Performance enhancement of a GIS-based facility location problem using desktop grid infrastructure

This paper presents the integration of desktop grid infrastructure with GIS technologies, by proposing a parallel resolution method in a generic distributed environment. A case study focused on a discrete facility location problem, in the biomass area, exemplifies the high amount of computing resources (CPU, memory, HDD) required to solve the spatial problem. A comprehensive analysis is undertaken in order to analyse the behaviour of the grid-enabled GIS system. This analysis, consisting of a set of the experiments on the case study, concludes that the desktop grid infrastructure is able to use a commercial GIS system to solve the spatial problem achieving high speedup and computational resource utilization. Particularly, the results of the experiments showed an increase in speedup of fourteen times using sixteen computers and a computational efficiency greater than 87 % compared with the sequential procedure.This work has been developed under the support of the program Formacion de Personal Investigador, grants number BFPI/2009/103 and BES-2007-17019, from the Conselleria d'Educacio of the Generalitat Valenciana and the Spanish Ministry of Science and Technology.García García, A.; Perpiñá Castillo, C.; Alfonso Laguna, CD.; Hernández García, V. (2013). Performance enhancement of a GIS-based facility location problem using desktop grid infrastructure. Earth Science Informatics. 6(4):199-207. https://doi.org/10.1007/s12145-013-0119-1S19920764Anderson D (2004) Boinc: a system for public-resource computing and storage. Proceedings of the 5th IEEE/ACM International Workshop on Grid Computing. IEEE Computer Society, Washington DC, pp 4–10Available scripts webpage: http://personales.upv.es/angarg12/Campos I et al (2012) Modelling of a watershed: a distributed parallel application in a grid framework. Comput Informat 27(2):285–296Church RL (2002) Geographical information systems and location science. Comput Oper Res 29:541–562Clarke KC (1986) Advances in geographic information systems, computers. Environ Urban Syst 10:175–184Dowers S, Gittings BM, Mineter MJ (2000) Towards a framework for high-performance geocomputation: handling vector-topology within a distributed service environment. Comput Environ Urban Syst 24:471–486Geograma SL (2009). Teleatlas. http://www.geograma.com . Accessed September 2009GRASS Development Team (2012) GRASS GIS. http://grass.osgeo.org/Hoekstra AG, Sloot PMA (2005) Introducing grid speedup: a scalability metric for parallel applications on the grid, EGC 2005, LNCS 3470, pp. 245–254Hu Y et al. (2004) Feasibility study of geo-spatial analysis using grid computing. Computational Science-ICCS. Springer Berlin Heidelberg, 956–963Huang Z et al (2009) Geobarn: a practical grid geospatial database system. Adv Electr Comput Eng 9:7–11Huang F et al (2011) Explorations of the implementation of a parallel IDW interpolation algorithm in a Linux cluster-based parallel GIS. Comput Geosci 37:426–434Laure E et al (2006) Programming the grid with gLite. CMST 12(1):33–45Li WJ et al (2005) The Design and Implementation of GIS Grid Services. In: Zhuge H, Fox G (eds) Grid and Cooperative Computing. Vol. 3795 of Lecture Notes in Computer Science 10. Springer, Berlin, pp 220–225National Geographic Institute (2010) BCN25: numerical cartographic database. http://www.ign.es/ign/main/index.do . Accessed April 2010Open Geospatial Consortium, Inc (2012) Open GIS Specification Model, http://www.opengeospatial.org/Openshaw S, Turton I (1996) A parallel Kohonen algorithm for the classification of large spatial datasets. Comput Geosci 22:1019–1026Perpiñá C, Alfonso D, Pérez-Navarro A (2007) BIODER project: biomass distributed energy resources assessment and logistic strategies for sitting biomass plants in the Valencia province (Spain), 17th European Biomass Conference and Exhibition Proceedings, Hamburg, Germany, pp. 387–393Perpiñá C et al (2008) Methodology based on Geographic Information Systems for biomass logistics and transport optimization. Renew Energ 34:555–565Shen Z et al (2007) Distributed computing model for processing remotely sensed images based on grid computing. Inf Sci 177:504–518Spanish Ministry of Agriculture, fisheries and food (2009). http://www.magrama.gob.es/es/ . Accessed March 2009Spanish Ministry of Environment (2008). http://www.magrama.gob.es/es/ . Accessed May 2008University of California. List of BOINC projects. http://boinc.berkeley.edu/projects.phpXiao N, Fu W (2003) SDPG: Spatial data processing grid. J Comput Sci Technol 18:523–53

Toolkit of Approaches To Support Target-Focused Drug Discovery for Plasmodium falciparum Lysyl tRNA Synthetase

There is a pressing need for new medicines to prevent and treat malaria. Most antimalarial drug discovery is reliant upon phenotypic screening. However, with the development of improved target validation strategies, target-focused approaches are now being utilized. Here, we describe the development of a toolkit to support the therapeutic exploitation of a promising target, lysyl tRNA synthetase (PfKRS). The toolkit includes resistant mutants to probe resistance mechanisms and on-target engagement for specific chemotypes; a hybrid KRS protein capable of producing crystals suitable for ligand soaking, thus providing high-resolution structural information to guide compound optimization; chemical probes to facilitate pulldown studies aimed at revealing the full range of specifically interacting proteins and thermal proteome profiling (TPP); as well as streamlined isothermal TPP methods to provide unbiased confirmation of on-target engagement within a biologically relevant milieu. This combination of tools and methodologies acts as a template for the development of future target-enabling packages

Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs

Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described. The series has been developed against M. tuberculosis lysyl-tRNA synthetase (LysRS) and cellular studies support this mechanism of action. DDD02049209, the lead compound, is efficacious in mouse models of acute and chronic tuberculosis and has suitable physicochemical, pharmacokinetic properties and an in vitro safety profile that supports further development. Importantly, preliminary analysis using clinical resistant strains shows no pre-existing clinical resistance towards this scaffold

Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis

Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage; Plasmodium falciparum; and; Cryptosporidium parvum; in cell-culture studies. Target deconvolution in; P. falciparum; has shown that cladosporin inhibits lysyl-tRNA synthetase (; Pf; KRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both; Pf; KRS1 and; C. parvum; KRS (; Cp; KRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED; 90; = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between; Pf; KRS1 and; Cp; KRS. This series of compounds inhibit; Cp; KRS and; C. parvum; and; Cryptosporidium hominis; in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for; Pf; KRS1 and; Cp; KRS vs. (human); Hs; KRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis