It is generally agreed that an economic agent is successful to the extent that he/she can generate profit, or more accurately "value", especially by improving the production function or the market strategies. The strategies thus picked determine what value is created, and the most efficient ones gain privileged status through competition. However, what seems obvious for economic theory is far less clear historically, since the very definition of profit is somewhat confused, and the evaluation of profit-generating strategies far from self-evident, as soon as one turns to eras preceding the XIXth century and industrial development.. Merchants, the most clearly profit-oriented agents in pre-industrial times, have often been studied. But their profits and actual practices (accounting, business plans, profit-seeking strategies generally speaking) have turned out to be almost impossible to analyze with post-1850 conceptual tools, so much so that one would be hard put to find one complete balance sheet of a merchant firm anywhere in the historiography. The building of quantified analyses of merchant accounts has so far been defeated by a number of features of these accounts, including the indeterminacy of price and quality hierarchies, the impossibility to trace goods through the various transactions, and the high proportion of assets not accounted for or of a non-quantifiable nature such as information, credit or networks. There are actually very few data on the topic, which means that merchant entrepreneurial strategies remain to this day largely opaque, with serious consequences for the understanding of what was after all the starting point of XIXth-century industrial development. We propose to start with the structure of Early Modern merchant accounting, and use its internal coherence to highlight agent strategies both quantitatively and qualitatively, following a two-pronged thrust. On one hand, we plan to record each transaction as the evolution of a specific account in a universe of creditor and debitor accounts; on the other hand, we will build categories of products with their associated prices without trying to differentiate within these sets of products. Rather than trying to understand discrete transactions,we end up with a global vision of a series of accounts, each associated with a tendency toward profit or loss, as well as a series of associated sets of products / prices, each also linked to a positive or negative balance. We can thus avoid the pitfalls which one meets with when attempting to analyse discrete transactions, and build an approximation of what the merchant entrepreneur himself "saw" in his accounts, in other words a perceived profit rather than a profit per se. In a second stage of this study, we plan to confront this perceived profit with the qualitative data one can derive from letters, diaries, etc., and eventually with actual merchant strategies. This should enable us to better understand the latter, and in particular to weigh the influence exerted on them by historically contextual variables such as kinship, socio-cultural networks, ideological and generally non strictly economic preferences, as well as the legal-institutional or customary framework agents operated in. In practice, entering individual accounting transactions into a database is an extremely time-consuming process, and we believe that the project can only be completed for ten archival funds or so, picked for their wealth of data, since we need to combine quantitative and qualitative sources. We will concentrate on a limited number of large merchant cities, Bordeaux, Nantes, Rouen, Nancy, Verviers, Amsterdam, London, Boston, and Philadelphia. Beyond the synergies born from the putting in common of the intellectual resources of a good proportion of the researchers interested in this question in France, a first, concrete result will be the building of a digitized data set of accounting transactions, available for statistical analysis. But our main goal is to reach more precise conclusions on how merchant entrepreneurs perceived their profit, and what strategies this perception brought about. This should help us understand better the economic evolutions of the Early Modern period, little known and hard to explain because of the lack of detailed information on agent behaviour. Our conclusions should also be applicable to more recent periods, since they could be used to understand better the continuities and discontinuities in the economic strategies of agents, and how much the historical context influenced the latter.

Rationale: there is a strong relationship between environmental conditions and allergic diseases including asthma, the major allergic respiratory disease, the incidence of which, in France, reaches 6% and 10% in adults and children, respectively. Asthma is characterized by an inflammation of the airways associated with bronchial hyperresponsiveness, the mechanisms of which are not completely elucidated. In allergic asthma, the effect of short term allergic exposure is relatively well understood. In contrast very little is known regarding long term exposure to allergens, a condition much more relevant to the clinical situation. Under such conditions, recent data derived from animal experiments indicate that allergen exposure causes bronchial remodelling leading to very poorly reversible and drug-resistant airways alteration. In connection with airway remodelling, there is evidence that mast cells infiltrate the bronchial smooth muscle layer thus creating an auto-activation loop involving the two types of cell. Aim: the aim of the present proposal is to investigate the interactions between mast cells and bronchial smooth muscle cells in humans as well as in a mouse model of allergic asthma by chronic exposure to allergens. Expected results: the project has 2 majors goals: • pathophysiology: identification of molecular and cellular factors involved in the mast cell – smooth muscle cell auto-activation loop; • therapeutic: identification of therapeutic targets that could antagonize the onset and ongoing of this auto-activation loop. Methodology: the project combines cell biology approaches in vitro in human isolated cells, immuno-histo-cytochemistry ex vivo on bronchial samples from asthmatic patients and in vivo mouse model that can be applied to KO animals. Three specific pathophysiological issues are to be addressed: • identification of ligand - receptor pairs involved in the auto-activation loop with special attention to CX3CL1 (fractalkine, FKN) - CX3CR1 ; • determination of molecular mechanism implicated in cell to cell adhesion • analysis of functional consequences of mast cell adhesion on airway smooth muscle phenotype; completed by 3 therapeutic issues: • identification of mast cell subtype that may act as therapeutic targets; • effect of inhibition of specific smooth muscle cell receptors (e.g. PAR-2…) ; • effect of inhibition of molecules implicated in cell to cell adhesion. Conclusion: the project aims at determining specific modulations of therapeutic targets able to antagonize the onset and ongoing of an auto-activation loop between mast cell and bronchial smooth muscle cell. This auto-activation loop results from the chronic aggression of allergens, a major determinant of the effect of environmental conditions on respiratory health.