Pathway databases and tools for their exploitation: benefits, current limitations and challenges

In past years, comprehensive representations of cell signalling pathways have been developed by manual curation from literature, which requires huge effort and would benefit from information stored in databases and from automatic retrieval and integration methods. Once a reconstruction of the network of interactions is achieved, analysis of its structural features and its dynamic behaviour can take place. Mathematical modelling techniques are used to simulate the complex behaviour of cell signalling networks, which ultimately sheds light on the mechanisms leading to complex diseases or helps in the identification of drug targets. A variety of databases containing information on cell signalling pathways have been developed in conjunction with methodologies to access and analyse the data. In principle, the scenario is prepared to make the most of this information for the analysis of the dynamics of signalling pathways. However, are the knowledge repositories of signalling pathways ready to realize the systems biology promise? In this article we aim to initiate this discussion and to provide some insights on this issue.

A Carrot and Stick Approach to Agenda-Setting

This paper models a legislature in which the same agenda setter serves for two periods, showing how he can exploit a legislature (completely) in the first period by promising future benefits to legislators who support him. In equilibrium, a large majority of legislators vote for the first-period proposal because they thereby maintain the chance of belonging to the minimum winning coalition in the future. Legislators may therefore approve policies by large majorities, or even unanimously, that benefit few, or even none, of them. The results are robust; but institutional arrangements (such as entitlements) can reduce the agenda setter's power by reducing his discretion to reward and punish legislators, and rules (such as sequential voting) can increase a legislator's ability to resist exploitation. Keywords: Legislative bargaining, distributive politics, agenda-setting, proposal power. JEL C72, D72, D78.

The fate and persistence of Leishmania major in mice of different genetic backgrounds: an example of exploitation of the immune system by intracellular parasites.

Leishmania spp. are intracellular protozoan parasites that are delivered within the dermis of their vertebrate hosts. Within this peripheral tissue and the draining lymph node, they find and/or rapidly create dynamic microenvironments that determine their ultimate fate, namely their more or less successful expansion, and favour their transmission to another vertebrate host though a blood-feeding vector. Depending on their genetic characteristics as well as the genetic make-up of their hosts, once within the dermis Leishmania spp. very rapidly drive and maintain sustained T cell-dependent immune responses that arbitrate their ultimate fate within their hosts. The analysis of the parasitism exerted by Leishmania major in mice of different genetic backgrounds has allowed us to recognize some of the early and late mechanisms driven by this parasite that lead to either uncontrolled or restricted parasitism. Uncontrolled parasitism by Leishmania major characterizing mice from a few inbred strains (e.g. BALB/c) is associated with the expansion of parasite reactive Th2 CD4 lymphocytes and results from their rapid and sustained activity. In contrast, restricted parasitism characteristic of mice from the majority of inbred strains results from the development of a polarized parasite-specific Th1 CD4 response. This murine model of infection has already been and will continue to be particularly instrumental in dissecting the rules controlling the pathway of differentiation of T cells in vivo. In the long run, the understanding of these rules should contribute to the rational development of novel immunotherapeutic interventions against severe infectious diseases.

The role of teriparatide in sequential and combination therapy of osteoporosis.

Osteoporosis is complicated by the occurrence of fragility fractures. Over past years, various treatment options have become available, mostly potent antiresorptive agents such as bisphosphonates and denosumab. However, antiresorptive therapy cannot fully and rapidly restore bone mass and structure that has been lost because of increased remodelling. Alternatively recombinant human parathyroid hormone (rhPTH) analogues do increase the formation of new bone material. The bone formation stimulated by intermittent PTH analogues not only increases bone mineral density (BMD) and bone mass but also improves the microarchitecture of the skeleton, thereby reducing incidence of vertebral and nonvertebral fractures. Teriparatide, a recombinant human PTH fragment available in Switzerland, is reimbursed as second-line treatment in postmenopausal women and men with increased fracture risk, specifically in patients with incident fractures under antiresorptive therapy or patients with glucocorticoid-induced osteoporosis and intolerance to antiresorptives. This position paper focuses on practical aspects in the management of patients on teriparatide treatment. Potential first-line indications for osteoanabolic treatment as well as the benefits and limitations of sequential and combination therapy with antiresorptive drugs are discussed.

UPLC-TOF-MS for plant metabolomics: a sequential approach for wound marker analysis in Arabidopsis thaliana.

The model plant Arabidopsis thaliana was studied for the search of new metabolites involved in wound signalling. Diverse LC approaches were considered in terms of efficiency and analysis time and a 7-min gradient on a UPLC-TOF-MS system with a short column was chosen for metabolite fingerprinting. This screening step was designed to allow the comparison of a high number of samples over a wide range of time points after stress induction in positive and negative ionisation modes. Thanks to data treatment, clear discrimination was obtained, providing lists of potential stress-induced ions. In a second step, the fingerprinting conditions were transferred to longer column, providing a higher peak capacity able to demonstrate the presence of isomers among the highlighted compounds.

L'exploitation des ressources végétales dans les Pyrénées orientales durant l'holocène: analyse anthracologique des structures d'élevage, de four et de charbonnières dans l'Alt Urgell (Chaîne du Cadí) et la Vallée du Madriu (Andorre)

Dans ce travail, nous présentons le résultat des recherches anthracologiques réalisées sur des sites archéologiques de haute montagne dans les Pyrénées orientales. Cette recherche s’insère dans un projet d’archéologie du paysage. Les zones d’étude se situent dans les Pré-Pyrénées sur le versant méridional de la chaîne du Cadí (vallée de la Vansa, Alt Urgell), et dans la vallée du Madriu, située dans les Pyrénées axiales, en Andorre. Le but principal de l’analyse anthracologique a été de connaître et comprendre la dynamique et la relation qui unissent les populations qui ont occupé ces vallées avec le milieu forestier de haute montagne. Les échantillons ont été récupérés sur des structures archéologiques associés à l’exploitation forestière (charbonnières, fours pour la fabrication de résine), au pastoralisme (cabanes et enclos) et à l’exploitation minière-métallurgique (four de grillage), avec une chronologie qui débute au Néolithique Ancien et finit à l’époque moderne et contemporaine (XVIII-XIXe siècles). Les résultats indiquent une variabilité taxonomique pauvre avec la présence majoritaire du Pinus et la présence ponctuelle d’autres espèces arbustives (Ericaceae et Juniperus) et arborées, comme Betula alba ou Abies alba. Différentes formations végétales de haute montagne ont été identifiées, selon leur localisation en versant ensoleillé ou ombragé, ainsi que leur altitude. Les résultats montrent des traces d’exploitation forestière dès le Néolithique Ancien, une intensification des activités à l’Antiquité, même si l’impact anthropique majeur correspond à l’activité de charbonnage d’époque moderne.

Financial Exploitation

Financial exploitation is the unauthorized and illegal use of an individual’s funds, property or resources and includes identity theft. Financial exploitation can be committed by a family member, friend, neighbor or a complete stranger.