The linear programing algorithms available for optimizing the routing of shipments in multi-plant, multi-destination systems cannot, in the current state of knowledge, be applied directly to the more general problem of determining the number and location of regional warehouses in large-scale distribution networks. This paper outlines a heuristic computer program for locating warehouses and compares it with recently published efforts at solving the problem either by means of simulation or as a variant of linear programing. The heuristic approach outlined in this paper appears to offer significant advantages in the solution of this class of problems in that it (1) provides considerable flexibility in the specification (modeling) of the problem to be solved, (2) can be used to study large-scale problems, that is, complexes with several hundred potential warehouse sites and several thousand shipment destinations, and (3) is economical of computer time. The results obtained in applying the program to small scale problems have been equal to or better than those provided by the alternative methods considered.
Background Plasmodium falciparum malaria is one of the most widespread parasitic infections in humans and remains a leading global health concern. Malaria elimination efforts are threatened by the emergence and spread of resistance to artemisinin-based combination therapy, the first-line treatment of malaria. Promising molecular markers and pathways associated with artemisinin drug resistance have been identified, but the underlying molecular mechanisms of resistance remains unknown. The genomic data from early period of emergence of artemisinin resistance (2008–2011) was evaluated, with aim to define k13 associated genetic background in Cambodia, the country identified as epicentre of anti-malarial drug resistance, through characterization of 167 parasite isolates using a panel of 21,257 SNPs.ResultsEight subpopulations were identified suggesting a process of acquisition of artemisinin resistance consistent with an emergence-selection-diffusion model, supported by the shifting balance theory. Identification of population specific mutations facilitated the characterization of a core set of 57 background genes associated with artemisinin resistance and associated pathways. The analysis indicates that the background of artemisinin resistance was not acquired after drug pressure, rather is the result of fixation followed by selection on the daughter subpopulations derived from the ancestral population.ConclusionsFunctional analysis of artemisinin resistance subpopulations illustrates the strong interplay between ubiquitination and cell division or differentiation in artemisinin resistant parasites. The relationship of these pathways with the P. falciparum resistant subpopulation and presence of drug resistance markers in addition to k13, highlights the major role of admixed parasite population in the diffusion of artemisinin resistant background. The diffusion of resistant genes in the Cambodian admixed population after selection resulted from mating of gametocytes of sensitive and resistant parasite populations.Electronic supplementary materialThe online version of this article (10.1186/s12936-017-2140-1) contains supplementary material, which is available to authorized users.
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