In Silico Studies on DARC.

International audienceThe Duffy Antigen/Receptor for Chemokine (DARC) is a seven segment transmembrane protein. It was firstly discovered as a blood group antigen and was the first specific gene locus assigned to a specific autosome in man. It became more famous as an erythrocyte receptor for malaria parasites (Plasmodium vivax and Plasmodium knowlesi), and finally for chemokines. DARC is an unorthodox chemokine receptor as (i) it binds chemokines of both CC and CXC classes and (ii) it lacks the Asp-Arg-Tyr consensus motif in its second cytoplasmic loop hence cannot couple to G proteins and activate their signaling pathways. DARC had also been associated to cancer progression, numerous inflammatory diseases, and possibly to AIDS. In this review, we will summarize important biological data on DARC. Then we shall focus on recent development of the elaboration and analyzes of structural models of DARC. We underline the difficulty to propose pertinent structural models of transmembrane protein using comparative modeling process, and other dedicated approaches as the Protein Blocks. The chosen structural models encompass most of the biochemical data known to date. Finally, we present recent development of protein - protein docking between DARC structural models and CXCL-8 structures. We propose a hierarchal search based on separated rigid and flexible docking

A Probabilistic Forecast-Driven Strategy for a Risk-Aware Participation in the Capacity Firming Market: extended version

This paper addresses the energy management of a grid-connected renewable generation plant coupled with a battery energy storage device in the capacity firming market, designed to promote renewable power generation facilities in small non-interconnected grids. The core contribution is to propose a probabilistic forecast-driven strategy, modeled as a min-max-min robust optimization problem with recourse. It is solved using a Benders-dual cutting plane algorithm and a column and constraints generation algorithm in a tractable manner. A dynamic risk-averse parameters selection strategy based on the quantile forecasts distribution is proposed to improve the results. A secondary contribution is to use a recently developed deep learning model known as normalizing flows to generate quantile forecasts of renewable generation for the robust optimization problem. This technique provides a general mechanism for defining expressive probability distributions, only requiring the specification of a base distribution and a series of bijective transformations. Overall, the robust approach improves the results over a deterministic approach with nominal point forecasts by finding a trade-off between conservative and risk-seeking policies. The case study uses the photovoltaic generation monitored on-site at the University of Li\`ege (ULi\`ege), Belgium.Comment: Extended version of the paper accepted for publication in IEEE Transactions on Sustainable Energ

Microglial Involvement in Neuroplastic Changes Following Focal Brain Ischemia in Rats

The pathogenesis of ischemic stroke is a complex sequence of events including inflammatory reaction, for which the microglia appears to be a major cellular contributor. However, whether post-ischemic activation of microglial cells has beneficial or detrimental effects remains to be elucidated, in particular on long term brain plasticity events. The objective of our study was to determine, through modulation of post-stroke inflammatory response, to what extent microglial cells are involved in some specific events of neuronal plasticity, neurite outgrowth and synaptogenesis. Since microglia is a source of neurotrophic factors, the identification of the brain-derived neurophic factor (BDNF) as possible molecular actor involved in these events was also attempted. As a means of down-regulating the microglial response induced by ischemia, 3-aminobenzamide (3-AB, 90 mg/kg, i.p.) was used to inhibit the poly(ADP-ribose) polymerase-1 (PARP-1). Indeed, PARP-1 contributes to the activation of the transcription factor NF-kB, which is essential to the upregulation of proinflammatory genes, in particular responsible for microglial activation/proliferation. Experiments were conducted in rats subjected to photothrombotic ischemia which leads to a strong and early microglial cells activation/proliferation followed by an infiltration of macrophages within the cortical lesion, events evaluated at serial time points up to 1 month post-ictus by immunostaining for OX-42 and ED-1. Our most striking finding was that the decrease in acute microglial activation induced by 3-AB was associated with a long term down-regulation of two neuronal plasticity proteins expression, synaptophysin (marker of synaptogenesis) and GAP-43 (marker of neuritogenesis) as well as to a significant decrease in tissue BDNF production. Thus, our data argue in favour of a supportive role for microglia in brain neuroplasticity stimulation possibly through BDNF production, suggesting that a targeted protection of microglial cells could represent an innovative approach to potentiate post-stroke neuroregeneration

The cytotoxic domain of colicin E9 is a channel-forming endonuclease

Bacterial toxins commonly translocate cytotoxic enzymes into cells using dedicated channelforming subunits or domains as conduits. We demonstrate that the small cytotoxic endonuclease domain from the bacterial toxin colicin E9 (the E9 DNase) exhibits nonvoltage- gated, channel-forming activity in planar lipid bilayers and that this activity is linked to toxin translocation into cells. A disulfide bond engineered into the DNase abolished channel activity and colicin toxicity but left endonuclease activity unaffected, with NMR experiments suggesting decreased conformational flexibility as the likely reason for these alterations. Concomitant with the reduction of the disulfide bond was the restoration of conformational flexibility, DNase channel activity and colicin toxicity. Our data suggest that endonuclease domains of colicins may mediate their own translocation across the bacterial inner membrane through an intrinsic channel activity that is dependent on structural plasticity in the protein

Focal Laser Ablation of Prostate Cancer: Definition, Needs, and Future

Current challenges and innovations in prostate cancer management concern the development of focal therapies that allow the treatment of only the cancer areas sparing the rest of the gland to minimize the potential morbidity. Among these techniques, focal laser ablation (FLA) appears as a potential candidate to reach the goal of focusing energy delivery on the identified targets. The aim of this study is to perform an up-to-date review of this new therapeutic modality. Relevant literature was identified using MEDLINE database with no language restrictions (entries: focal therapy, laser interstitial thermotherapy, prostate cancer, FLA) and by cross-referencing from previously identified studies. Precision, real-time monitoring, MRI compatibility, and low cost of integrated system are principal advantages of FLA. Feasibility and safety of this technique have been reported in phase I assays. FLA might eventually prove to be a middle ground between active surveillance and radical treatment. In conclusion, FLA may have found a role in the management of prostate cancer. However, further trials are required to demonstrate the oncologic effectiveness in the long term

Functional Reconstitution into Liposomes of Purified Human RhCG Ammonia Channel

BACKGROUND: Rh glycoproteins (RhAG, RhBG, RhCG) are members of the Amt/Mep/Rh family which facilitate movement of ammonium across plasma membranes. Changes in ammonium transport activity following expression of Rh glycoproteins have been described in different heterologous systems such as yeasts, oocytes and eukaryotic cell lines. However, in these complex systems, a potential contribution of endogenous proteins to this function cannot be excluded. To demonstrate that Rh glycoproteins by themselves transport NH(3), human RhCG was purified to homogeneity and reconstituted into liposomes, giving new insights into its channel functional properties. METHODOLOGY/PRINCIPAL FINDINGS: An HA-tag introduced in the second extracellular loop of RhCG was used to purify to homogeneity the HA-tagged RhCG glycoprotein from detergent-solubilized recombinant HEK293E cells. Electron microscopy analysis of negatively stained purified RhCG-HA revealed, after image processing, homogeneous particles of 9 nm diameter with a trimeric protein structure. Reconstitution was performed with sphingomyelin, phosphatidylcholine and phosphatidic acid lipids in the presence of the C(12)E(8) detergent which was subsequently removed by Biobeads. Control of protein incorporation was carried out by freeze-fracture electron microscopy. Particle density in liposomes was a function of the Lipid/Protein ratio. When compared to empty liposomes, ammonium permeability was increased two and three fold in RhCG-proteoliposomes, depending on the Lipid/Protein ratio (1/300 and 1/150, respectively). This strong NH(3) transport was reversibly inhibited by mercuric and copper salts and exhibited a low Arrhenius activation energy. CONCLUSIONS/SIGNIFICANCE: This study allowed the determination of ammonia permeability per RhCG monomer, showing that the apparent Punit(NH3) (around 1x10(-3) microm(3)xs(-1)) is close to the permeability measured in HEK293E cells expressing a recombinant human RhCG (1.60x10(-3) microm(3)xs(-1)), and in human red blood cells endogenously expressing RhAG (2.18x10(-3) microm(3)xs(-1)). The major finding of this study is that RhCG protein is active as an NH(3) channel and that this function does not require any protein partner

A Machine-Learning Approach for Classifying Defects on Tree Trunks using Terrestrial LiDAR

International audienceThree-dimensional data are increasingly prevalent in forestry thanks to terrestrial LiDAR. This work assesses the feasibility for an automated recognition of the type of local defects present on the bark surface. These sin-gularities are frequently external markers of inner defects affecting wood quality, and their type, size, and frequency are major components of grading rules. The proposed approach assigns previously detected abnormalities in the bark roughness to one of the defect types: branches, branch scars, epi-cormic shoots, burls, and smaller defects. Our machine learning approach is based on random forests using potential defects shape descriptors, including Hu invariant moments, dimensions, and species. The results of our experiments involving different French commercial species, oak, beech, fir, and pine showed that most defects were well classified with an average F 1 score of 0.86

Antitrypanosomatid Pharmacomodulation at Position 3 of the 8-Nitroquinolin-2(1H)-one Scaffold Using Palladium-Catalysed Cross-Coupling Reactions

International audienceAn antikinetoplastid pharmacomodulation study at position 3 of the recently described hit molecule 3-bromo-8-nitroquinolin-2(1H)-one was conducted. Twenty-four derivatives were synthesised using the Suzuki-Miyaura cross-coupling reaction and evaluated in vitro on both Leishmania infantum axenic amastigotes and Trypanosoma brucei brucei trypomastigotes. Introduction of a para-carboxyphenyl group at position 3 of the scaffold led to the selective antitrypanosomal hit molecule 3-(4-carboxyphenyl)-8-nitroquinolin-2(1H)-one (21) with a lower reduction potential (-0.56 V) than the initial hit (-0.45 V). Compound 21 displays micromolar antitrypanosomal activity (IC50 =1.5 μm) and low cytotoxicity on the human HepG2 cell line (CC50 =120 μm), having a higher selectivity index (SI=80) than the reference drug eflornithine. Contrary to results previously obtained in this series, hit compound 21 is inactive toward L. infantum and is not efficiently bioactivated by T. brucei brucei type I nitroreductase, which suggests the existence of an alternative mechanism of action