Locating a weak change using diffuse waves (LOCADIFF) : theoretical approach and inversion procedure

We describe a time-resolved monitoring technique for heterogeneous media. Our approach is based on the spatial variations of the cross-coherence of coda waveforms acquired at fixed positions but at different dates. To locate and characterize a weak change that occurred between successive acquisitions, we use a maximum likelihood approach combined with a diffusive propagation model. We illustrate this technique, called LOCADIFF, with numerical simulations. In several illustrative examples, we show that the change can be located with a precision of a few wavelengths and its effective scattering cross-section can be retrieved. The precision of the method depending on the number of source receiver pairs, time window in the coda, and errors in the propagation model is investigated. Limits of applications of the technique to real-world experiments are discussed.Comment: 11 pages, 14 figures, 1 tabl

La protéine Tat du VIH-1 active la voie TLR4 : effets sur l'expression des facteurs immunosuppressifs IL-10, PD-L1 et IDO

Au cours de l'infection par le virus de l'immunodéficience humaine de type 1 (VIH-1) on observe une augmentation progressive de l'expression des molécules inhibitrices du système immunitaire (IL-10, PD-L1 et IDO) principalement par les cellules présentatrices d'antigènes (CPA) telles que les cellules dendritiques (DCs). Ces molécules agissent négativement sur la réponse immunitaire anti-VIH et sont associées à la persistance du virus et à l'évolution de la maladie vers le stade SIDA. Une des protéines virales impliquée dans ce mécanisme est la protéine Tat. En plus de son rôle direct dans la transactivation du génome viral, Tat est sécrétée par les cellules infectées et se retrouve à des concentrations de l'ordre du nanomolaire dans le sérum des patients. Dans la circulation, Tat interagit avec les cellules immunitaires et module l'expression de nombreux facteurs incluant des facteurs immunosuppressifs. Les travaux précédents du laboratoire, ont montré que Tat agit au niveau membranaire, par son domaine N-terminal 1-45, afin de stimuler l'expression des cytokines pro-inflammatoires TNF-a, et immunosuppressives IL-10 par les monocytes et les macrophages humains. Plus récemment, la recherche du récepteur membranaire recruté par Tat a permis de mettre en évidence l'implication du TLR4/MD2 dans l'interaction avec Tat. Objectifs : Mon projet de thèse qui s'inscrit dans la continuité des travaux du laboratoire a pour objectif 1) de caractériser davantage le rôle du TLR4 comme récepteurs de Tat en utilisant une approche basée sur des modèles murins invalidés (KO) pour le TLR4 ou ses partenaires moléculaires (CD14, MD2, MyD88, TRIF) 2) d'étudier l'effet de la protéine Tat et de son interaction avec le TLR4 sur la modulation de la fonction des DCs incluant : la production de cytokines, la maturation, l'expression des facteurs immunosuppressifs et la capacité à activer/inhiber les lymphocytes T. Résultats : L'utilisation du modèle de souris KO nous a permis de confirmer le rôle central du TLR4/MD2 comme récepteur de la protéine Tat ainsi que de mieux comprendre le mécanisme moléculaire mis en jeu par Tat pour induire la production de l'IL-10 et du TNF-a impliquant le TLR4 mais également les cofacteurs CD14 et MD2 ainsi que l'activation des deux voies de signalisation MyD88 et TRIF dépendantes. L'étude des effets de l'interaction Tat-TLR4 sur la modulation de la réponse immunitaire des DCs nous a permis de montrer que i) Tat induit la production des cytokines pro-inflammatoires IL-6, IL-12 et des IFN-a et IFN-? en plus de l'IL-10 et du TNF-a ; ii) Tat induit la maturation des DCs en augmentant l'expression de CD83, CD80, CD86 ; iii) Tat stimule l'expression des facteurs immunosuppressifs IL-10, PD-L1 et IDO associées à une inhibition de la prolifération des LT ; iv) l'ensemble de ces effets sont abolis ou inhibés en bloquant l'interaction Tat-TLR4. Conclusions : Nos résultats suggèrent que le VIH-1, par l'intermédiaire de sa protéine Tat, détourne le TLR4 à la surface des CPA pour induire la production de facteurs pro-inflammatoires et stimuler l'expression des molécules immunosuppressives directement associées à la perte de fonction du système immunitaire. Il n'est donc pas exclu que Tat, à cause de son expression précoce, contribue à instaurer un état immunosuppressif très tôt après l'infection et serait aussi impliquée dans l'affaiblissement du système immunitaire et la persistance virale.Human immunodeficiency virus type 1 (HIV-1) infection is associated with a gradual increase in the expression of inhibitory molecules including IL-10, PD-L1 and IDO essentially by antigen presenting cells (APCs) such as dendritic cells (DCs). These molecules act negatively on the anti-HIV immune response and are associated with viral persistence and disease progression towards AIDS. One of the viral protein involved in this mechanism is Tat. In HIV-1 infected patients, Tat is secreted in the sera at nanomolar levels. In addition to its role in viral cycle, Tat interacts with immune cells to modulate the expression of many host genes including immunosuppressive factors. Previous work from our laboratory have shown that Tat protein, by acting at the membrane level, via its 1-45 N-terminal domain, stimulates the expression of pro-inflammatory cytokines TNF-a, and immunosuppressive IL-10 production in human monocytes and macrophages. More recently, we have shown the involvement of TLR4/MD2 in the interaction with Tat. Aim of the study: The objective of my thesis was to 1) Further characterize the implication of TLR4/MD2 as potential receptor of Tat protein. To this end mouse models invalidated (KO) for TLR4 or its molecular partners (CD14, MD2, MyD88, TRIF) were used 2) Study the effect of Tat protein and its interaction with TLR4/MD2 on the modulation of DCs functions including cytokine production, maturation, and the expression of immunosuppressive factors and their effects on the stimulation or inhibition of T cells activation. Results: The use of knockout mouse models has allowed us to confirm the central role of TLR4/MD2 as receptor for Tat protein and to better understand the signalling pathways recruited by Tat to stimulate the production of IL-10 and TNF-a. Our results showed the importance of CD14 and MD2 in addition to TLR4 and demonstrated that Tat activates both TRIF and MyD88-dependent pathways. In parallel, the study of the effects of Tat-TLR4 interaction on the modulation of the immune response of DCs allowed us to show that i) Tat induces the production of pro-inflammatory cytokines IL-6, IL-12 and IFN-a and IFN-? in addition to IL-10 and TNF-a ii) Tat induces the maturation of DCs by increasing the expression of CD83, CD80, CD86 and iii) Tat stimulates the expression of immunosuppressive factors IL-10, PD-L1 and IDO in association with the inhibition of T cells proliferation. iv) All these effects were abolished or inhibited following the blockade of Tat-TLR4 interaction. Conclusions: Our results suggest that HIV-1 by its Tat protein hijacks TLR4 pathway in APCs to induce the production of pro-inflammatory and immunosuppressive factors which are associated with the impairment of immune functions. It is therefore possible that, because of its early expression, Tat may help to establish an immunosuppressive state early after infection and thus contributed in the weakening of the immune system and viral persistence

Effect of neutrophil elastase and its inhibitor EPI-hNE4 on transepithelial sodium transport across normal and cystic fibrosis human nasal epithelial cells

<p>Abstract</p> <p>Background</p> <p>Hyperactivity of the epithelial sodium (Na⁺) channel (ENaC) and increased Na⁺absorption by airway epithelial cells leading to airway surface liquid dehydration and impaired mucociliary clearance are thought to play an important role in the pathogenesis of cystic fibrosis (CF) pulmonary disease. In airway epithelial cells, ENaC is constitutively activated by endogenous trypsin-like serine proteases such as Channel-Activating Proteases (CAPs). It was recently reported that ENaC activity could also be stimulated by apical treatment with human neutrophil elastase (hNE) in a human airway epithelial cell line, suggesting that hNE inhibition could represent a novel therapeutic approach for CF lung disease. However, whether hNE can also activate Na⁺reabsorption in primary human nasal epithelial cells (HNEC) from control or CF patients is currently unknown.</p> <p>Methods</p> <p>We evaluated by short-circuit current (<it>I</it>_sc) measurements the effects of hNE and EPI-hNE4, a specific hNE inhibitor, on ENaC activity in primary cultures of HNEC obtained from control (9) and CF (4) patients.</p> <p>Results</p> <p>Neither hNE nor EPI-hNE4 treatments did modify <it>I</it>_scin control and CF HNEC. Incubation with aprotinin, a Kunitz-type serine protease inhibitor that blocks the activity of endogenous CAPs, decreased <it>I</it>_scby 27.6% and 54% in control and CF HNEC, respectively. In control and CF HNEC pretreated with aprotinin, hNE did significantly stimulate <it>I</it>_sc, an effect which was blocked by EPI-hNE4.</p> <p>Conclusions</p> <p>These results indicate that hNE does activate ENaC and transepithelial Na⁺transport in both normal and CF HNEC, on condition that the activity of endogenous CAPs is first inhibited. The potent inhibitory effect of EPI-hNE4 on hNE-mediated ENaC activation observed in our experiments highlights that the use of EPI-hNE4 could be of interest to reduce ENaC hyperactivity in CF airways.</p

Simulation and evaluation of sustainable climate trajectories for aviation

In 2019, aviation was responsible for 2.6% of world CO2 emissions as well as additional climate impacts such as contrails. Like all industrial sectors, the aviation sector must implement measures to reduce its climate impact. This paper focuses on the simulation and evaluation of climate scenarios for air transport. For this purpose, a specific tool (CAST for “Climate and Aviation - Sustainable Trajectories”) has been developed at ISAE-SUPAERO. This tool follows a methodology for the assessment of climate impacts adapted to aviation. Firstly, models for the main levers of action, such as air traffic, aircraft energy consumption and energy decarbonization, are provided using trend projections from historical data or assumptions from the literature. Second, the evaluation of scenarios is based on aviation carbon budgets, which are also extended to non-CO2 effects using the concept of GWP*. Several scenario analyses are performed in this paper using CAST allowing different conclusions to be drawn. For instance, the modelling of the scenarios based on the more recent ATAG (Air Transport Action Group) commitments shows that aviation would consume 6.5% of the world carbon budget for +1.5 ◦C. Some illustrative scenarios are also proposed. By allocating 2.6% of the world carbon budget to aviation, it is shown that air transport is compatible with a +2 ◦C trajectory when the annual growth rate of air traffic varies between +1.8% and +2.9%, depending on the technological improvements considered. However, using the same methodology for a +1.5 ◦C trajectory shows that a drastic decrease in air traffic is necessary. Lastly, analyses including non- CO2 effects emphasize the importance of implementing specific strategies for mitigating contrails

Modeling and Design Optimization of an Electric Environmental Control System for Commercial Passenger Aircraft

The aircraft environmental control system (ECS) is the second-highest fuel consumer system, behind the propulsion system. To reduce fuel consumption, one research direction intends to replace conventional aircraft with more electric aircraft. Thus, new electric architectures have to be designed for each system, such as for the ECS. In this paper, an electric ECS is modeled and then sized and optimized for different sizing scenarios with the aim of minimizing fuel consumption at the aircraft level. For the system and for each component, such as air inlets and heat exchangers, parametric models are developed to allow the prediction of relevant characteristics. These models, developed in order to be adapted to aircraft design issues, are of different types, such as scaling laws and surrogate models. They are then assembled to build a preliminary sizing procedure for the ECS by using a multidisciplinary design analysis and optimization (MDAO) formulation. Results show that the ECS design is highly dependent on the sizing scenario considered. An approach to size the ECS globally with respect to all the sizing scenarios leads to an ECS that accounts for around 200 N of drag, 190 kW of electric power, and 1500 kg of mass for the CeRAS aircraft

Aircraft fleet models using a bottom-up approach for simulating aviation technological prospective scenarios

Modeling prospective scenarios for aviation in the context of climate issues is a scientific topic of major interest. For this purpose, the development of models to integrate technological improvements in these scenarios is necessary. This paper focuses on the use of a bottom-up approach to establish aircraft fleet models, in order to integrate them into CAST, an open-source tool for simulating and evaluating prospective scenarios for air transport. These models are based on logistic functions which allow representing the gradual replacement of current aircraft by future aircraft architectures obtained from overall aircraft design. The efficiency improvement of the aircraft fleet can then be assessed. To illustrate the use of the models, some case studies, considering for example turboprop and hydrogen aircraft, are performed for analyzing efficiency scenarios for air transport. Also, the effect of accelerated fleet renewal and earlier introduction of new aircraft architectures is studied

Sizing and optimization of a more electric aircraft integrating short-term incremental technologies

In order to reduce the environmental impact of aviation, one of the solutions is to develop more efficient aircraft. These gains can be achieved in different fields such as propulsion, aerodynamics or electrification of systems. This paper focuses on the sizing and optimization of BEITA, a short-medium range aircraft architecture available in the short term by 2025-2030. The aircraft is based on incremental technologies for propulsion, aerostructure and bleedless systems. Light-weight models are proposed for the different improvements, particularly for more electric systems. FAST-OAD, an open source framework for rapid overall aircraft design based on multidisciplinary design analysis and optimization, is used to size the new architecture and a specific life cycle assessment module is used to estimate the environmental impacts. BEITA allows a reduction in fuel consumption of 15% compared to the CeRAS reference aircraft. Optimizations of this architecture are achieved minimizing different cost functions. This study ends with a sizing on a shorter range based on specific payload-range diagrams