Endocannabinoid System Modulation By Natural Products From Ancient Medicinal Plants

Herbal drugs have been important for the treatment of multiple pathological conditions since ancient times. A multitude of historical texts document the importance of plant-based therapies, but the therapeutic effectiveness of many described applications remains questionable. Concomitantly, the pharmacological properties and the associated chemistry of many herbal drugs described in ancient texts remain poorly studied. The development of modern pharmacology and analytical tools in the past century has led to the discovery of a plethora of novel plant-derived compounds and propelled advancements in medicine and pharmacology. The identification of (-)-trans-Δ9-tetrahydrocannabinol (THC) as the active principle of Cannabis sativa L., triggered research activities conductive to the elucidation of the endocannabinoid system (ECS). The ECS is a major modulatory system involved in a variety of physiological functions including the regulation of appetite, pain perception, memory, mood, and the modulation of inflammation and immune responses. A deregulation of the ECS is commonly associated with pathological conditions such as mood disorders, pain, inflammation, and neurodegenerative and immune diseases. Therefore, identifying target specific agonists, antagonists and inhibitors constitutes a promising strategy to tackle these conditions. The inhibition of fatty acid amide hydrolase (FAAH), the major enzyme involved in the termination of endocannabinoid signalling via the degradation of the endocannabinoid anandamide (AEA), represents a pharmacological strategy to treat conditions such as anxiety, depression or metabolic disorders. Besides the main cannabinoid type-1 (CB1) receptors, activation of cannabinoid type-2 (CB2) receptors represents as well an interesting pharmacological approach to treat diverse disorders such as diabetes, and neurodegenerative and immune diseases. Therefore, the main aim of this doctoral thesis was to identify and characterize plant-derived compounds able to target and modulate specific components of the ECS. As a starting point to address this objective, a plant extract library of drug samples mainly associated with the herbal drugs described in Dioscorides’ De Materia Medica (DMM; ex Matthioli, 1568) was built up. The extracts were tested for in vitro inhibition of FAAH and affinity towards CB2 receptors. In addition, as an indication of non-specific cytotoxicity, their antiproliferative activity was evaluated. For the screened extracts, the possible relationship between investigated bioactivity and plant phylogeny was first questioned. From the results of the FAAH inhibition screening, it emerged that extracts with significant FAAH inhibitory activity are phylogenetically clustered, as they are associated preponderantly with herbal drugs derived from the Fabaceae family. Isoflavonoids and prenylated derivatives, secondary metabolites commonly produced in Fabaceae, were proposed as potential FAAH inhibitors. Among the isoflavonoids tested, the prenylated luteone and neobavaisoflavone proved to be highly potent, selective, competitive and reversible FAAH inhibitors at the nanomolar range. In addition, preliminary results from the screening of the extract library towards CB2 receptors suggested the identification of sesquiterpene coumarins as a new class of CB2 receptor ligands at the low micromolar range. In conclusion, in this thesis project we have identified two classes of natural products showing in vitro pharmacological interaction with the ECS. Moreover, the compounds may prove promising scaffolds for the development of new therapeutic agents with anti-inflammatory, anti-nociceptive, anxiolytic, anti-diabetic or immunomodulatory activities

Development and characterisation of Monolithic Active Pixel Sensor prototypes for the upgrade of the ALICE Inner Tracking System

ALICE (A Large Ion Collider Experiment) is dedicated to the study and characterisation of the Quark-­‐Gluon Plasma (QGP), exploiting the unique potential of ultrarelativistic heavy-­‐ion collisions at the CERN Large Hadron Collider (LHC). The increase of the LHC luminosity leading up to about 50 kHz Pb-­‐Pb interaction rate after the second long shutdown (in 2018-­‐2019) will offer the possibility to perform high precision measurements of rare probes over a wide range of momenta. These measurements are statistically limited or not even possible with the present experimental set up. For this reason, an upgrade strategy for several ALICE detectors is being pursued. In particular, it is foreseen to replace the Inner Tracking System (ITS) by a new detector which will significantly improve the tracking and vertexing capabilities of ALICE in the upgrade scenario. The new ITS will have a barrel geometry consisting of seven layers of Monolithic Active Pixel Sensors (MAPS) with high granularity, which will fulfil the material budget, readout and radiation hardness requirements for the upgrade. Intensive R&D has been carried out in the last four years on MAPS in the framework of the ALICE ITS upgrade. Various small scale sensors have been designed in the TowerJazz 0.18 um imaging sensor technology to study noise, charge collection efficiency and signal-­‐to-­‐noise ratio. This work presents the main characterization results obtained from the measurements performed on two small scale prototypes (MIMOSA-­‐32 and MIMOSA-­‐32ter) with X-­‐ray sources and beams of particles. The architecture of an innovative full scale MAPS prototype (Alice Pixel Detector, ALPIDE) is also presented that is based on an AC-­‐sensitive front end and on a hit-­‐ driven readout. The first results on the ALPIDE prototype showed that the sensor is fully functional and that it provides performance in terms of readout time, power density and noise much better than the state of the art MAPS based on the rolling shutter readout, which makes this type of sensors very attractive for employment in the new ALICE ITS

Operational modal analysis of a spar-type floating platform using frequency domain decomposition method

System identification of offshore floating platforms is usually performed by testing small-scale models in wave tanks, where controlled conditions, such as still water for free decay tests, regular and irregular wave loading can be represented. However, this approach may result in constraints on model dimensions, testing time, and costs of the experimental activity. For such reasons, intermediate-scale field modelling of offshore floating structures may become an interesting as well as cost-effective alternative in a near future. Clearly, since the open sea is not a controlled environment, traditional system identification may become challenging and less precise. In this paper, a new approach based on Frequency Domain Decomposition (FDD) method for Operational Modal Analysis is proposed and validated against numerical simulations in ANSYS AQWA v.16.0 on a simple spar-type structure. The results obtained match well with numerical predictions, showing that this new approach, opportunely coupled with more traditional wave tanks techniques, proves to be very promising to perform field-site identification of the model structures

Progress on the experimental set-up for the testing of a floating offshore wind turbine scaled model in a field site

This document describes design and realization of a small-scale field experiment on a 1:30 model of spar floating support structure for offshore wind turbines. The aim of the experiment is to investigate the dynamic behaviour of the floating wind turbine under extreme wave and parked rotor conditions. The experiment has been going on in the Natural Ocean Engineering Laboratory of Reggio Calabria (Italy). In this article, all the stages of the experimental activity are presented, and some results are shown in terms of motions and response amplitude operators. Finally, a comparison with corresponding results obtained using ANSYS AQWA software package is shown, and conclusions are drawn. The presented experimental set-up seems promising to test offshore floating structures for marine renewable energy at a relatively large scale in the Natural Ocean Engineering Laboratory field site

La matrice religieuse de Jacques Copeau, une lecture anthropologique du fonctionnement de la communauté des Copiaus (1924-1929)

Les communautés théâtrales du XXe siècle sont l'œuvre de projets visionnaires menés par des figures charismatiques. En 1924, lassé de l'exploitation de sa salle parisienne du Vieux- Colombier, Jacques Copeau fonde en Bourgogne, à l'abri des rumeurs citadines, une communauté d'élèves et de comédiens férus d'expérimentation. A la même époque, il retrouve la foi catholique. Si les travaux antérieurs sur les Copiaus (1924-1929) mentionnent systématiquement la " crise religieuse " de Jacques Copeau à partir de 1925, il n'existe aucune étude approfondie sur le lien entre la vie communautaire des Copiaus et la ferveur catholique de son fondateur. La référence explicite de Jacques Copeau à la Règle de saint Benoît, ainsi que l'examen de sources inexplorées, révèlent que Jacques Copeau entretient des liens étroits avec le milieu des intellectuels catholiques de l'époque. Dès octobre 1924, Jacques Copeau est profondément inspiré par la " première " Règle monastique chrétienne ainsi que par les notions religieuses d'obéissance librement consentie et de moralité de l'art. Cette étude contribue à comprendre les aspirations contradictoires et les difficultés d'entente entre un " Patron " et un groupe de jeunes gens animé par le désir de créations théâtrales collectives

A comparison on the dynamics of a floating vertical axis wind turbine on three different floating support structures

To increase the competitiveness of offshore wind energy in the global energy market, it is necessary to identify optimal offshore wind turbine configurations to deliver the lowest cost of energy. For deep waters where floating wind turbines are the feasible support structure option, the vertical axis wind turbine concept might prove to be one of these optimal configurations. This paper carries out a preliminary investigation into the dynamics of a vertical axis wind turbine coupled with three generic floating support structures originally intended for horizontal axis wind turbines. The modifications to the original characteristics of the support structures were kept to a minimum to illustrate the use of floating horizontal axis wind turbine platforms for floating vertical axis wind turbines Issues regarding the adequacy of the mooring systems are outlined and an overview of platform responses in a number of varying met-ocean conditions is presented and discussed

Longitudinal static stability requirements for wing in ground effect vehicle

ABSTRACT:The issue of the longitudinal stability of a WIG vehicle has been a very critical design factor since the first experimental WIG vehicle has been built. A series of studies had been performed and focused on the longitudinal stability analysis. However, most studies focused on the longitudinal stability of WIG vehicle in cruise phase, and less is available on the longitudinal static stability requirement of WIG vehicle when hydrodynamics are considered: WIG vehicle usually take off from water. The present work focuses on stability requirement for longitudinal motion from taking off to landing. The model of dynamics for a WIG vehicle was developed taking into account the aerodynamic, hydrostatic and hydrodynamic forces, and then was analyzed. Following with the longitudinal static stability analysis, effect of hydrofoil was discussed. Locations of CG, aerodynamic center in pitch, aerodynamic center in height and hydrodynamic center in heave were illustrated for a stabilized WIG vehicle. The present work will further improve the longitudinal static stability theory for WIG vehicle

Critical review of floating support structures for offshore wind farm deployment

Floating structures enable offshore wind power deployment at numerous deep water sites with promising wind potential where bottom-fixed systems are no longer feasible. However, the large diversity in existing floater concepts slows down the development and maturing processes of floating offshore wind turbines. Thus, in this work, different floating support structures are assessed with respect to their suitability for offshore wind farm deployment. A survey is conducted to examine the capacities of selected floater types, grouped into ten categories, with respect to ten specified criteria focusing on wind farm deployment. By this means, a multi-criteria decision analysis (MCDA) is carried out, using the technique for order preference by similarity to ideal solution (TOPSIS). With the individual scores of the different systems, considering the weighting of each criterion, suitable concepts are identified and potential hybrid designs, combining advantages of different solutions, are suggested

Use of a wave energy converter as a motion suppression device for floating wind turbines

Floating offshore wind turbines (FOWTs) are subjected to large amplitude motions that induce greater loads on components and reduce aerodynamic performance. One approach to counteract this has been to use passive damping systems for FOWTs to dissipate the wave-induced energy and therefore reduce the global platform motions. This paper proposes that rather than discard this energy, a wave energy converter (WEC) is utilized on the floating platform to absorb it. A study is carried out on a floating vertical axis wind turbine (VAWT) combined with WEC moving in heave. A range of damping and stiffness coefficients are applied between the FOWT and WEC to establish strategies for two cases: maximum motion reduction and maximum energy extraction. The results and conclusions obtained are presented in terms of modifying the WEC natural frequency, damping and stiffness values