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Byline: Claudio Balducelli, Sandro Bologna, Antonio Di Pietro, Giordano Vicoli The paper explores the possibility of using interacting agents for modelling and discrete event simulation as a tool to approach interdependencies analysis and evaluation for critical infrastructures. A discrete event simulation system was developed, using agent-oriented programming, considering the following limited sets of critical infrastructures: a great hospital infrastructure, a railway transportation infrastructure and other public transportation infrastructures. Faults inside the electricity distribution system are simulated, producing electrical power outages whose duration could be variable with respect to time and space, and generating consequences inside the transportation infrastructures. The hospital infrastructure users, such as different types of physicians, nurses, subsidiary personnel, students and patients are also modelled using agent oriented architectures. The objective of the simulations is to study and analyse the interdependencies of the considered infrastructures Many typologies of test scenarios are also executed and the severity of the generated consequences are analysed in the paper.

Soilborne fungal pathogens cause devastating yield losses and are highly persistent and difficult to control. During the infection process, these organisms must cope with limited availability of iron. Here we show that the bZIP protein HapX functions as a key regulator of iron homeostasis and virulence in the vascular wilt fungus Fusarium oxysporum. Deletion of hapX does not affect iron uptake but causes derepression of genes involved in iron-consuming pathways, leading to impaired growth under iron-depleted conditions. F. oxysporum strains lacking HapX are reduced in their capacity to invade and kill tomato (Solanum lycopersicum) plants and immunodepressed mice. The virulence defect of Δ hapX on tomato plants is exacerbated by coinoculation of roots with a biocontrol strain of Pseudomonas putida , but not with a siderophore-deficient mutant, indicating that HapX contributes to iron competition of F. oxysporum in the tomato rhizosphere. These results establish a conserved role for HapX-mediated iron homeostasis in fungal infection of plants and mammals. [ABSTRACT FROM AUTHOR]

Fungal pathogenicity in plants requires a conserved mitogen-activated protein kinase (MAPK) cascade homologous to the yeast filamentous growth pathway. How this signaling cascade is activated during infection remains poorly understood. In the soil-borne vascular wilt fungus Fusarium   oxysporum , the orthologous MAPK Fmk1 (Fusarium MAPK1) is essential for root penetration and pathogenicity in tomato (Solanum lycopersicum) plants. Here, we show that Msb2, a highly glycosylated transmembrane protein, is required for surface-induced phosphorylation of Fmk1 and contributes to a subset of Fmk1-regulated functions related to invasive growth and virulence. Mutants lacking Msb2 share characteristic phenotypes with the Δ fmk1 mutant, including defects in cellophane invasion, penetration of the root surface, and induction of vascular wilt symptoms in tomato plants. In contrast with Δ fmk1 , Δ msb2 mutants were hypersensitive to cell wall targeting compounds, a phenotype that was exacerbated in a Δ msb2 Δ fmk1 double mutant. These results suggest that the membrane mucin Msb2 promotes invasive growth and plant infection upstream of Fmk1 while contributing to cell integrity through a distinct pathway. [ABSTRACT FROM AUTHOR]

During infection, fungal pathogens activate virulence mechanisms, such as host adhesion, penetration and invasive growth. In the vascular wilt fungus Fusarium oxysporum , the mitogen-activated protein kinase Fmk1 is required for plant infection and controls processes such as cellophane penetration, vegetative hyphal fusion, or root adhesion. Here, we show that these virulence-related functions are repressed by the preferred nitrogen source ammonium and restored by treatment with l -methionine sulfoximine or rapamycin, two specific inhibitors of Gln synthetase and the protein kinase TOR, respectively. Deletion of the bZIP protein MeaB also resulted in nitrogen source–independent activation of virulence mechanisms. Activation of these functions did not require the global nitrogen regulator AreA, suggesting that MeaB-mediated repression of virulence functions does not act through inhibition of AreA. Tomato plants (Solanum lycopersicum) supplied with ammonium rather than nitrate showed a significant reduction in vascular wilt symptoms when infected with the wild type but not with the Δ meaB strain. Nitrogen source also affected invasive growth in the rice blast fungus Magnaporthe oryzae and the wheat head blight pathogen Fusarium graminearum. We propose that a conserved nitrogen-responsive pathway might operate via TOR and MeaB to control virulence in plant pathogenic fungi. [ABSTRACT FROM AUTHOR]

H+-ATPases are ubiquitous in nature; V-ATPases pump protons against an electrochemical gradient, whereas F-ATPases reverse the process, synthesizing ATP. We demonstrate here that mutations in ATP6B1, encoding the B-subunit of the apical proton pump mediating distal nephron acid secretion, cause distal renal tubular acidosis, a condition characterized by impaired renal acid secretion resulting in metabolic acidosis. Patients with ATP6B1 mutations also have sensorineural hearing loss; consistent with this finding, we demonstrate expression of ATP6B1 in cochlea and endolymphatic sac. Our data, together with the known requirement for active proton secretion to maintain proper endolymph pH, implicate ATP6B1 in endolymph pH homeostasis and in normal auditory function. ATP6B1 is the first member of the H+-ATPase gene family in which mutations are shown to cause human disease. [ABSTRACT FROM AUTHOR]

Antifungal protein (AFP) from Aspergillus giganteus was assayed for toxicity against the Fusarium oxysporum wild-type strain and mutants in genes involved in cell signaling (ΔpacC, pacCc Δfmk1) or cell-wall biogenesis (ΔchsV, Δchs7, Δgas1). The mutants were classified into two groups according to their sensitivity to AFP: ΔpacC, Δgas1 and Δchs7, which were significantly more resistant to AFP than the wild-type, and pacCC, Δfmk1 and ΔchsV, which were more sensitive. Western blot analysis revealed increased binding of AFP to the three resistant mutants, ΔpacC, Δgas1 and Δchs7, but also to ΔchsV, indicating that differential binding may not be a key determinant for sensitivity. Addition of Ca2+ or K+ dramatically reduced antifungal activity and binding of AFP, suggesting that these cations compete for the same targets as AFP at the surface of the fungal cell. [ABSTRACT FROM AUTHOR]