ABCG2 Is Overexpressed on Red Blood Cells in Ph-Negative Myeloproliferative Neoplasms and Potentiates Ruxolitinib-Induced Apoptosis

Acknowledgments: The authors would like to thank Dominique Gien, Sirandou Tounkara, and Eliane Véra at Centre National de Référence pour les Groupes Sanguins for the management of blood samples. Funding: The work was supported by Institut National de la Santé et de la Recherche Médicale (Inserm), Institut National de la Transfusion Sanguine (INTS), the University of Paris, and grants from Laboratory of Excellence (Labex) GR-Ex, reference No. ANR-11-LABX-0051. The Labex GR-Ex is funded by the IdEx program “Investissements d’avenir” of the French National Research Agency, reference No. ANR-18-IDEX-0001. R.B. was funded by the European Union’s Horizon 2020 Research and Innovation Program under grant agreement No. 675115-RELEVANCE-H2020-MSCA-ITN-2015. M.B. was funded by Ministère de l’Enseignement Supérieur et de la Recherche at the BioSPC Doctoral School. R.B. and M.B. also received financial support from Société Française d’Hématologie (SFH) and Club du Globule Rouge et du Fer (CGRF).Peer reviewedPublisher PD

Logic against Ghosts: Comparison of Two Proof Approaches for a List Module

International audienceModern verification projects continue to offer new challenges for formal verification. One of them is the linked list module of Contiki, a popular open-source operating system for the Internet of Things. It has a rich API and uses a particular list representation that make it different from the classical linked list implementations. Being widely used in the OS, the list module is critical for reliability and security. A recent work verified the list module using ghost arrays. This article reports on a new verification effort for this module. Realized in the Frama-C/Wp tool, the new approach relies on logic lists. A logic list provides a convenient high-level view of the linked list. The specifications of all functions are now proved faster and almost all automatically, only a small number of auxiliary lemmas and a couple of assertions being proved interactively in Coq. The proposed specifications are validated by proving a few client functions manipulating lists. During the verification, a more efficient implementation for one function was found and verified. We compare the new approach with the previous effort based on ghost arrays, and discuss the benefits and drawbacks of both techniques

Clinically relevant mutations in the ABCG2 transporter uncovered by genetic analysis linked to erythrocyte membrane protein expression

The ABCG2 membrane protein is a key xeno- and endobiotic transporter, modulating the absorption and metabolism of pharmacological agents and causing multidrug resistance in cancer. ABCG2 is also involved in uric acid elimination and its impaired function is causative in gout. Analysis of ABCG2 expression in the erythrocyte membranes of healthy volunteers and gout patients showed an enrichment of lower expression levels in the patients. By genetic screening based on protein expression, we found a relatively frequent, novel ABCG2 mutation (ABCG2-M71V), which, according to cellular expression studies, causes reduced protein expression, although with preserved transporter capability. Molecular dynamics simulations indicated a stumbled dynamics of the mutant protein, while ABCG2-M71V expression in vitro could be corrected by therapeutically relevant small molecules. These results suggest that personalized medicine should consider this newly discovered ABCG2 mutation, and genetic analysis linked to protein expression provides a new tool to uncover clinically important mutations in membrane proteins. © 2018 The Author(s)

Towards Formal Verification of Contiki: Analysis of the AES–CCM* Modules with Frama-C

International audienceThe number of Internet of Things (IoT) applications is rapidly increasing and allows embedded devices today to be massively connected to the Internet. This raises software security questions. This paper demonstrates the usage of formal verification to increase the security of Con-tiki, a popular open-source operating system for the IoT. We present a case study on deductive verification of encryption-decryption modules of Contiki (namely, AES–CCM*) using Frama-C, a software analysis platform for C code

An Online Replanning Approach for Crop Fields Mapping with Autonomous UAVs

For managing production at the scale of crop fields, maps of plant pests are used to support farmer decisions. Such maps are costly to obtain since they require intensive surveys in the field, most of the time performed by human annotators or with human-controlled Unmanned Aerial Vehicles (UAVs). In this paper, we look at the next challenge from an AI planning point of view: flying fully autonomous UAVs equipped with online sequential decision-making capabilities for pests sampling and mapping in crop fields. Following existing work, we use a Markov Random Field framework to represent knowledge about the uncertain map and its quality, in order to compute an optimised pest-sampling policy. Since this planning problem is Pspace hard, thus too hard to be exactly solved either offline or online, we propose an approach interleaving planning and execution, inspired by recent works on fault-tolerant planning. From past observations at a given time step, we compute a full plan consisting in a sequence of observed locations and expected observations untill the end of the pest-sampling phase. The plan is then applied until the number of actual observations that differ from expected ones exceeds a given threshold, which triggers a new replanning episode. Our planning method favourably compares on the problem of weed map construction against an existing greedy approach - the only one working online - while adding the advantage of being adapted to the autonomous UAVs' flying time constraints

Extending an Online (Re)Planning Platform for Crop Mapping with Autonomous UAVs through a Robotic Execution Framework

Maps of plant pests are widely used to support farmer decisions to manage production at the scale of crop fields. Such maps are generally obtained manually, by human annotators or with human-controlled Unmanned Aerial Vehicles (UAVs), but this process is slow and costly. We propose an AI planning approach to fly fully autonomous UAVs equipped with on-line sequential decision-making capabilities for pests sampling and mapping in crop fields. We use a Markov Random Field framework to represent knowledge about the uncertain map and its quality, in order to compute an optimised pest-sampling policy. Since this planning problem is PSPACE hard, thus too complex to be solved exactly, we thus interleave planning and execution, generating plans from a subset of sampling sites selected. This approach has already been proved to be successful (Albore et al. 2015), favourably comparing with existing methods, but encounters some computation limits due to this division of tasks, considering that the planning execution framework is not adapted to the anytime-like behavior needed by real-world applications. We discuss the next steps in developing our approach, namely integrating the planning process and calculus of probabilities distribution in a framework able to deal with task management and execution under time constraints. Such extension, and integration within the AMPLE robotic execution framework, is promising as it associates the success of the replanning approach to the flexibility of an anytime executing architecture

Structural Basis for the ABO Blood-Group Dependence of Plasmodium falciparum Rosetting

International audienceThe ABO blood group influences susceptibility to severe Plasmodium falciparum malaria. Recent evidence indicates that the protective effect of group O operates by virtue of reduced rosetting of infected red blood cells (iRBCs) with uninfected RBCs. Rosetting is mediated by a subgroup of PfEMP1 adhesins, with RBC binding being assigned to the N-terminal DBL1α1 domain. Here, we identify the ABO blood group as the main receptor for VarO rosetting, with a marked preference for group A over group B, which in turn is preferred to group O RBCs. We show that recombinant NTS-DBL1α1 and NTS-DBL1α1-CIDR1γ reproduce the VarO-iRBC blood group preference and document direct binding to blood group trisaccharides by surface plasmon resonance. More detailed RBC subgroup analysis showed preferred binding to group A1, weaker binding to groups A2 and B, and least binding to groups Ax and O. The 2.8 Å resolution crystal structure of the PfEMP1-VarO Head region, NTS-DBL1α1-CIDR1γ, reveals extensive contacts between the DBL1α1 and CIDR1γ and shows that the NTS-DBL1α1 hinge region is essential for RBC binding. Computer docking of the blood group trisaccharides and subsequent site-directed mutagenesis localized the RBC-binding site to the face opposite to the heparin-binding site of NTS-DBLα1. RBC binding involves residues that are conserved between rosette-forming PfEMP1 adhesins, opening novel opportunities for intervention against severe malaria. By deciphering the structural basis of blood group preferences in rosetting, we provide a link between ABO blood grouppolymorphisms and rosette-forming adhesins, consistent with the selective role of falciparum malaria on human genetic makeup

Modelling the role of riverbed compartments in the regulation of water quality as an ecological service

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Endo-MitoEGFP mice: a novel transgenic mouse with fluorescently marked mitochondria in microvascular endothelial cells.

Blood vessel-specific fluorescent transgenic mice are excellent tools to study the development of the vasculature and angiogenic processes. There is growing interest in the biological processes relevant to endothelial cells but limited tools exist to selectively evaluate subcellular functions of this cell type in vivo. Here, we report a novel transgenic animal model that expresses mitochondrially targeted enhanced green fluorescent protein (EGFP) via the Hb9 promoter, a homeobox transcription factor with limited known involvement in the vasculature. Random integration of the transgene, containing the entire mouse Hb9 promoter, was found to be expressed in a variety of vascularised tissues. Further inspection revealed that Mito-EGFP localizes to the endothelial cells (ECs) of a subset of microvascular blood vessels, especially in the central nervous system (CNS), heart, spleen, thymus, lymph nodes and skin. We demonstrate the utility of this novel transgenic mouse, named Endo-MitoEGFP, in the detection, imaging, and isolation of microvascular ECs and evaluation of EC mitochondrial function isolated from adult animals. These transgenic mice will be useful to studies of ECs in development, physiology, and pathology