Single machine scheduling with controllable processing times by submodular optimization

In scheduling with controllable processing times the actual processing time of each job is to be chosen from the interval between the smallest (compressed or fully crashed) value and the largest (decompressed or uncrashed) value. In the problems under consideration, the jobs are processed on a single machine and the quality of a schedule is measured by two functions: the maximum cost (that depends on job completion times) and the total compression cost. Our main model is bicriteria and is related to determining an optimal trade-off between these two objectives. Additionally, we consider a pair of associated single criterion problems, in which one of the objective functions is bounded while the other one is to be minimized. We reduce the bicriteria problem to a series of parametric linear programs defined over the intersection of a submodular polyhedron with a box. We demonstrate that the feasible region is represented by a so-called base polyhedron and the corresponding problem can be solved by the greedy algorithm that runs two orders of magnitude faster than known previously. For each of the associated single criterion problems, we develop algorithms that deliver the optimum faster than it can be deduced from a solution to the bicriteria problem

Comparative Gene Expression Analysis throughout the Life Cycle of Leishmania braziliensis: Diversity of Expression Profiles among Clinical Isolates

Leishmania is a group of parasites (Protozoa, Trypanosomatidae) responsible for a wide spectrum of clinical forms. Among the factors explaining this phenotypic polymorphism, parasite features are important contributors. One approach to identify them consists in characterizing the gene expression profiles throughout the life cycle. In a recent study, the transcriptome of 3 Leishmania species was compared and this revealed species-specific differences, albeit in a low number. A key issue, however, is to ensure that the observed differences are indeed species-specific and not specific of the strains selected for representing the species. In order to illustrate the relevance of this concern, we analyzed here the gene expression profiles of 5 clinical isolates of L. braziliensis at seven time points of the life cycle. Our results clearly illustrate the unique character of each isolate in terms of gene expression dynamics: one Leishmania strain is not necessarily representative of a given species

ATG5 is essential for ATG8-dependent autophagy and mitochondrial homeostasis in Leishmania major

Macroautophagy has been shown to be important for the cellular remodelling required for Leishmania differentiation. We now demonstrate that L. major contains a functional ATG12-ATG5 conjugation system, which is required for ATG8-dependent autophagosome formation. Nascent autophagosomes were found commonly associated with the mitochondrion. L. major mutants lacking ATG5 (Δatg5) were viable as promastigotes but were unable to form autophagosomes, had morphological abnormalities including a much reduced flagellum, were less able to differentiate and had greatly reduced virulence to macrophages and mice. Analyses of the lipid metabolome of Δatg5 revealed marked elevation of phosphatidylethanolamines (PE) in comparison to wild type parasites. The Δatg5 mutants also had increased mitochondrial mass but reduced mitochondrial membrane potential and higher levels of reactive oxygen species. These findings indicate that the lack of ATG5 and autophagy leads to perturbation of the phospholipid balance in the mitochondrion, possibly through ablation of membrane use and conjugation of mitochondrial PE to ATG8 for autophagosome biogenesis, resulting in a dysfunctional mitochondrion with impaired oxidative ability and energy generation. The overall result of this is reduced virulence

Metabolomic analyses of Leishmania reveal multiple species differences and large differences in amino acid metabolism

Comparative genomic analyses of Leishmania species have revealed relatively minor heterogeneity amongst recognised housekeeping genes and yet the species cause distinct infections and pathogenesis in their mammalian hosts. To gain greater information on the biochemical variation between species, and insights into possible metabolic mechanisms underpinning visceral and cutaneous leishmaniasis, we have undertaken in this study a comparative analysis of the metabolomes of promastigotes of L. donovani, L. major and L. mexicana. The analysis revealed 64 metabolites with confirmed identity differing 3-fold or more between the cell extracts of species, with 161 putatively identified metabolites differing similarly. Analysis of the media from cultures revealed an at least 3-fold difference in use or excretion of 43 metabolites of confirmed identity and 87 putatively identified metabolites that differed to a similar extent. Strikingly large differences were detected in their extent of amino acid use and metabolism, especially for tryptophan, aspartate, arginine and proline. Major pathways of tryptophan and arginine catabolism were shown to be to indole-3-lactate and arginic acid, respectively, which were excreted. The data presented provide clear evidence on the value of global metabolomic analyses in detecting species-specific metabolic features, thus application of this technology should be a major contributor to gaining greater understanding of how pathogens are adapted to infecting their hosts

Sterol 14α-demethylase mutation leads to amphotericin B resistance in Leishmania mexicana

Amphotericin B has emerged as the therapy of choice for use against the leishmaniases. Administration of the drug in its liposomal formulation as a single injection is being promoted in a campaign to bring the leishmaniases under control. Understanding the risks and mechanisms of resistance is therefore of great importance. Here we select amphotericin B-resistant Leishmania mexicana parasites with relative ease. Metabolomic analysis demonstrated that ergosterol, the sterol known to bind the drug, is prevalent in wild-type cells, but diminished in the resistant line, where alternative sterols become prevalent. This indicates that the resistance phenotype is related to loss of drug binding. Comparing sequences of the parasites’ genomes revealed a plethora of single nucleotide polymorphisms that distinguish wild-type and resistant cells, but only one of these was found to be homozygous and associated with a gene encoding an enzyme in the sterol biosynthetic pathway, sterol 14α-demethylase (CYP51). The mutation, N176I, is found outside of the enzyme’s active site, consistent with the fact that the resistant line continues to produce the enzyme’s product. Expression of wild-type sterol 14α-demethylase in the resistant cells caused reversion to drug sensitivity and a restoration of ergosterol synthesis, showing that the mutation is indeed responsible for resistance. The amphotericin B resistant parasites become hypersensitive to pentamidine and also agents that induce oxidative stress. This work reveals the power of combining polyomics approaches, to discover the mechanism underlying drug resistance as well as offering novel insights into the selection of resistance to amphotericin B itself

Analytical techniques for multiplex analysis of protein biomarkers

Introduction: The importance of biomarkers for pharmaceutical drug development and clinical diagnostics is more significant than ever in the current shift toward personalized medicine. Biomarkers have taken a central position either as companion markers to support drug development and patient selection, or as indicators aiming to detect the earliest perturbations indicative of disease, minimizing therapeutic intervention or even enabling disease reversal. Protein biomarkers are of particular interest given their central role in biochemical pathways. Hence, capabilities to analyze multiple protein biomarkers in one assay are highly interesting for biomedical research. Areas covered: We here review multiple methods that are suitable for robust, high throughput, standardized, and affordable analysis of protein biomarkers in a multiplex format. We describe innovative developments in immunoassays, the vanguard of methods in clinical laboratories, and mass spectrometry, increasingly implemented for protein biomarker analysis. Moreover, emerging techniques are discussed with potentially improved protein capture, separation, and detection that will further boost multiplex analyses. Expert commentary: The development of clinically applied multiplex protein biomarker assays is essential as multi-protein signatures provide more comprehensive information about biological systems than single biomarkers, leading to improved insights in mechanisms of disease, diagnostics, and the effect of personalized medicine.</div

A Recovering Beam Search algorithm for the one-machine dynamic total completion time scheduling problem

International audienceThis paper deals with the one-machine dynamic total completion time scheduling problem. This problem is known to be NP-hard in the strong sense. A polynomial time heuristic algorithm is proposed which applies the recently introduced Recovering Beam Search (RBS) approach. The algorithm is based on a beam search procedure with unitary beam width and includes a recovering subroutine that allows to overcome wrong decisions taken at higher levels of the beam search tree. It is shown that the total number of considered nodes is bounded by n where n is the jobsize. The proposed algorithm is able to solve in very short CPU time problems with up to 500 jobs outperforming the best state of the art heuristics

Improving the preemptive bound for the one-machine dynamic total completion time scheduling problem

International audienceWe consider the single machine dynamic total completion time scheduling problem. This problem is known to be NP-hard in the strong sense. The currently best available lower bound for the problem is known to be the optimal solution value of the corresponding preemptive problem which can be computed in $O(n \log n)$ time. We propose an improvement on this bound by exploiting the properties of the preemptive solution. The proposed improvement reduces by approximately 44% on the average the gap between the preemptive solution value and the optimal solution value

Exponential time algorithms for just-in-time scheduling problems with common due date and symmetric weights

This paper focuses on the solution, by exact exponential-time algorithms, of just-in-time scheduling problems when jobs have symmetric earliness/tardiness weights and share a non restrictive common due date. For the single machine problem, a Sort & Search algorithm is proposed with worst-case time and space complexities in O∗(1. 4143 n). This algorithm relies on an original modeling of the problem. For the case of parallel machines, an algorithm integrating a dynamic programming algorithm across subsets and machines and the above Sort & Search algorithm is proposed with worst-case time and space complexities in O∗(3 n). To the best of our knowledge, these are the first worst-case complexity results obtained for non regular criteria in scheduling