Generating optimal aircraft trajectories with respect to weather conditions

International audienceTwo major projects have been initiated to improve air traffic management by enabling 4D trajectory planning, whereby the aircraft plan their trajectory both in position and in time. In this paper, we are interested in a Free Flight variant of the concept, whereby airspace users are allowed maximum freedom when selecting routes: aircraft are no longer restricted to fly along airways; rather, they are allowed to fly along optimal routes, from origin to destination, following optimal altitudes, using favourable winds and avoiding hazards. Such optimal routes are good for the environment, for the airlines, and for passengers. The goal of our research is to generate trajectories which minimize congestion and travel time of each aircraft in a way that is fair and efficient. We first optimize the route of a single aircraft relying on an algorithm called Ordered Upwind. And then, with a multi-agent system, we modify trajectories in order to minimize the congestion and to stay as close as possible to the optimal trajectories

CAP: Collaborative advanced planning, trade-off between airspace management and optimized flight performance: Demonstration of En-Route reduced airspace congestion through collaborative flight planning

International audience; High demand of flights on elementary air traffic control sectors results in high delays, extra-fuel burn and CO2 emissions, and may also lead to safety issues due to the destabilization of the aviation network. This paper presents a new control strategy approach to keep control of the current flight demand in European busiest sectors (Reims, Paris and Marseille sectors). Flow management positions in Area Control Centers suggest to airline operations centers delay-free routes for the most capacity impeding flights within the French airspace. Instead of spreading flight demand over time, this innovative approach aims at spreading the demand in space, relying on local expertise and enhanced collaboration. The trials conducted from July to September 2015 proved to be beneficial for airlines operations with more than 12,000 minutes of delay saved compared to summer 2014 while traffic increased by more than 6% from 9h to 13h UTC. Following Airport-Collaborative Decision Making, the Collaborative Advanced Planning process paves the way for the En-Route Collaborative Decision Making concept

A drug repurposing screen identifies altiratinib as a selective inhibitor of a key regulatory splicing kinase and a potential therapeutic for toxoplasmosis and malaria

The apicomplexa comprise a large phylum of single-celled, obligate intracellular protozoa that infect humans and animals and cause severe parasitic diseases. Available therapeutics against these devastating diseases are limited by suboptimal efficacy and frequent side effects, as well as the emergence and spread of resistance. Here, we use a drug repurposing strategy and identify altiratinib, a compound originally developed to treat glioblastoma, as a promising drug candidate with broad spectrum activity against apicomplexans. Altiratinib is parasiticidal and blocks the development of intracellular zoites in the nanomolar range and with a high selectivity index. We have identified TgPRP4K of T. gondii as the primary target of altiratinib by genetic target deconvolution, highlighting key residues within the kinase catalytic site that, when mutated, confer resistance to the drug. We have further elucidated the molecular basis of the inhibitory mechanism and species selectivity of altiratinib for TgPRP4K as well as for its P. falciparum counterpart PfCLK3. Our data also point to structural features critical for binding of the other PfCLK3 inhibitor, TCMDC-135051. Consistent with the role of this kinase family in splicing in a broad spectrum of eukaryotes, we have shown that altiratinib causes global disruption of splicing, primarily through intron retention in both T. gondii and P. falciparum. Thus, our data establish parasitic PRP4K/CLK3 as a promising pan-apicomplexan target whose repertoire of inhibitors can be expanded by the addition of altiratinib

Altiratinib blocks Toxoplasma gondii and Plasmodium falciparum development by selectively targeting a spliceosome kinase

International audienceThe Apicomplexa comprise a large phylum of single-celled, obligate intracellular protozoa that include Toxoplasma gondii , Plasmodium , and Cryptosporidium spp., which infect humans and animals and cause severe parasitic diseases. Available therapeutics against these diseases are limited by suboptimal efficacy and frequent side effects, as well as the emergence and spread of resistance. We use a drug repurposing strategy and identify altiratinib, a compound originally developed to treat glioblastoma, as a promising drug candidate with broad spectrum activity against apicomplexans. Altiratinib is parasiticidal and blocks the development of intracellular zoites in the nanomolar range and with a high selectivity index when used against T. gondii . We have identified Tg PRP4K of T. gondii as the primary target of altiratinib using genetic target deconvolution, which highlighted key residues within the kinase catalytic site that conferred drug resistance when mutated. We have further elucidated the molecular basis of the inhibitory mechanism and species selectivity of altiratinib for Tg PRP4K and for its Plasmodium falciparum counterpart, Pf CLK3. Our data identified structural features critical for binding of the other Pf CLK3 inhibitor, TCMDC-135051. Consistent with the splicing control activity of this kinase family, we have shown that altiratinib can cause global disruption of splicing, primarily through intron retention in both T. gondii and P. falciparum . Thus, our data establish parasitic PRP4K/CLK3 as a potential pan-apicomplexan target whose repertoire of inhibitors can be expanded by the addition of altiratinib

Host cell subversion by Toxoplasma GRA16, an exported dense granule protein that targets the host cell nucleus and alters gene expression.

International audienceAfter invading host cells, Toxoplasma gondii multiplies within a parasitophorous vacuole (PV) that is maintained by parasite proteins secreted from organelles called dense granules. Most dense granule proteins remain within the PV, and few are known to access the host cell cytosol. We identify GRA16 as a dense granule protein that is exported through the PV membrane and reaches the host cell nucleus, where it positively modulates genes involved in cell-cycle progression and the p53 tumor suppressor pathway. GRA16 binds two host enzymes, the deubiquitinase HAUSP and PP2A phosphatase, which exert several functions, including regulation of p53 and the cell cycle. GRA16 alters p53 levels in a HAUSP-dependent manner and induces nuclear translocation of the PP2A holoenzyme. Additionally, certain GRA16-deficient strains exhibit attenuated virulence, indicating the importance of these host alterations in pathogenesis. Therefore, GRA16 represents a potentially emerging subfamily of exported dense granule proteins that modulate host function

Toxoplasma gondii TgIST co-opts host chromatin repressors dampening STAT1-dependent gene regulation and IFN-γ–mediated host defenses

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A Toxoplasma dense granule protein, GRA24, modulates the early immune response to infection by promoting a direct and sustained host p38 MAPK activation

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