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We deal here with the routing of vehicles in charge of performing internal logistics tasks inside someprotected area. Those vehicles are provided in energy by a local solar hydrogen production facility, with limited storage and time-dependent production capacities. One wants to synchronize energy production and consumption in order to minimize both production and routing costs. Because of the complexity of resulting bi-level model, we deal with it by shortcutting the production scheduling level with the help of surrogate estimators, whose values are estimated through fast dynamic programming algorithms and through machine learning.

BackgroundAsiDNA, a first-in-class oligonucleotide-mimicking double-stranded DNA breaks, acts as a decoy agonist to DNA damage response in tumour cells. It also activates DNA-dependent protein kinase and poly (adenosine diphosphate [ADP]-ribose) polymerase enzymes that induce phosphorylation of H2AX and protein PARylation.MethodsThe aim of this Phase 1 study was to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), safety and pharmacokinetics/pharmacodynamics of AsiDNA administered daily for 3 days in the first week then weekly thereafter. Twenty-two patients with advanced solid tumours were enrolled in 5 dose levels: 200, 400, 600, 900, and 1300 mg, using a 3 + 3 design.ResultsThe MTD was not reached. IV AsiDNA was safe. Two DLTs (grade 4 and grade 3 hepatic enzymes increased at 900 and 1300 mg), and two related SAE at 900 mg (grade 3 hypotension and grade 4 hepatic enzymes increased) were reported. AsiDNA PK increased proportionally with dose. A robust activation of DNA-PK by a significant posttreatment increase of γH2AX was evidenced in tumour biopsies.ConclusionThe dose of 600 mg was identified as the optimal dose for further clinical development.Clinical trial registrationClinical trial registration (NCT number): NCT03579628.

International audience

A problem of scheduling n unit-time jobs with a small number of distinct release dates and deadlines, on identical parallel machines, to minimize the number of active machines is studied. The feature that makes this problem challenging is that no machine can stand idle between its start and completion times. A number of properties of this problem is established, and heuristic and optimal algorithms based on these properties are designed. They include optimal algorithms with running times O ( k n k ) and O ( k n 2 3 n ) for the general case, where k is the number of distinct release dates and deadlines, optimal O ( n log n ) algorithms for the cases of a common release date or a common deadline, and an optimal O ( k n 2 ) algorithm for the case of agreeable release dates and deadlines. Algorithms to find lower and upper bounds on the optimal (minimal) number of active machines are developed, and an integer linear programming (ILP) formulation with O ( k ) variables and O ( k 2 ) constraints is provided. Computer experiments demonstrated that the ILP problem is solved by CPLEX to optimality within a few hours for n ≤ 400 and k ≤ 50 , and that the quality of the lower and upper bounds is sufficiently good.

International audience; Synchronizing heterogeneous processes remains a difficult issue in Scheduling area. Related ILP models are in trouble, because of large gaps induced by rational relaxation. We choose here to deal with it while emulating the interactions which take place between the various players of such heterogeneous processes, and propose a pipe-line decomposition of a dynamic programming process designed in order to schedule energy production and energy consumption

The emergence of locally produced renewable energies induces the appearance of a new generation of local energy players, which are at the same time producers and consumers. In case of time dependent solar energy production, it raises the question of synchronizing production and consumption. We deal here with this issue, in the context of an experimental Solar Hydrogen (H2) production platform. More precisely, we try here to simultaneously schedule a H2fueled vehicle which follows a pre-computed route while being compelled to periodically refuel, and the H2production micro-plant which is required to produce related energy under time dependent production costs and productivity rates, both processes being subject to storage capacity constraints. In order to do it, we design a global dynamic programming (DP) algorithm for the resulting NP-Hard problem. This DP algorithm involves a 2D time space which links energy consumption by the vehicle and its production by the micro-plant. Since the number of states induced by this DP algorithm becomes an issue as soon as the size of the problem increases, we first propose a theoretical Polynomial Time Approximation Scheme (PTAS), next design several practical pruning devices and finally perform numerical tests in order to check their efficiency.

International audience; We study here a variant of the multimode Resource Constrained Project Scheduling problem (RCPSP), which involves continuous modes, and a notion of Safety Margin maximization. Our interest was motivated by a work package inside the GEOSAFE H2020 project, devoted to the design of evacuation plans in face of natural disasters, and more specifically wildfire.

Synchronizing heterogeneous processes remains a difficult issue in Scheduling area. Related ILP models are in trouble. So we propose here a pipe-line collaboration of a dynamic programming process for energy production and consumption scheduling.

The emergence of H2 energy produced through photolysis makes appear a new generation of local energy players, which are at the same time producers and consumers. This raises the question of synchronizing H2 production, which deeply depends on the time, and its consumption through some transportation activity. We deal here with this issue, in the context of an experimental H2 production platform, through dynamic programming augmented with ad hoc filtering devices.

International audience; In this article, we address the preemptive Resource-Constrained Precedence Scheduling Problem. We propose two mixed integer formulations containing an exponential number of variables and inequalities. An antichain is a set of pairwise incomparable elements with respect to the precedence constraints. In the first formulation, the integer variables are associated with the antichains. For the second, the integer variables are limited to a particular subset of antichains. We propose two Branch-and-Cut-and-Price algorithms for each of these formulations. We introduce some valid inequalities in order to reinforce the second formulation. Finally, we give some computational results on instances of the PSPLIB and compare the formulations.

Managing a one-way vehicle sharing system means periodically using carriers (trucks, drivers, self-platoon convoys…) in order to move free access vehicles from excess to deficit stations in order to avoid local shortages. Most authors deal with a preemptive version of this problem while considering carrier routes as the master object and focusing on carrier riding costs. We address here a non preemptive version constrained by strong makespan restrictions, which we handle, with the purpose of linking static and on line paradigms, according to a vehicle driven approach which puts vehicle routing strategies at the core of the decisional process.

International audience; We deal here, in the context of a H2020 project, with the design of evacuation plans in face of natural disasters: wildfire, flooding… People and goods have to been transferred from endangered places to safe places. So we schedule evacuee moves along pre-computed paths while respecting arc capacities and deadlines. We model this scheduling problem as a kind of multi-mode Resource Constrained Project Scheduling problem (RCPSP) and handle it through network flow techniques

We study a problem of scheduling unit-time jobs with given release dates and deadlines on identical parallel machines. No machine can stand idle between its start and completion times. The objective is to minimize the number of machines in use. A number of properties of this problem is established, and heuristic and optimal algorithms based on these properties are developed. They include optimal exponential algorithms for the general case and optimal polynomial algorithms for special cases. Lower and upper bounds are determined and an integer linear programming formulation is provided.

Managing a one-way vehicle sharing system means periodically moving free access vehicles from excess to deficit stations in order to avoid local shortages. While putting here the stress on routes followed by the vehicles while being exchanged between excess and deficit stations, we propose and study models and algorithmic approaches for a preemptive version of this problem which involves carrier riding cost, vehicle riding time and carrier number minimization. These approaches are based on the use of Layered Network.

We deal here with theLinear Arrangement Problem(LAP) onintervalgraphs, any interval graph being given here together with its representation as theintersectiongraph of some collection of intervals, and so with relatedprecedenceandinclusionrelations. We first propose a lower boundLB, which happens to be tight in the case ofunit intervalgraphs. Next, we introduce the restriction PCLAP of LAP which is obtained by requiring any feasible solution of LAP to be consistent with theprecedencerelation, and prove that PCLAP can be solved in polynomial time. Finally, we show both theoretically and experimentally that PCLAP solutions are a good approximation for LAP onintervalgraphs.

We consider a static decision model related to the management of a Dial-a-Ride (DAR) system involving small autonomous electrical vehicles in a closed industrial site. Because of the specific features of the system, in this paper we concentrate on its reliability and propose a model that aims at assigning requests to vehicles by minimizing the number of loading/unloading operations. We propose an integer linear programming formulation of such Stop Number Minimization Problem and examine the behavior of some of its variants. Next, we consider and analyze a set covering oriented reformulation of the model. Finally, we propose a Greedy Randomized Adaptive Search Procedure (GRASP) based heuristic approach that implements insertion mechanisms and is well fitted to realistic dynamic contexts. All proposed methods are tested on benchmark instances involving some tens of requests.

Background: AsiDNA is a first-in-class oligonucleotide that mimics double-stranded DNA breaks and acts as a decoy to disrupt the DNA damage response at the “real” sites of DNA damage. It also activates the DNA-PK and PARP enzymes that induce the phosphorylation of H2AX and HSP90 and proteins parylation, respectively. As a result, repair enzymes are no longer recruited to the damage sites, ultimately leading to tumor cell death. Importantly, healthy cells, which display proficient cell cycle control, halt their cell division until AsiDNA is depleted. Patients and Methods: The primary objective was to establish dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) of IV AsiDNA. Other objectives included the safety profile, PK/PD and preliminary efficacy data. Six dose levels (DLs) were planned: 200, 400, 600, 900, 1300 and 1800 mg. All patients (pts) received a loading dose of AsiDNA for 3 consecutive days (D), followed by a 1 hour IV infusion once a week in 21 days cycles (C). In each subsequent cycle, AsiDNA was given weekly. AsiDNA was administered until disease progression, unacceptable toxicity or patient’s decision. Results: Twenty-two pts were treated in the first 5 DLs (153 infusions). Two DLTs were reported (hepatic enzyme increased Gr 3 and Gr 4 at DL 1300 and DL 900, respectively). One related SAE at D42 (Gr 3 orthostatic hypotension) and one related AE at D28 (Gr 3 hypophosphatemia) both at DL 900. AsiDNA PK increased proportionally and consistently with dose from DL1 to DL5. Baseline and on-treatment biopsies were available for 10 pts. There was a robust activation of DNA-PK evidenced by a significant post-treatment increase of γH2AX and pHSP90 from DL 400 with a maximum at DL 600. The quantification of Ki67 showed a clear decrease of the tumor proliferation rate in 7 out of 10 pts evaluated. Best overall response was disease stabilization in 2 pts (9%) with colorectal cancer at DL 600. Conclusions: AsiDNA IV-MTD was not reached. Biological activity was evidenced by the increase of γH2AX and pHSP90. The favorable safety profile was confirmed. DL 600 has been identified as the optimal biological dose for further development given the favorable safety and PK profiles, robust target engagement, and disease stabilization in 2 pts. Citation Format: Christophe Le Tourneau, Jean-Pierre Delord, Philippe Cassier, Nuria Kotecki, Edith Borcoman, Ségolène Hescot, Christiane Jungels, Audrey Mole, Hélène Toussaint, Olga Adamiec, Olivier de Beaumont. Phase I dose escalation study evaluating the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of AsiDNA, a first-in-class DNA Repair Inhibitor, administered intravenously (IV) in patients with advanced solid tumors [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A076. doi:10.1158/1535-7163.TARG-19-A076

Resume Les problemes diagnostiques et therapeutiques que soulevent les algies de la sphere crâniofaciale sont si nombreux et si varies qu’ils semblent devoir defier toute systematisation et meme toute schematisation. Cette complexite n’est guere etonnante, en raison meme de l’extraordinaire richesse de l’innervation sensitive de la face, a laquelle il faut ajouter une vascularisation extremement dense qui peut, elle-meme, etre le siege de « desordres vasomoteurs » a l’origine d’algies particulierement rebelles. Ces particularites anatomophysiologiques sont encore compliquees par le fait que la plupart des regions de la face sont des regions frontieres, chacune d’elles relevant du domaine de specialites souvent bien differentes. Enfin, on ne saurait oublier que le visage constitue pour l’etre humain l’essentiel de ce qu’il livre aux autres, et cela explique la frequence et l’importance du retentissement psychologique qui vient parfois modifier, et tres souvent enrichir la semeiologie clinique des algies de la face.

This paper aims at describing the way Flow machinery may be used in order to deal with Resource Constrained Project Scheduling Problems (RCPSP). In order to do it, it first introduces the Timed Flow Polyhedron related to a RCPSP instance. Next it states several structural results related to connectivity and to cut management. It keeps on with a description of the way this framework gives rise to a generic Insertion operator, which enables programmers to design greedy and local search algorithms. It ends with numerical experiments.

This paper deals with an extension of the Resource Constrained Scheduling Problem (RCPSP), which involves resource transportation delays. We address it through a Timed Flow model, which contains standard RCPSP. Several structure results are then stated. This framework gives rise to a generic Insertion operator, and to greedy and local search algorithms. The paper ends with numerical experiments.

In this paper we deal with the preemptive asymmetric stacker crane problem in a heuristic way. We first present some theoretical results which allow us to turn this problem into a specific tree design problem. We next derive from this new representation an integer linear programming model together with simple and efficient greedy and local search heuristics. We conclude by presenting experimental results which aim at both testing the efficiency of our heuristic and evaluating the impact of the preemption hypothesis.

This paper addresses an extension of the capacitated vehicle routing problem where customer demand is composed of two-dimensional weighted items (2L-CVRP). The objective consists in designing a set of trips minimizing the total transportation cost with a homogenous fleet of vehicles based on a depot node. Items in each vehicle trip must satisfy the two-dimensional orthogonal packing constraints. A GRASPxELS algorithm is proposed to compute solutions of a simpler problem in which the loading constraints are transformed into resource constrained project scheduling problem (RCPSP) constraints. We denote this relaxed problem RCPSP-CVRP. The optimization framework deals with RCPSP-CVRP and lastly RCPSP-CVRP solutions are transformed into 2L-CVRP solutions by solving a dedicated packing problem. The effectiveness of our approach is demonstrated through computational experiments including both classical CVRP and 2L-CVRP instances. Numerical experiments show that the GRASPxELS approach outperforms all previously published methods.

In this paper, we aim at making appear the way Flow Theory may be used in order to deal with combinatorial geometry problems like the 2D-Bin Packing problem. In order to do it, we state a Reformulation Theorem which associates some flow model with a given Bin-Packing problem, and we provide an algorithm.

In this paper, we deal with the preemptive asymmetric stacker crane problem in an heuristic way. We first turn this problem into a specific tree design problem. We next derive from this new representation simple, efficient greedy and local search heuristics. We conclude by presenting experimental results which aim at both testing the efficiency of our heuristic and at evaluating the impact of the preemption hypothesis.

Purpose: while being registered and used in restricted subset of T-cell lymphoma, HDAC inhibitors (HDACi) have shown limited antitumor effect as single agents. Recent studies have shown an effect of HDACi on DNA damage accumulation, rationalizing their combination with DNA repair inhibitors. In the current study, we propose a novel therapeutic strategy, based on drug combination of HDACi with the pan-DNA break repair inhibitor AsiDNA to promote their antitumor activity. Experimental design: AsiDNATM is a double stranded DNA molecule (decoy oligo-nucleotide) that mimics double stranded DNA breaks (DSBs) to interfere with DNA repair, redirecting repair enzymes away from sites of tumor DNA damage. Belinostat is a pan-HDACi displaying a better safety profile compared to other HDACi. We characterized the effects of each drug on DNA break accumulation and genetic instability by γH2AX analysis, COMET assay and micronuclei detection. We further studied the antitumor efficacy of the combination of the two drugs. Finally, we assessed the effect of AsiDNA on the occurrence of acquired resistance after long term treatment with belinostat. Results: Molecular analyses of DNA damage after treatment demonstrate that belinostat paves the way for AsiDNA efficacy by inducing DNA DSBs as measured by γH2AX accumulation and tail moment increase on COMET assay. Moreover, continuous treatment with belinostat induced an increase of basal genetic instability in tumor cells measured by micronuclei accumulation, a prerequisite for AsiDNA antitumor efficacy1. On the other hand, AsiDNA enhances the effects of belinostat on histone acetylation, demonstrating a high potentiation of belinostat activity on its targets by AsiDNA. This mechanism-based cross-potentiation between AsiDNA and belinostat results in a high synergistic antitumor efficacy of the combined treatment in different tumor models. This synergistic effect was further confirmed with several HDACi belonging to different classes. Importantly, the combined treatment do not induce any DNA damage increase and/or lethality in non-tumor cells. Finally, repeated treatments allowed the emergence of resistance to belinostat, which is abrogated in presence of AsiDNA, indicating an unlikely tumor escape to this combined therapy. Conclusion: Altogether these results indicate a cross potentiation between AsiDNA and belinostat, and support the rational to investigate the clinical activity of this novel synergistic combination in different tumor types. As belinostat has obtained FDA conditional approval, and AsiDNA is already tested in a first-in-man clinical trial, a potential exists for a rapid clinical confirmation of the interest of this new combination. Citation Format: Wael Jdey, Hélène Toussaint, Coraline Cassegrain, Laura Bellassen, Richard Tripelon, Vincent Hayes, Perrine Pivette, Véronique Trochon-Joseph, Jean-Louis Labernardière, Marie Dutreix, Françoise Bono Colombie. AsiDNA and HDAC inhibitors: A cross-potentiation team working to kill tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2818.

Resume Nous avons rapporte le recit clinique d’un patient sri lankais souffrant depuis 12 ans des sequelles de tortures multiples, dont la methode de suspension par les pouces. Les douleurs neuropathiques des pouces/eminences thenar constituaient sa plainte essentielle. Mais la faible efficacite des traitements specifiques ont permis d’evoquer une souffrance psychique post-traumatique. C’est la l’occasion d’attirer l’attention des praticiens et medecins de la douleur sur la conduite a tenir en presence d’un patient victime de torture. Ce sujet n’est pas aborde dans les revues ou ouvrages medicaux, mais le ministere de la Sante et l’Association pour les victimes de repression en exil (Avre) ont coedite un indispensable opuscule. Le traitement medicamenteux est insuffisant. L’aide a la victime se fait en lien avec les organismes sociaux, juridiques et les associations qui jouent un role essentiel.

The lentiviral Nef protein has been studied extensively for its ability to induce the downregulation of several immunoreceptors on the surfaces of infected cells. However, Nef expression is unique in inducing highly effective upregulation of the major histocompatibility complex class II-associated chaperone invariant (Ii) chain complexes in different cell types. Under normal conditions, endocytosis of the Ii chain and other molecules, like the transferrin receptor and CD4, is rapid and AP-2 dependent. Human immunodeficiency virus type 1 (HIV-1) Nef expression strongly reduces the internalization of the Ii chain, enhances that of CD4, and does not modify transferrin uptake. The mutation of AP-2 binding motifs LL164 and DD174 in Nef leads to the inhibition of Ii chain upregulation. In AP-2-depleted cells, surface levels of the Ii chain are high and remain unmodified by Nef expression, further indicating that Nef regulates Ii chain internalization via the AP-2 pathway. Immunoprecipitation experiments revealed that the Ii chain can interact with Nef in a dileucine-dependent manner. Importantly, we have shown that Nef-induced CD4 downregulation and Ii chain upregulation are genetically distinguishable. We have identified natural nef alleles that have lost one of the two functions but not the other one. Moreover, we have characterized Nef mutant forms possessing a similar phenotype in the context of HIV-1 infection. Therefore, the Nef-induced accumulation of Ii chain complexes at the cell surface probably results from a complex mechanism leading to the impairment of AP-2-mediated endocytosis rather than from direct competition between Nef and the Ii chain for binding AP-2.

International audience; This paper first describes an efficient exact algorithm to solve Preemptive RCPSP and next discusses its extension to Non Preemptive RCPSP. In case of Preemptive RCPSP, we propose a very original and efficient branch and bound/price procedure based upon minimal interval order enumeration, which is implemented with the help of the generic SCIP software. We perform tests on the famous PSPLIB instances which provide very satisfactory results. To the best of our knowledge it is the first algorithm able to solve at optimality all the set of j30 instances of PSPLIB in a preemptive way. The two last sections are devoted to the description of some heuristics, which also involve the interval order framework and the basic antichain linear program and which aim at handling larger scale RCPSP preemptive instances, and to a discussion of the way our algorithm may be extended to Non Preemptive RCPSP.

The Territorial Climate Energy Plan (PCET) of the agglomeration of Dijon (Grand Dijon) includes ameasurement campaign (6 June to 28 September 2014). 50 Hobo proV2 thermometers were deployed. The selection of siteswas carried out so that the different types of urban environment (Oke, 2006) are documented. The Urban Heat Island (UHI)is discernible mainly at night, when radiative conditions are well established the day before. It is estimated to 1°C onaverage for the summer, 3-4°C during nights of fine weather. It reached 6°C during the warmest periods of the 2014 summer.A cool axis through the agglomeration shows that vegetation and water can sensibly mitigate the ICU effect., Dans le cadre du Plan Climat Énergie Territoire (PCET) du Grand Dijon, une campagne de mesures a étéconduite du 6 juin au 28 septembre 2014. 50 sondes Hobo proV2 ont été déployées. Le choix des sites a été effectué demanière à ce que les différents types d'environnement urbain (Oke, 2006) soient représentés. L’Îlot de Chaleur Urbain (ICU)s'exprime principalement la nuit, lorsque des conditions radiatives étaient bien établies la veille. L'ICU est estimé à 1°C enmoyenne sur l'été et 3 à 4°C les nuits de beau temps. Il a atteint 6°C lors des périodes les plus chaudes de l'été 2014. Un axefrais traversant l'agglomération montre que la présence de végétation et d'eau atténue l'effet de l'ICU.

International audience; In this paper we address the Preemptive Resource Constrained Project Scheduling Problem (PRCPSP). PRCPSP requires a partially ordered set of activities to be scheduled using limited renewable resources such that any activity can be interrupted and later resumed without penalty. The objective is to minimize the project duration. This paper proposes an effective branch-and-price algorithm for solving PRCPSP based upon minimal Interval Order Enumeration involving column generation as well as constraint propagation. Experiments conducted on various types of instances have given very satisfactory results. Our algorithm is able to solve to optimality the entire set of J30, BL and Pack instances while satisfying the preemptive requirement. Furthermore, this algorithm provides improved best-known lower bounds for some of the J60, J90 and J120 instances in the non-preemptive case (RCPSP).

International audience; This paper describes an efficient exact algorithm to solve the Resource Constrained Project Scheduling Problem (RCPSP). We propose an original and efficient branch and price procedure which involves minimal interval order enumeration as well as constraint propagation and which is implemented with the help of the generic SCIP software. We perform tests on the famous PSPLIB instances which provide very satisfactory results.

This paper addresses an extension of the capacitated vehicle routing problem where the client demand consists of three-dimensional weighted items (3L-CVRP). The objective is to design a set of trips for a homogeneous fleet of vehicles based at a depot node which minimizes the total transportation cost. Items in each vehicle trip must satisfy the three-dimensional orthogonal packing constraints. This problem is strongly connected to real-life transportation systems where the packing of items to be delivered by each vehicle can have a significant impact on the routes. We propose a new way to solve the packing sub-problem. It consists of a two-step procedure in which the z-constraints are first relaxed to get a (x,y) positioning of the items. Then, a compatible z-coordinate is computed to get a packing solution. Items can be rotated but additional constraints such as item fragility, support and LIFO are not considered. This method is included in a GRASPxELS hybrid algorithm dedicated to the computation of VRP routes. The route optimization alternates between two search spaces: the space of VRP routes and the space of giant trips. The projection from one to the other is done by dedicated procedures (namely the Split and the concatenation algorithms). Moreover, a Local Search is defined on each search space. Furthermore, hash tables are used to store the result of the packing checks and thus save a substantial amount of CPU time. The effectiveness of our approach is illustrated by computational experiments on 3L-CVRP instances from the literature. A new set of realistic instances based on the 96 French districts are also proposed. They range from 19 nodes for the small instances to 255 nodes for the large instances and they can be stated as realistic since they are based on true travel distances in kilometers between French cities. The impact of the hash tables is illustrated as well.

This paper deals with two extensions of the Resource Constrained Project Scheduling Problem (RCPSP), which involve resource transfer delays and ”Financial” resources. Flow models are used in order to formalize those extended RCPSP, which contain the standard RCPSP and lead us to the Timed Flow Polyhedron and to several structural results. This framework gives rise to generic Insertion operators, as well as greedy/local search algorithms. We end with numerical tests.

This paper addresses an extension of the Capacitated Vehicle Routing Problem where the client demand consists of three-dimensional weighted items (3L-CVRP). The objective is to design a set of trips for a homogenous fleet of vehicles based on a depot node which minimizes the total transportation cost. Items in each vehicle trip must satisfy the three-dimensional orthogonal packing constraints. A GRASP ELS algorithm is proposed to compute the best possible solution. We propose a new method to address the 3D packing which allows items to be rotated or not. It is based on a relaxation of the 3D problem in which items coordinates are first computed before getting compatible z-coordinates. Additional techniques are used to reduce as much as possible the time to check the 3D packing feasibility of trips. The effectiveness of our approach is evidenced through computational experiments on 3L-CVRP instances from the literature. New realistic instances are also proposed. These instances are based on the 96 French districts and encompass both small scale instances and large scale instances with up to 200 nodes.

This paper addresses an extension of the well-known Capacitated Vehicle Routing Problem (CVRP) where the customer demands represented by two-dimensional weighted items have to be packed into the vehicles. This problem, denoted 2L-CVRP, is NP-hard and it is particularly difficult to solve in practice. We propose a GRASP algorithm in which the loading constraint is handled by a Resource Constraint Project Scheduling Problem (RCPSP) heuristic specially tuned to address the bin-packing part of the problem. The effectiveness of our approach is demonstrated through computational experiments on both CVRP and non-sequential 2L-CVRP instances. Three new best average costs for class 2–5 are provided for 2L-CVRP instances.

Newly synthesized MHC II alpha- and beta-chains associated with the invariant chain chaperone (Ii) enter the endocytic pathway for Ii degradation and loading with peptides before transport to the cell surface. It is unclear how alphabetaIi complexes are sorted from the Golgi apparatus and directed to endosomes. However, indirect evidence tends to support direct transport involving the AP1 clathrin adaptor complex. Surprisingly, we show here that knocking down the production of AP1 by RNA interference did not affect the trafficking of alphabetaIi complexes. In contrast, AP2 depletion led to a large increase in surface levels of alphabetaIi complexes, inhibited their rapid internalization, and strongly delayed the appearance of mature MHC II in intracellular compartments. Thus, in the cell systems studied here, rapid internalization of alphabetaIi complexes via an AP2-dependent pathway represents a key step for MHC II delivery to endosomes and lysosomes.

Effective vaccine design depends in part on the ability to target specific antigens (Ag) to Ag presenting cells (APCs), including dendritic cells (DCs). Further, to generate effective antitumor and antiviral immunity, vaccine platforms should enable efficient MHC class I and class II restricted antigen processing leading to synergistic CD4 and CD8 T-cell responses. To facilitate targeted vaccine delivery, we have developed Poly(dG)-protein Ags. These Ag conjugates have the potential to greatly increase vaccine efficiency by inducing spontaneous aggregation of Ag into particulate complexes with intrinsic adjuvant function. The resulting particulate structure includes exposed phosphate groups with affinity for scavenger receptors expressed by APCs. We have successfully conjugated Poly(dG) residues to the model Ag ovalbumin (OVA) and found that Poly(dG)-OVA can be rapidly endocytosed, and efficiently presented to class II-restricted T cells, and cross-presented to class I-restricted T cells in vitro and in vivo. We compared DCs internalization of Poly(dG) conjugated and unconjugated Ag using confocal microscopy and found that Poly(dG)-OVA bound to the cell surface of DCs with higher affinity and was internalized several times more efficiently than Ag alone. These results suggest that coupling Poly(dG) to Ags enables efficient APCs targeting. Understanding the mechanisms of internalization, processing, and presentation of Poly(dG)-Ags will contribute to future vaccine design.

Efficient and specific targeting of antigen (Ag) to Ag presenting cells (APCs) in vivo is a critical challenge for vaccine design. Ag delivery and formulation strategies have been directly linked to type and the quality of induced immune responses. APCs acquire Ags in a variety of forms from a variety of sources and endocytic mechanisms can predetermine intracellular Ag routing, processing and presentation to CD4 or CD8 T cells. We have designed an APCs targeting strategy based on simple and direct coupling of Poly(dG) oligo deoxynucleotides to protein Ags. In comparison to soluble OVA, we find that conjugates of Poly(dG) and OVA (Poly(dG)-OVA) are rapidly internalized by DCs and follow distinct intracellular processing pathways. Importantly, immunization of naïve animals by direct injection of Poly(dG)-OVA induces protective multifunctional T cell immunity. This includes efficient priming of potent antigen specific CTL responses, differentiation of naïve CD4 T cells into Th1 CD4 T cells, induction of specific memory T cell responses, and generation of Ag-specific antibody responses. Extending our findings to human skin, we show that intradermal injection of Poly(dG)-Ag results in efficient uptake by human skin migratory DCs, preferentially dermal CD14+ DCs, that also acquire potent T cells stimulatory functions. Our data suggest that Poly(dG) can both target Ags to human skin immune APCs and function as an adjuvant to induce potent CD4 and CD8 mediated T cell immunity.

International audience; Ce travail présente les résultats préliminaires de caractérisation de l'ilot de chaleur urbain de l'agglomération dijonnaise (extension, intensité, variabilité) obtenus d'une part à l'aide d'une campagne de mesure instrumentale, d'autre part à l'aide du modèle de canopée urbaine BEP-BEM couplé au modèle de climat régional WRF/ARW. Les simulations numériques sont d'abord effectuées en mode hindcast sur l'été 2006 (ayant connu un épisode caniculaire) à une résolution horizontale de 150m. Un travail important a consisté à produire des conditions aux limites aussi réalistes que possible pour obtenir une occupation du sol et une morphologie urbaine de bonne qualité. L'approche retenue se base sur les bases de données Corine Land Cover, IGN, INSEE et OpenStreetMap pour rendre la démarche aussi généralisable que possible. Les résultats de ces simulations montrent une variabilité temporelle satisfaisante en regard des stations Météo-France locales. La campagne de mesure, réalisée pendant l'été 2014 dans le cadre du Plan Climat Énergie Territoire (PCET) du Grand Dijon, comprend 50 sondes Hobo proV2 déployées sur l'ensemble de l'agglomération. Le choix des sites a été effectué de manière à ce que les différents types d'environnement urbain (Oke, 2006) soient représentés. Afin que chaque site de mesure soit représentatif du quartier, et le moins possible influencé par son environnement immédiat (rue, cour, ....), des sites ouverts ont été sélectionnés, évitant le plus possible les ombres portées (bâtiments, arbres, ...). Les abris M-RSA contenant les sondes ont été fixés à 3 m du sol sur des candélabres, côté sud, ce au moyen de pattes prolongées afin d'éviter que la température soit influencée par le candélabre (variable en couleur comme en matériau). La densité du réseau de mesures permet une spatialisation relativement fine du champ de température (en dépit d'un été ayant connu un déficit radiatif très élevé, en particulier sur le nord-est de la métropole). L'étape suivante consiste à croiser et comparer les deux approches sur les années 2013-2014 : à l'heure de ces AMA2015, ce travail poursuit son cours.