Depuis les années 70, la production et la commercialisation des biens et services, la circulation des capitaux et des systèmes se sont fortement internationalisées. Ce phénomène a poussé les entreprises à optimiser leurs chaînes logistiques pour rester compétitives. Le Maroc s'inscrit dans la même tendance, vue sa position géographique joue un rôle de carrefour et de hub des échanges commerciaux. Le développement d'une réelle compétitivité logistique constitue un pilier du programme gouvernemental 2010-2020, d'où le lancement de la stratégie nationale pour le développement de la compétitivité logistique, dont principalement le contrat programme régissant le développement des plateformes logistiques, dites zones logistiques multi flux. La stratégie vise la réduction du poids du coût logistique de 5 points pour 2015, la création de 70 zones logistiques dans 17 villes sur environ 3 300 hectares. La mise en œuvre de ce programme logistique nécessite un effort cohérent, s'inscrivant dans le temps et des arbitrages complexes à opérer sur des domaines ne relevant pas des prérogatives d'un seul intervenant de la chaîne logistique. À la lumière de ces propos, nous avons vu en cette problématique un enjeu majeur nécessitant des actions managériales, une réflexion académique aussi par un focus sur le principe de la Supply Chain et plus précisément la logistique des plateformes. L'agencement et la connectivité des plateformes logistiques s'avère décisionnelle pour la réussite d'une politique commerciale compétitive d'une entreprise : nous ne pouvons pas concevoir des flux juste en mouvement, in fine, ils commencent d'un point de création de valeur vers un point de consommation et que ce sont ces nœuds (plateformes) qui œuvrent pour l'optimisation de l'organisation de toute la chaîne. Un retour vers l'histoire de la logistique, ses définitions et son évolution managériale dans le temps s'avérait nécessaire pour expliciter l'approche transversale et intégrée de la chaîne logistique ; et s'attarder par la suite sur les composantes, intégration des flux physiques et d'information, sur le poids de la stratégie logistique comme arme de différenciation vis-à-vis de la concurrence et sur les leviers d'optimisation des plateformes logistiques dans ces modèles. Le dernier chapitre traitera de la compétitivité logistique au Maroc, au regard des standards précités et les axes de développement du réseau des zones logistiques comme première orientation du contrat programme logistique national. / Since earlier years, production and sales of goods and services. capital flows and systems are highly internationalized. This has led companies to optimize their supply chain to remain competitive. Morocco is part of the same trend, for its geographical position acts as a hub and crossroads of trade. The development of logistics real competitiveness is a pillar of the government program 2010-2020. Hence the launch of the national strategy for the development of logistics competitiveness, mainly the program contract governing the development of logistics platforms. The strategy aims to reduce the weight of the logistics cost of 5 points for 2015, creating 70 logistics warehouses in 17 cities on 3 300 hectares. The implementation of the logistics program requires a coherent effort, registering in time and complex trade-offs in different areas in the supply chain. In the light of these remarks, we have seen this problem a major issues requiring managerial actions, academic reflection as a focus on the basics of suppl y chain and specifically logistics platforms. The layout and connectivity of logistics platforms proves the success of a competitive sales policy of a company : we cannot just design flow, ultimately, they start a creative point value to a consumption point and that it is these nodes (platforms) working to optimize the organization of the whole chain. A return to the story of logistics was important to present it, its definitions and managerial changes over time was needed to explain the cross and integrated approach to the supply chain; and linger afterwards on the components. integration of physical and information flows. the weight of the logistics strategy as a weapon of differentiation regarding the competition and logistics platforms optimization levers in these models. The final part will present logistics competitiveness in Morocco, in view of the above standards and network development axes logistics areas as a first orientation of the national logistics program.

Les canaux nucléotidiques cycliques activés par hyperpolarization (HCN) sont un type de canaux ioniques voltage-dépendants qui contrôlent l'activité rythmique et la plasticité synaptique dans le cœur et le cerveau. Ces canaux permettent aux ions K+ et Na+ de passer, créant ainsi un courant entrant lors de l'hyperpolarization de la membrane. En raison de ses propriétés biophysiques inhabituelles, ce courant est appelé courant «If» ou courant d'hyperpolarization «Ih». Des anomalies du courant Ih sont associées à des arythmies et des troubles neurologiques, y compris l'épilepsie. On constate que différentes molécules modulent ce courant. Des résultats expérimentaux ont montré que les lipides jouent un rôle dans le déplacement de la dépendance en tension des canaux HCN vers des tensions plus positives ou dépolarisées. Le phosphatidylinositol 4,5-bisphosphate de phospholipide endogène et exogène, ou PI (4,5) P2, régule les canaux HCN en déplaçant l'ouverture du canal vers une tension plus dépolarisée. Cette modulation est supposée être par interaction directe de PI (4,5) P2 avec le canal HCN. Ici, nous utilisons la dynamique moléculaire et l'amarrage pour explorer et identifier le site de liaison grâce à l'analyse des contacts et de la stabilité des liaisons hydrogène impliquées dans les molécules de phsiphoinositide et l'interaction des canaux HCN. Nous proposons LYS et ARG du domaine HCN et S3 pour être des résidus clés dans le site de liaison à travers lequel les molécules de phosphoinositide peuvent potentiellement activer le canal. / Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are a type of voltage gated ion channels that control rhythmic activity and synaptic plasticity in the heart and brain. These channels allow K+ and Na+ ions to pass, thereby creating an inward current upon hyperpolarization of the membrane. Due to its unusual biophysical properties, this current is called funny « If» or hyperpolarization « Ih » current. Abnormalities in Ih current are associated with arrythmia and neurological disorders including epilepsy. Different molecules are found to modulate this current. Experimental results have shown that lipids play a role in shifting the voltage dependence of HCN channels to more positive, or depolarized voltages. Both endogenous and exogenous phospholipid phosphatidylinositol 4,5-bisphosphate, or PI(4,5)P2, regulates HCN channels by shifting the opening of the channel to a more depolarized voltage. This modulation is postulated to be through direct interaction of PI(4,5)P2 with the HCN channel. Here, we use molecular dynamics and docking to explore and identify the binding site through analysis of the contacts and stability of the hydrogen bonds involved in phosphoinositide molecules and HCN channel interaction. We propose LYS and ARG residues of the HCN domain and S3 to be key residues in the binding site through which phosphoinositide molecules can potentially activate the channel.

Philosophiae Doctor - PhD / Tsetse flies are the biological vectors of human and animal trypanosomiasis and hence representant medical and veterinary importance. The sense of smell plays a significant role in tsetse and its ecological interaction, such as finding blood meal source, resting, and larvicidal sites and for mating. Tsetse olfactory behaviour can be exploited for their management; however, olfactory studies in tsetse flies are still fragmentary. Here in my PhD thesis, using scanning electron microscopy, electrophysiology, behaviour, bioinformatics and molecular biology techniques, I have investigated tsetse flies (Glossina fuscipes fuscipes) olfaction using behaviourally well studied odorants, tsetse repellent by comparing with attractant odour. Insect olfaction is mediated by olfactory sensory neurons (OSNs), located in olfactory sensilla, which are cuticular structures exposed to the environment through pore and create a platform for chemical communication. In the sensilla shaft the dendrite of OSNs are housed, which are protected by called the sensillum lymph produced by support cells and contains a variety of olfactory proteins, including the odorant binding protein (OBP) and chemosensory proteins (CSP). While on the dendrite of OSNs are expressed olfactory receptors. In my PhD, studies I tried to decipher the sense of smell in tsetse fly. In the second chapter, I demonstrated that G. f. fuscipes is equipped with diverse olfactory sensilla, that various from basiconic, trichoid and coeloconic. I also demonstrated, there is shape, length, number difference between sensilla types and sexual dimorphism. There is a major difference between male and female, while male has the unique basiconic sensilla, club shaped found in the pits, which is absent from female pits. In my third chapter, I investigated the odorant receptors which are expressed on the dendrite of the olfactory sensory neurons (OSNs). G. f. fuscipes has 42 ORs, which were not functionally characterised. I used behaviourally well studied odorants, tsetse repellents, composed of four components blend. I demonstrated that tsetse repellent is also a strong antifeedant for both G. pallidipes and G. f. fuscipes using feeding bioassays as compared to the attractant odour, adding the value of tsetse repellent. However, the attractant odour enhanced the feeding index. Using DREAM (deorphanization of receptors based on expression alterations of mRNA levels). I found that in G. f. fuscipes, following a short in vivo exposure to the individual tsetse repellent component as well as an attractant volatile chemical, OSNs that respond to these compounds altered their mRNA expression in two opposite direction, significant downregulation and upregulation in their number of transcripts corresponding to the OR that they expressed and interacted with odorant. Also, I found that the odorants with opposite valence already segregate distinctly at the cellular and molecular target at the periphery, which is the reception of odorants by OSNs, which is the basis of sophisticated olfactory behaviour. Deorphanization of ORs in none model insect is a challenge, here by combining DREAM with molecular dynamics, as docking score, physiology and homology modelling with Drosophila a well-studied model insects, I was able to predict putative receptors of the tsetse repellent components and an attractant odour. However, many ORs were neutral, showing they were not activated by the odorants, demonstrating the selectivity of the technique as well as the receptors. In my fourth chapter, I investigated the OBPs structures and their interaction with odorants molecules. I demonstrated that OBPs are expressed both in the antenna, as well as in other tissues, such as legs. I also demonstrated that there are variations in the expression of OBPs between tissues as well as sexes. I also demonstrated that odorants induced a fast alteration in OBP mRNA expression, some odorants induced a decrease in the transcription of genes corresponding to the activated OBP and others increased the expression by many fold in OBPs in live insect, others were neutral after 5 hours of exposure. Moreover, with subsequent behavioural data showed that the behavioural response of G. f. fuscipes toward 1-octen-3-ol decreased significantly when 1-octen-3-ol putative OBPs were silenced with feeding of double-stranded RNA (dsRNA). In summary, our finding whereby odorant exposure affects the OBPs mRNA, their physiochemical properties and the silencing of these OBPs affected the behavioural response demonstrate that the OBPs are involved in odour detection that affect the percept of the given odorant. The expression of OBPs in olfactory tissues, antenna and their interaction with odorant and their effect on behavioural response when silenced shows their direct involvement in odour detection and reception. Furthermore, their expression in other tissues such as legs indicates they might also have role in other physiological functions, such as taste.

<div>Exploring and surveilling the marine environment away from shore is critical for scientific, economic, and military purposes as we progress through the 21st century. Until recently, these missions far from shore were only possible using manned surface vehicles. Over the past decade, advances in energy density, actuators, electronics, and controls have enabled great improvements in vehicle endurance, yet, no solution is capable of supporting persistent operation especially when considering power hungry scientific surveys. This dissertation summarizes contributions related to the development of an adaptable underwater docking station and associated navigation solutions to allow applications in the wide range of maritime missions. The adaptable docking system is a novel approach to the standard funnel shaped docking station design that enables the dock to be collapsible, portable, and support a wide range of vehicles. It has been optimized and tested extensively in simulation. Field experiments in both pool and open water validate the simulation results. The associated control strategies for approach and terminal homing are also introduced and studied in simulation and field trials. These strategies are computationally efficient and enable operation in a variety of scenarios and conditions. Combined, the adaptable docking system and associated navigation strategies can form a baseline for future extended endurance missions away from manned support.</div>

Die Dissertation beschreibt Arbeiten zur Herstellung neuer Cetrorelixkomplexe, zur Kinetik der dynamischen Liberation, zur Struktur von Aggregaten und Komplexen von Cetrorelix und zur Berechnung von Komplexeigenschaften mit Molecular Modeling. / Presented are results about new complexes of cetrorelix, the kinetics of dynamical liberations, the structure of Cetrorelix aggregates and complexes and the computation of properties of complexes by molecular modeling.

In drug development, molecular docking methods aim at characterizing the binding of a drug-like molecule to a protein. In a typical drug development process, a docking task is repeated millions of time, which makes optimization efforts essential. In particular, modern heterogeneous architectures, such as GPUs, allow for significant acceleration opportunities. AutoDock-GPU, a state-of-the-art GPU-accelerated molecular docking software, estimates the geometrical conformation of a docked ligand-protein complex by minimizing an energy-based scoring function. Our profiling results indicated that a reduction operation, which is performed several millions times in a single docking run, limits performance in AutoDock-GPU. Thus, we proposed a method to accelerate the block-level sum reduction of four-element vectors by using matrix operations. We implemented our method to make use of the high throughput capabilities offered by NVIDIA Tensor Cores to perform matrix operations. We evaluated our approach by designing a simple benchmark, and achieved a 4 to 7-fold runtime improvement compared to the original method. We then integrated our reduction operation into AutoDock-GPU and evaluated it on multiple chemical complexes on three GPUs. This evaluation allowed to assess the possibility to use half-precision reduction operations in parts of AutoDock-GPU code, without detrimental effects on the simulation result. In addition, our implementation achieved an average 27% improvement on the overall docking time during a real-world docking run. / Vid läkemedelsutveckling syftar molekylär dockningsmetoder till att karakterisera bindningen av en läkemedelsliknande molekyl till ett protein. I en typisk läkemedelsutvecklingsprocess upprepas en dockinguppgift miljontals gånger, vilket gör optimeringsinsatser nödvändiga. Framför allt moderna heterogena arkitekturer som GPU:er ger betydande accelerationsmöjligheter. AutoDock-GPU, en modern GPU-accelererad programvara för molekylär dockning, uppskattar den geometriska konformationen hos ett ligand-protein-komplex genom att minimera en energibaserad poängsättningsfunktion. Våra profileringsresultat visade att en reduktionsoperation, som utförs flera miljoner gånger i en enda dockningskörning, begränsar prestandan i AutoDock-GPU. Vi har därför föreslagit en metod för att accelerera summareduktionen på blocknivå av vektorer med fyra element med hjälp av matrisoperationer. Vi implementerade vår metod för att utnyttja den höga genomströmningskapacitet som erbjuds av NVIDIA Tensor Cores för att utföra matrisoperationer. Vi utvärderade vårt tillvägagångssätt genom att utforma ett enkelt testfall och uppnådde en 4- till 7-faldig förbättring av körtiden jämfört med den ursprungliga metoden. Vi integrerade sedan vår reduktionsoperation i AutoDock-GPU och utvärderade den på flera kemiska komplex på tre GPU:er. Denna utvärdering lät oss bedöma möjligheten att använda reduktionsoperationer med halvprecision i delar av AutoDock-GPU-koden, utan negativa effekter på simuleringsresultatet. Dessutom uppnådde vår version en genomsnittlig förbättring på 27% av den totala dockningstiden under en riktig dockningskörning.

No description available.

La tetracaína (Ttc), cuyas moléculas en solución fisiológica se encuentran mayoritariamente (97 %) en forma protonada, bloquea la corriente (IACh) evocada por acetilcolina (ACh) en ovocitos a los que se ha microtrasplantado receptores nicotínicos de acetilcolina (nAChRs) de la electroplaca de Torpedo marmorata. El bloqueo del nAChRm por Ttc fue muy potente, en el rango submicromolar (IC50= 0.5 μM) y reversible, recuperándose las respuestas a valores control tras un periodo de varios minutos. A concentraciones tan bajas como 0.1 μM, la Ttc ejerció un bloqueo que fue dependiente de voltaje, indicando que ejerce un bloqueo a canal abierto. El sitio de unión se pudo determinar en el interior del canal mediante técnicas de acoplamiento molecular. A concentraciones mayores (0.7 μM) se pudo observar un mecanismo de bloqueo distinto, a canal cerrado, que es independiente de voltaje y que se puede explicar por la unión de la Ttc a lugares situados en el ECD del nAChRm, que fueron determinados en los experimentos de docking virtual. Además, a esta concentración la Ttc aceleró la cinética de desensibilización de la IACh, cuando las células se mantuvieron en presencia sostenida del agonista. Esta se evocó cuando se co-aplicó la Ttc junto a la ACh a potenciales negativos. Por el contrario, cuando solamente se pre-aplicó la Ttc (aplicación previa a la de ACh), o cuando se co-aplicó a potenciales positivos, no se modificó la cinética de desensibilización, a pesar de que sí hubo una cierta inhibición de la IACh. Estos experimentos permitieron determinar que el sitio de unión de la Ttc que acelera la desensibilización se encuentra en el interior del canal. El ensayo de docking permitió localizar los residuos a los que su une la Ttc dentro del canal a altas concentraciones (con menor afinidad), que es más superficial que el implicado en el bloqueo a canal abierto. El lugar de unión determinado por anclaje virtual incluye la interacción de Ttc con αE262, γN224, γK271, y γE274, residuos que han sido previamente involucrados en el proceso de activación y desensibilización (Bouzat y cols., 2008; Forman y cols., 2007). El otro anestésico local (LA) estudiado, la benzocaína (Bzc), no posee carga al pH al que se efectúan los registros electrofisiológicos. La Bzc, al igual que la Ttc, inhibió la IACh, pero con una potencia menor, en el rango submilimolar y, a diferencia de la Ttc, su bloqueo fue independiente de voltaje. A pesar de mediar un bloqueo independiente de voltaje, la Bzc, evoca una corriente de rebote (IRb), similar a la que median moléculas que ejercen un bloqueo de canal abierto, sugiriendo que la Bzc podría estar uniéndose en el interior del canal. Otro efecto destacado de la Bzc sobre el nAChRms fue la aceleración de la desensibilización, haciéndola marcadamente más rápida incluso a potenciales positivos (a diferencia del efecto mediado por la Ttc). Además, se observó que, tras su pre-aplicación, la cinética de activación de la IACh se enlenteció y hubo un bloqueo de nAChRs, a canal cerrado, cuya recuperación fue especialmente lenta. Los efectos de ambos LAs fueron muy diferentes sobre los GABAAR. Así, la Ttc apenas tuvo efectos sobre este receptor, incluso a una concentración 10 veces superior a la IC50 determinada para el nAChRm. Por el contrario, la Bzc, aplicada a concentraciones similares a las que inhiben la IACh, aumentó la desensibilización y evocó una IRb similar a la observada en los nAChRs. Adicionalmente, la Bzc tuvo efectos sobre otros canales, como el ClC-0 y el CaCC. En relación con la Bzc, es interesante destacar que debido a su estructura química tiene una muy baja solubilidad al agua y, por tanto, debe solubilizarse en solventes como el etanol (EtOH) o el DMSO. Debido a que estos solventes pueden no ser totalmente inertes se probaron, en las mismas condiciones experimentales. No observándose efectos sobre los nAChRms.

Three-finger toxins (3FTX) are a group of peptides that affect multiple receptor types. One group of proteins affected by 3FTX are nicotinic acetylcholine receptors (nAChR). Structural information on how neurotoxins interact with nAChR is limited and is confined to a small group of neurotoxins. Therefore, in silico methods are valuable in understanding the interactions between 3FTX and different nAChR subtypes, but there are no established protocols to model 3FTX–nAChR interactions. We followed a homology modeling and protein docking protocol to address this issue and tested its success on three different systems. First, neurotoxin peptides co-crystallized with acetylcholine binding protein (AChBP) were re-docked to assess whether Rosetta protein–protein docking can reproduce the native poses. Second, experimental data on peptide binding to AChBP was used to test whether the docking protocol can qualitatively distinguish AChBP-binders from non-binders. Finally, we docked eight peptides with known α7 and muscle-type nAChR binding properties to test whether the protocol can explain the differential activities of the peptides at the two receptor subtypes. Overall, the docking protocol predicted the qualitative and some specific aspects of 3FTX binding to nAChR with reasonable success and shed light on unknown aspects of 3FTX binding to different receptor subtypes.

Although computational structure prediction has had great successes in recent years, it regularly fails to predict the interactions of large protein complexes with residue-level accuracy, or even the correct orientation of the protein partners. The performance of computational docking can be notably enhanced by incorporating experimental data from structural biology techniques. A rapid method to probe protein-protein interactions is hydrogen-deuterium exchange mass spectrometry (HDX-MS). HDX-MS has been increasingly used for epitope-mapping of antibodies (Abs) to their respective antigens (Ags) in the past few years. In this paper, we review the current state of HDX-MS in studying protein interactions, specifically Ab-Ag interactions, and how it has been used to inform computational structure prediction calculations. Particularly, we address the limitations of HDX-MS in epitope mapping and techniques and protocols applied to overcome these barriers. Furthermore, we explore computational methods that leverage HDX-MS to aid structure prediction, including the computational simulation of HDX-MS data and the combination of HDX-MS and protein docking. We point out challenges in interpreting and incorporating HDX-MS data into Ab-Ag complex docking and highlight the opportunities they provide to build towards a more optimized hybrid method, allowing for more reliable, high throughput epitope identification.