A community effort towards a knowledge-base and mathematical model of the human pathogen Salmonella Typhimurium LT2

<p>Abstract</p> <p>Background</p> <p>Metabolic reconstructions (MRs) are common denominators in systems biology and represent biochemical, genetic, and genomic (BiGG) knowledge-bases for target organisms by capturing currently available information in a consistent, structured manner. <it>Salmonella enterica </it>subspecies I serovar Typhimurium is a human pathogen, causes various diseases and its increasing antibiotic resistance poses a public health problem.</p> <p>Results</p> <p>Here, we describe a community-driven effort, in which more than 20 experts in <it>S</it>. Typhimurium biology and systems biology collaborated to reconcile and expand the <it>S</it>. Typhimurium BiGG knowledge-base. The consensus MR was obtained starting from two independently developed MRs for <it>S</it>. Typhimurium. Key results of this reconstruction jamboree include i) development and implementation of a community-based workflow for MR annotation and reconciliation; ii) incorporation of thermodynamic information; and iii) use of the consensus MR to identify potential multi-target drug therapy approaches.</p> <p>Conclusion</p> <p>Taken together, with the growing number of parallel MRs a structured, community-driven approach will be necessary to maximize quality while increasing adoption of MRs in experimental design and interpretation.</p

Article Commentary: Promise and Reality in the Expanding Field of Network Interaction Analysis: Metabolic Networks

In the last few decades, metabolic networks revealed their capabilities as powerful tools to analyze the cellular metabolism. Many research fields (eg, metabolic engineering, diagnostic medicine, pharmacology, biochemistry, biology and physiology) improved the understanding of the cell combining experimental assays and metabolic network-based computations. This process led to the rise of the “systems biology” approach, where the theory meets experiments and where two complementary perspectives cooperate in the study of biological phenomena. Here, the reconstruction of metabolic networks is presented, along with established and new algorithms to improve the description of cellular metabolism. Then, advantages and limitations of modeling algorithms and network reconstruction are discussed

Effect of polyamines on perfused rat heart contractility

The influence of polyamines (putrescine, spermidine and spermine) on heart contractility was studied using perfused rat ventricle strips (2 X 10 mm), electrically driven at 1 Hz. Putrescine (100 microM) caused a negative inotropic effect gradually increasing in intensity, whereas spermidine and spermine (10 and 100 microM) caused a sharp, positive inotropic effect, followed by a rapid and more marked fall. The possibility that these effects of polyamines on heart contractility may be due to their role in Ca++ fluxes and mobilization, and in membrane functions, is discussed

Network-based assessment of the selectivity of metabolic drug targets in <it>Plasmodium falciparum</it> with respect to human liver metabolism

<p>Abstract</p> <p>Background</p> <p>The search for new drug targets for antibiotics against <it>Plasmodium falciparum</it>, a major cause of human deaths, is a pressing scientific issue, as multiple resistance strains spread rapidly. Metabolic network-based analyses may help to identify those parasite’s essential enzymes whose homologous counterparts in the human host cells are either absent, non-essential or relatively less essential.</p> <p>Results</p> <p>Using the well-curated metabolic networks PlasmoNet of the parasite <it>Plasmodium falciparum</it> and HepatoNet1 of the human hepatocyte, the selectivity of 48 experimental antimalarial drug targets was analyzed. Applying <it>in silico</it> gene deletions, 24 of these drug targets were found to be perfectly selective, in that they were essential for the parasite but non-essential for the human cell. The selectivity of a subset of enzymes, that were essential in both models, was evaluated with the reduced fitness concept. It was, then, possible to quantify the reduction in functional fitness of the two networks under the progressive inhibition of the same enzymatic activity. Overall, this <it>in silico</it> analysis provided a selectivity ranking that was in line with numerous <it>in vivo</it> and <it>in vitro</it> observations.</p> <p>Conclusions</p> <p>Genome-scale models can be useful to depict and quantify the effects of enzymatic inhibitions on the impaired production of biomass components. From the perspective of a host-pathogen metabolic interaction, an estimation of the drug targets-induced consequences can be beneficial for the development of a selective anti-parasitic drug.</p

Putrescine reverses aconitine-induced arrhythmia in rats

Putrescine, (150-300 mg kg-1 i.v.) injected into anaesthetized rats reversed aconitine-induced arrhythmia and restored sinus rhythm. In the same experimental model, quinidine and lignocaine had a transient therapeutic effect, procainamide was practically ineffective and verapamil worsened the aconitine arrhythmia, causing the death of all treated animals. These data demonstrate that putrescine has an antiarrhythmic effect in an experimental model particularly resistant to usual antiarrhythmic treatments

Treatment with polyamine synthesis inhibitors reduces the positive inotropic effect of ouabain, noradrenaline and calcium

Polyamines (putrescine, spermidine and spermine) are considered to act as intracellular second messengers by increasing Ca++ influx and mobilizing intracellular calcium. On the other hand, intracellular Ca++ increase is the common final step of the mechanism of action of many inotropic agents. To discover whether the functional integrity of the cardiac ornithine decarboxylase (ODC)/polyamine system is necessary to cope with a stimulated inotropism, we studied the effect of ouabain, noradrenaline, and calcium on ventricle strips obtained from rats treated with polyamine synthesis inhibitors. The combined administration of methylglioxal bis (guanylhydrazone) (MGBG) (single i.p. injection of 50 mgkg-1) and of alpha-di fluoromethylornithine (DFMO) (100 mgkg-1 every 12 h for 7 consecutive days) caused a 62.5% inhibition of ventricular ODC activity, and a significant decrease of the ventricular content of putrescine and spermidine (-59.5%, and -40.1%, respectively). While the basal isometric tension developed by ventricle strips obtained from rats treated with MGBG+DFMO was similar to that developed by ventricle strips from controls, the response to ouabain (1 microM), noradrenaline (10 microM), or Ca++ (3.6 mM) was significantly reduced. It cannot be excluded that effects of MGBG unrelated to the inhibition of polyamine synthesis may have also concurred in part to influence the effect of ouabain, Ca++ and noradrenaline adversely. However, the present results seem to indicate that the heart response to inotropic agents requires an efficient ODC/polyamine system, polyamines probably being involved in calcium ion movements or affecting the Ca++ sensitivity of contractile proteins

Putrescine has antiarrhythmic effects in rat models of arrhythmia.

The influence of putrescine on cardiac arrhythmias induced by either permanent ligature of the left anterior coronary artery or heart reperfusion following a 5-min coronary occlusion was studied in anesthetized rats. Reperfusion-induced arrhythmias were significantly prevented by the i.v. injection of 150-200 mg/kg of putrescine, the survival rate being 100% in treated animals and 40% in controls. At a dose level of 200-300 mg/kg i.v., putrescine also significantly reduced the duration of ventricular tachycardia induced by permanent coronary occlusion. These findings show that putrescine significantly reduces the consequences of cardiac ischemia and reperfusion, probably as a consequence of its multiple stabilizing effects at the membrane level

Individual mobility deep insight using mobile phones data

Abstract The data sets provided by Information and Communication Technologies have been extensively used to study the human mobility in the framework of complex systems. The possibility of detecting the behavior of individuals performing the urban mobility may offer the possibility of understanding how to realize a transition to a sustainable mobility in future smart cities. The Statistical Physics approach considers the statistical distributions of human mobility to discover universal features. Under this point of view the power laws distributions has been extensively studied to propose model of human mobility. In this paper we show that using a GPS data set containing the displacements of mobile devices in an area around the city Rimini (Italy), it is possible to reconstruct a sample of mobility paths and to study the statistical properties of urban mobility. Applying a fuzzy c-means clustering algorithm, we succeed to detect different mobility types that highlight the multilayer structure of the road network. The disaggregation into homogeneous mobility classes explains the power law distributions for the path lengths and the travel times as an overlapping of exponential distributions, that are consistent with a maximum entropy Principle. Under this point of view it is not possible to infer other dynamical properties on the individual mobility, except for the average values of the different classes. We also study the role of the mobility types, when one restricts the analysis to the an origin-destination framework, by analyzing the daily evolution of the mobility flows