Stress testing and non-invasive coronary angiography in patients with suspected coronary artery disease: time for a new paradigm

Diagnosis and management of coronary artery disease represents major challenges to our health care system, affecting millions of patients each year. Until recently, the diagnosis of coronary artery disease was possible only through cardiac catheterization and invasive coronary angiography. To avoid the risks of an invasive procedure, stress testing is often employed for an initial assessment of patients with suspected coronary artery disease, serving as a gatekeeper for cardiac catheterization. With the emergence of non-invasive coronary angiography, the question arises if such a strategy is still sensible, particularly, in view of only a modest agreement between stress testing results and the presence of coronary artery disease established by cardiac catheterization. Much data in support of the diagnostic accuracy and prognostic value of non-invasive coronary angiography by computed tomography have emerged within the last few years. These data challenge the role of stress testing as the initial imaging modality in patients with suspected coronary artery disease. This article reviews the clinical utility, limitations, as well as the hazards of stress testing compared with non-invasive coronary artery imaging by computed tomography. Finally, the implications of this review are discussed in relation to clinical practice

Thiopurine metabolism and identification of the thiopurine metabolites transported by MRP4 and MRP5 overexpressed in human embryonic kidney cells.

Mercaptopurines have been used as anticancer agents for more than 40 years, and most acute lymphoblastic leukemias are treated with 6-mercaptopurine (6MP) or 6-thioguanine (TG). Overexpression of the two related multidrug resistance proteins MRP4 and MRP5 has been shown to confer some resistance against mercaptopurines, which has been attributed to extrusion of mercaptopurine metabolites by these transporters. We have analyzed the mercaptopurine metabolites formed in human embryonic kidney cells and determined which metabolites are extruded by MRP4 and MRP5. Incubation with 6MP led to the formation of thioinosine and thioxanthosine metabolites and we found that thio-IMP was transported by both MRP4 and MRP5; MRP5 showed the highest transport rate. In contrast, only MRP5 transported thioxanthosine monophosphate (tXMP). During incubation with TG, the monophosphorylated form of thioguanosine was transported by both MRP4 and MRP5; the highest transport rate was for MRP4. Similarly, only 6-methyl-thio-IMP was formed during incubation with 6-methyl mercaptopurine riboside. This compound was a substrate for both MRP4 and MRP5; MRP4 showed the highest transport rate. Our results show that all major thiopurine monophosphates important in the efficacy of mercaptopurine treatment are transported by MRP4 and MRP5, although the substrate specificity of the two transporters differs in detail

Multi-objective optimisation, sensitivity and robustness analysis in FBA modelling

In this work, we propose a computational framework to design in silico robust bacteria able to overproduce multiple metabolites. To this end, we search the optimal genetic manipulations, in terms of knockout, which also guarantee the growth of the organism. We introduce a multi-objective optimisation algorithm, called Genetic Design through Multi-Objective (GDMO), and test it in several organisms to maximise the production of key intermediate metabolites such as succinate and acetate. We obtain a vast set of Pareto optimal solutions; each of them represents an organism strain. For each solution, we evaluate the fragility by calculating three robustness indexes and by exploring reactions and metabolite interactions. Finally, we perform the Sensitivity Analysis of the metabolic model, which finds the inputs with the highest influence on the outputs of the model. We show that our methodology provides effective vision of the achievable synthetic strain landscape and a powerful design pipeline.</p

Negative effects of nitrogen override positive effects of phosphorus on grassland legumes worldwide

Anthropogenic nutrient enrichment is driving global biodiversity decline and modifying ecosystem functions. Theory suggests that plant functional types that fix atmospheric nitrogen have a competitive advantage in nitrogen-poor soils, but lose this advantage with increasing nitrogen supply. By contrast, the addition of phosphorus, potassium, and other nutrients may benefit such species in lownutrient environments by enhancing their nitrogen-fixing capacity. We present a global-scale experiment confirming these predictions for nitrogen-fixing legumes (Fabaceae) across 45 grasslands on six continents. Nitrogen addition reduced legume cover, richness, and biomass, particularly in nitrogen-poor soils, while cover of non-nitrogenfixing plants increased. The addition of phosphorous, potassium, and other nutrients enhanced legume abundance, but did not mitigate the negative effects of nitrogen addition. Increasing nitrogen supply thus has the potential to decrease the diversity and abundance of grassland legumes worldwide regardless of the availability of other nutrients, with consequences for biodiversity, food webs, ecosystem resilience, and genetic improvement of protein-rich agricultural plant species

Negative effects of nitrogen override positive effects of phosphorus on grassland legumes worldwide

Anthropogenic nutrient enrichment is driving global biodiversity decline and modifying ecosystem functions. Theory suggests that plant functional types that fix atmospheric nitrogen have a competitive advantage in nitrogen-poor soils, but lose this advantage with increasing nitrogen supply. By contrast, the addition of phosphorus, potassium, and other nutrients may benefit such species in lownutrient environments by enhancing their nitrogen-fixing capacity. We present a global-scale experiment confirming these predictions for nitrogen-fixing legumes (Fabaceae) across 45 grasslands on six continents. Nitrogen addition reduced legume cover, richness, and biomass, particularly in nitrogen-poor soils, while cover of non-nitrogenfixing plants increased. The addition of phosphorous, potassium, and other nutrients enhanced legume abundance, but did not mitigate the negative effects of nitrogen addition. Increasing nitrogen supply thus has the potential to decrease the diversity and abundance of grassland legumes worldwide regardless of the availability of other nutrients, with consequences for biodiversity, food webs, ecosystem resilience, and genetic improvement of protein-rich agricultural plant species