such as Staphylococcus epidermidis RP62A enables the researcher to understand better their metabolic networks, which allows the design of effective strategies to treat infections caused by this species or others. S. epidermidis is the second most commoncause of infection in patients with joint implants, so treating its proliferation seems vital for public health. There are different approaches to the analysis of metabolic networks. Flux balance analysis (FBA) is one of the most widespread streams of research. It allows the study of large metabolic networks, the study their structural properties, the optimization of metabolic flux, and the search for intervention strategies to modify the state of the metabolic network. This work presents the validation of the Staphylococcus epidermidis RP62A metabolic network model elaborated by Díaz Calvo et al. Then, we elaborate further on the network analysis's essential reactions. The full set of essential reactions (including a previously unobserved one) was computed, and we classified them into equivalence classes. Some proposals to intervene in the network and design knock-outs by studying minimal cut sets of small length are also introduced. In particular, minimal cut sets related to the medium (including exchange reactions associated with medium metabolites) have been computed. In this sense, the unique external MCS (composed of cysteine and sulfate ion) has been found, and all hybrid MCS (based on knocking out both internal and exchange reactions) of length two have also been computed. The paper also points out the possible importance of these new intervention strategies.

Bird electrocution on power lines: Spatial gaps and identification of driving factors at global scales.

Universal energy access is one of the targets of the Sustainable Development Goals (SDGs), and thus the deployment of electricity grids is expected to expand globally in the coming decades. However, the installation of power lines is not biodiversity-friendly. In particular, electrocution on power pylons is a major cause of bird mortality worldwide, including for some severely endangered species. Over the last decades, different studies have improved our understanding of the factors influencing the risk of electrocution in birds, but until now spatial gaps in our knowledge of these impacts and the factors driving global patterns of bird electrocution have not been assessed. In this study, we evaluated data from a total of 114 studies that provided information on bird mortality rates on power lines, and we analyzed the factors driving electrocution rates for all bird species, and then for all raptors and large eagles separately. Our results showed a high spatial distribution bias, as more than 80% of the studies were carried out in developed countries, mostly in Europe and North America. By contrast, no systematic studies have been found for Oceania and very few for South America and Africa. Europe showed the highest electrocution rates for birds, South America for raptor species and Africa for eagles. Socio-economic factors best-explained bird and raptor electrocution rates, while climate-related factors were the most influential for eagles. Contrary to our expectations, factors related to pylon design were the least influential on overall electrocution rates. Variables related to study design showed highly variable levels of influence. This could be due to the lack of standardized protocols. Although bird electrocution has been extensively studied, there are large areas where no studies have been carried out or for which data are inaccessible. This could be because in these areas the power distribution network is still sparse, or that most studies are not public or accessible to the international community. Researchers and managers should promote the publication of studies, as awareness is the first step to solving these problems. The factors identified could be applied globally to the design and planning of power grids and the identification of mortality hotspots. This would help mitigate the creation of new mortality hotspots, especially in developing countries where the installation of new power lines has been growing exponentially in recent years.

Flux Coupling and the Objective Functions' Length in EFMs.

Structural analysis of constraint-based metabolic network models attempts to find the network's properties by searching for subsets of suitable modes or Elementary Flux Modes (EFMs). One useful approach is based on Linear Program (LP) techniques, which introduce an objective function to convert the stoichiometric and thermodynamic constraints into a linear program (LP), using additional constraints to generate different nontrivial modes. This work introduces FLFS-FC (Fixed Length Function Sampling with Flux Coupling), a new approach to increase the efficiency of generation of large sets of different EFMs for the network. FLFS-FC is based on the importance of the length of the objective functions used in the associated LP problem and the imposition of additional negative constraints. Our proposal overrides some of the known drawbacks associated with the EFM extraction, such as the appearance of unfeasible problems or multiple repeated solutions arising from different LP problems.

Boosting the extraction of elementary flux modes in genome-scale metabolic networks using the linear programming approach.

MOTIVATION: Elementary flux modes (EFMs) are a key tool for analyzing genome-scale metabolic networks, and several methods have been proposed to compute them. Among them, those based on solving linear programming (LP) problems are known to be very efficient if the main interest lies in computing large enough sets of EFMs. RESULTS: Here, we propose a new method called EFM-Ta that boosts the efficiency rate by analyzing the information provided by the LP solver. We base our method on a further study of the final tableau of the simplex method. By performing additional elementary steps and avoiding trivial solutions consisting of two cycles, we obtain many more EFMs for each LP problem posed, improving the efficiency rate of previously proposed methods by more than one order of magnitude. AVAILABILITY AND IMPLEMENTATION: Software is freely available at https://github.com/biogacop/Boost_LP_EFM. CONTACT: fguil@um.es. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Improving the EFMs quality by augmenting their representativeness in LP methods.

BACKGROUND: Although cellular metabolism has been widely studied, its fully comprehension is still a challenge. A main tool for this study is the analysis of meaningful pieces of knowledge called modes and, in particular, specially interesting classes of modes such as pathways and Elementary Flux Modes (EFMs). Its study often has to deal with issues such as the appearance of infeasibilities or the difficulty of finding representative enough sets of modes that are free of repetitions. Mode extraction methods usually incorporate strategies devoted to mitigate this phenomena but they still get a high ratio of repetitions in the set of solutions. RESULTS: This paper presents a proposal to improve the representativeness of the full set of metabolic reactions in the set of computed modes by penalizing the eventual high frequency of occurrence of some reactions during the extraction. This strategy can be applied to any linear programming based extraction existent method. CONCLUSIONS: Our strategy enhances the quality of a set of extracted EFMs favouring the presence of every reaction in it and improving the efficiency by mitigating the occurrence of repeated solutions. The new proposed strategy can complement other EFMs extraction methods based on linear programming. The obtained solutions are more likely to be diverse using less computing effort and improving the efficiency of the extraction.

Wildfires as collateral effects of wildlife electrocution: An economic approach to the situation in Spain in recent years.

The interaction between wildlife and power lines has collateral effects that include wildfires and Carbon Dioxide (CO2) emissions. However, currently available information is scarce and so new approaches are needed to increase our understanding of this issue. Here, we present the first analysis of wildfires and their incidence as a result of this interaction in Spain during the period 2000-2012. Amongst the 2788 Power-Line Mediated Wildfires (PLMW recorded) during this period, 30 records of Fauna Mediated Wildfires (FMW) were found, with an average affected vegetation cover of 9.06ha. Our findings suggest that no significant differences were observed between the amount of affected surface area due to fauna mediated wildfires and power-line mediated wildfires. In both cases, a space-grouping trend was observed. In terms of changing trends over time, after the first incident detected in 2005, the number of incidents increased until 2008, year in which the percentage of wildfires caused by wildlife stabilized at approximately 2.4% of all power-line-induced wildfires. Population density and road abundance were variables that better explained PLMW whereas for FMW, the models that included land use and raptor abundance. In the multivariate model, FMW emergence was positively related with population density, percentage of grazing areas and Natura 2000 cover, and predatory abundance; and negatively with the percentage of forested area. No significant differences were observed between the species of birds that caused wildfires and the species of ringed birds killed by electrocution. The economic and environmental impact due to necessary repairs, the loss of biodiversity and CO2 emissions represent an estimated net value of €7.6-12.4M for the period 2000-2012, which indicates the importance of the economic and environmental costs associated with wildfires.

Effect of methodological and ecological approaches on heterogeneity of nest-site selection of a long-lived vulture.

The application of scientific-based conservation measures requires that sampling methodologies in studies modelling similar ecological aspects produce comparable results making easier their interpretation. We aimed to show how the choice of different methodological and ecological approaches can affect conclusions in nest-site selection studies along different Palearctic meta-populations of an indicator species. First, a multivariate analysis of the variables affecting nest-site selection in a breeding colony of cinereous vulture (Aegypius monachus) in central Spain was performed. Then, a meta-analysis was applied to establish how methodological and habitat-type factors determine differences and similarities in the results obtained by previous studies that have modelled the forest breeding habitat of the species. Our results revealed patterns in nesting-habitat modelling by the cinereous vulture throughout its whole range: steep and south-facing slopes, great cover of large trees and distance to human activities were generally selected. The ratio and situation of the studied plots (nests/random), the use of plots vs. polygons as sampling units and the number of years of data set determined the variability explained by the model. Moreover, a greater size of the breeding colony implied that ecological and geomorphological variables at landscape level were more influential. Additionally, human activities affected in greater proportion to colonies situated in Mediterranean forests. For the first time, a meta-analysis regarding the factors determining nest-site selection heterogeneity for a single species at broad scale was achieved. It is essential to homogenize and coordinate experimental design in modelling the selection of species' ecological requirements in order to avoid that differences in results among studies would be due to methodological heterogeneity. This would optimize best conservation and management practices for habitats and species in a global context.

Minimising mortality in endangered raptors due to power lines: the importance of spatial aggregation to optimize the application of mitigation measures.

Electrocution by power lines is one of the main causes of non-natural mortality in birds of prey. In an area in central Spain, we surveyed 6304 pylons from 333 power lines to determine electrocution rates, environmental and design factors that may influence electrocution and the efficacy of mitigation measures used to minimise electrocution cases. A total of 952 electrocuted raptors, representing 14 different species, were observed. Electrocuted raptors were concentrated in certain areas and the environmental factors associated with increased electrocution events were: greater numbers of prey animals; greater vegetation cover; and shorter distance to roads. The structural elements associated with electrocutions were shorter strings of insulators, one or more phases over the crossarm, cross-shaped design and pylon function. Of the 952 carcasses found, 148 were eagles, including golden eagle (Aquila chrysaetos), Spanish imperial eagle (Aquila adalberti) and Bonelli's eagle (Aquila fasciata). Electrocuted eagles were clustered in smaller areas than other electrocuted raptors. The factors associated with increased eagle electrocution events were: pylons function, shorter strings of insulators, higher slopes surrounding the pylon, and more numerous potential prey animals. Pylons with increased string of insulators had lower raptor electrocution rates than unimproved pylons, although this technique was unsuccessful for eagles. Pylons with cable insulation showed higher electrocution rates than unimproved pylons, both for raptors and eagles, despite this is the most widely used and recommended mitigation measure in several countries. To optimize the application of mitigation measures, our results recommend the substitution of pin-type insulators to suspended ones and elongating the strings of insulators.

[Necrolytic migratory erythema associated with glucagonoma]. / Eritema necrolítico migratorio asociado a glucagonoma.

Glucagonoma is a rare pancreatic tumor that is usually associated with a syndrome that includes diabetes, anemia, weight loss and skin lesions in the form of necrolytic migratory erythema. We present the case of a patient with malignant glucagonoma treated with surgery and octreotide, which manifested with skin lesions. The discussion will review the physiopathology, other causes of necrolytic erythema, diagnosis and differential diagnosis and treatment.