Organophosphorus (OP) compounds are highly toxic chemicals widely used as pesticides, but also as chemical warfare agents (sarin, VX). The incidence of passive, active or accidental poisoning with OP pesticides is associated with nearly 100,000 annual deaths worldwide for nearly 2 million reported cases of intoxication. More alarming, the resurgent of neurotoxic weapons containing OP use during Syrian conflict, assassinations, and the emergence of new compounds (Novichok, used for Alexei Navalany and Sergei Skripal targeted attack) highlight the present threat. Pathophysiologically, exposure to OP leads to the irreversible inhibition of cholinesterases, increasing the concentration of acetylcholine throughout the body and at the central nervous system (CNS) level. In the CNS, if the cholinergic hyperactivity is not quickly stopped, it will lead to seizure and epileptic activity inducing brain damages, neuronal degeneration, blood-brain barrier (BBB) dysfunction, cerebral oedema and significant brain inflammation. Emergency treatment includes muscarinic receptor blockade, cholinesterases reactivation, and stabilization of epileptic seizures, but the action of this therapy is limited in the CNS. In addition, knowledge of the effects of OPs on the neurovascular system remains sparse. Based on the synergy between a laboratory specialized in the field of neurovascular diseases (INSERM U1237) and the department of Toxicology and Chemical Risks of French Armed Forces Biomedical Research Institute, the proposed project aim to study the neurovascular system following exposure to OP in order to 1/ identify molecular and cellular targets for the development of new tools to detect cerebral damages and 2 / test and validate a new therapeutic strategy on neurovascular dysfunctions induced by OP exposure.

Pathogenic bacteria must constantly adapt to environmental changes during infection. Our results show that the entomopathogenic bacterium Bacillus thuringiensis has developed an alternative to sporulation to survive in the host cadaver. This study, focused on bacteria of the Bacillus cereus group, pathogenic to humans and animals, aims to characterize this state, which has been obscured by sporulation, considered for a long time as the only survival strategy in spore-forming firmicutes. Our objective is to characterize the regulatory networks underlying this physiological state by implementing complementary global and targeted methods at the population and cellular level, using molecular biology, flow cytometry, an animal model and bioinformatics analyses. This project will allow the understanding of a new mechanism leading to phenotypic heterogeneity allowing bacteria to persist in their niche and potentially adapt more rapidly to environmental changes. This research could open new perspectives for the control of spore-forming pathogenic bacteria.

This project addresses the problematic raised in Thematic axis 7, concerning the analysis and evaluation of the risk arising from a NRBC threat, more specifically the biological threat due the consequences of anthrax contamination. It presents a strong dual outcome of the research, both civilian and with specificity for answering defense needs. The bioterrorist anthrax US attack in 2001 has exemplified the life threatening consequences on the health of the civil and military personnel exposed to anthrax spores, and the ensuing economy and societal disruptions. A better understanding of the disease could thus be a means to decrease the health consequences of exposure to anthrax spores and thus impact the costs generated by such bioterrist acts for the society. The initial steps of anthrax infection are still insufficiently understood. A gap of knowledge exist on the precise mechanisms used by B. anthracis to interact, successfully invade and disseminate into the host. A wealth of data has been accumulated in in vitro systems, but their relevance to in vivo conditions of infection is regularly questionned. Translation to in vivo models are severely hampered by a lack of appropriate methods. The proposed project aims at imaging in vivo and in real time the initial steps of anthrax, both cutaneous and inhalational, by combining powerful complementary fluorescence methodologies, biphotonic microscopy and ex vivo 3-D reconstruction on BSL3 B. anthracis infected tissues of mice displaying fluorescent lymphatic and blood vessels, or fluorescent immune cells (such as dendritic cells). Through these imaging technologies combined to histological and ultrastructural analysis, we will visualize and characterize in real time the entry of B. anthracis, the local dynamics of the bacterial differentiation steps (germination and capsule and toxin production) and dynamically define the local subversive effects of the toxins on the local host control mechanisms during an infection; more specifically on the integrity of lymphatic and blood endothelial cells and the dynamics of innate immune cell recruitment. Overall, the combination of these imaging approaches will provide a unique and novel picture of B. anthracis infection. The outcomes of this project include: - a better understanding of the critical initial steps of anthrax, both cutaneous and inhalational - the development of new molecular approaches to the early treatment of B. anthracis infection and vaccination strategies. - the development of novel visualization technologies to follow in real time an infection that could be applied to other pathogens of interest This work should also make it possible to improve the societal and economic countermeasures to be taken in cases of biological terrorist threats.

Thanks to the confidence gained in the numerical simulation methods through correlation with a wide range of tests, nonlinear “realistic simulations” are taking more and more place in the design and sizing of aeronautical components during development and Certification phases. Airworthiness Authorities agree more and more to use the “virtual testing” or “realistic simulations” as means of compliance for all the items for which an acceptable level of validation of methodologies has been demonstrated. The main objective of the TIOC-Wing project is the development and the validation of criteria and a virtual testing methodology that will allow to predict the resistance of a representative stiffened composite wing panel subjected to the impact of tyre debris and the residual strength capability of the damaged structure. This will be reached by means of a test program focused on tyre debris impact events on composite aircraft structures and using the acquired experimental data to develop and validate numerical computational tools. The Consortium of TIOC-Wing project joins expertise in composite material knowledge, testing and manufacturing, in tyre tread impact testing and numerical simulations from 3 partners: SONACA, DGA-TA and CENAERO coming from Aeronautical Industry, referenced Test Laboratory in foreign objects impact capabilities and Research and Technology Center in advanced numerical simulations. TIOC-Wing will give the opportunity for the partners of the Consortium to enhance the level of expertise in the field of foreign objects impact aircraft vulnerability. For the industrial partners, the anticipation of such particular risks in the early stage of the development of an aircraft will reduce inherent costs due to possible modifications in a more advanced phase of the program, needed to satisfy the Certification requirements. This also enables to increase the competitiveness through innovation by integration of advanced computational tools in the sizing loop. Decrease of development tests will have as consequence the decrease of non recurrent costs. Finally, during future development of the next generation of aircraft thanks to less conservative approaches, TIOC-Wing offers the means for possible optimization of design concepts and weight savings strategies with reducing the CO2 emissions.

Tracheotomy is procedure that involves introducing a tracheal tube through the neck, and then allows a patient to breathe without the use of upper airways (nose, mouth). It can be indicated in patient with respiratory distress due to a pulmonary infection by bacteria, parasites or respiratory viruses, notably viruses implicated in Severe Acute Respiratory syndrome (SARS). Tracheotomy procedures have a high risk of causing healthcare workers contamination because they generate bronchial secretion aerosols. Two tracheotomy procedures are currently available: surgical tracheotomy by neck incision and instrumental tracheotomy by dilatation of a percutaneous tracheal neck puncture. Our project aims to quantify and compare aerosols generated by these two procedures in order to build recommendations of the best procedure to optimize health care worker’s protection.