Human disease and drug pharmacology, complex as real life

In the past decades drug discovery practice has escaped from the complexity of the formerly used phenotypic screening in animals to focus on assessing drug effects on isolated protein targets in the search for drugs that exclusively and potently hit one selected target, thought to be critical for a given disease, while not affecting at all any other target to avoid the occurrence of side-effects. However, reality does not conform to these expectations, and, conversely, this approach has been concurrent with increased attrition figures in late-stage clinical trials, precisely due to lack of efficacy and safety. In this context, a network biology perspective of human disease and treatment has burst into the drug discovery scenario to bring it back to the consideration of the complexity of living organisms and particularly of the (patho)physiological environment where protein targets are (mal)functioning and where drugs have to exert their restoring action. Under this perspective, it has been found that usually there is not one but several disease-causing genes and, therefore, not one but several relevant protein targets to be hit, which do not work on isolation but in a highly interconnected manner, and that most known drugs are inherently promiscuous. In this light, the rationale behind the currently prevailing single-target-based drug discovery approach might even seem a Utopia, while, conversely, the notion that the complexity of human disease must be tackled with complex polypharmacological therapeutic interventions constitutes a difficult-torefuse argument that is spurring the development of multitarget therapies.

Life designing: A paradigm for career construction in the 21st century

At the beginning of the 21st century, a new social arrangement of work poses a series of questions and challenges to scholars who aim to help people develop their working lives. Given the globalization of career counseling, we decided to address these issues and then to formulate potentially innovative responses in an international forum. We used this approach to avoid the difficulties of creating models and methods in one country and then trying to export them to other countries where they would be adapted for use. This article presents the initial outcome of this collaboration, a counseling model and methods. The life-designing model for career intervention endorses five presuppositions about people and their work lives: contextual possibilities, dynamic processes, non-linear progression, multiple perspectives, and personal patterns. Thinking from these five presuppositions, we have crafted a contextualized model based on the epistemology of social constructionism, particularly recognizing that an individual's knowledge and identity are the product of social interaction and that meaning is co-constructed through discourse. The life-design framework for counseling implements the theories of self-constructing [Guichard, J. (2005). Life-long self-construction. International Journal for Educational and Vocational Guidance, 5, 111-124] and career construction [Savickas, M. L. (2005). The theory and practice of career construction. In S. D. Brown & R. W. Lent (Eds.), Career development and counselling: putting theory and research to work (pp. 42-70). Hoboken, NJ: Wiley] that describe vocational behavior and its development. Thus, the framework is structured to be life-long, holistic, contextual, and preventive.

A spatially explicit life cycle inventory of the global textile chain

Life cycle analyses (LCA) approaches require adaptation to reflect the increasing delocalization of production to emerging countries. This work addresses this challenge by establishing a country-level, spatially explicit life cycle inventory (LCI). This study comprises three separate dimensions. The first dimension is spatial: processes and emissions are allocated to the country in which they take place and modeled to take into account local factors. Emerging economies China and India are the location of production, the consumption occurs in Germany, an Organisation for Economic Cooperation and Development country. The second dimension is the product level: we consider two distinct textile garments, a cotton T-shirt and a polyester jacket, in order to highlight potential differences in the production and use phases. The third dimension is the inventory composition: we track CO2, SO2, NO (x), and particulates, four major atmospheric pollutants, as well as energy use. This third dimension enriches the analysis of the spatial differentiation (first dimension) and distinct products (second dimension). We describe the textile production and use processes and define a functional unit for a garment. We then model important processes using a hierarchy of preferential data sources. We place special emphasis on the modeling of the principal local energy processes: electricity and transport in emerging countries. The spatially explicit inventory is disaggregated by country of location of the emissions and analyzed according to the dimensions of the study: location, product, and pollutant. The inventory shows striking differences between the two products considered as well as between the different pollutants considered. For the T-shirt, over 70% of the energy use and CO2 emissions occur in the consuming country, whereas for the jacket, more than 70% occur in the producing country. This reversal of proportions is due to differences in the use phase of the garments. For SO2, in contrast, over two thirds of the emissions occur in the country of production for both T-shirt and jacket. The difference in emission patterns between CO2 and SO2 is due to local electricity processes, justifying our emphasis on local energy infrastructure. The complexity of considering differences in location, product, and pollutant is rewarded by a much richer understanding of a global production-consumption chain. The inclusion of two different products in the LCI highlights the importance of the definition of a product's functional unit in the analysis and implications of results. Several use-phase scenarios demonstrate the importance of consumer behavior over equipment efficiency. The spatial emission patterns of the different pollutants allow us to understand the role of various energy infrastructure elements. The emission patterns furthermore inform the debate on the Environmental Kuznets Curve, which applies only to pollutants which can be easily filtered and does not take into account the effects of production displacement. We also discuss the appropriateness and limitations of applying the LCA methodology in a global context, especially in developing countries. Our spatial LCI method yields important insights in the quantity and pattern of emissions due to different product life cycle stages, dependent on the local technology, emphasizing the importance of consumer behavior. From a life cycle perspective, consumer education promoting air-drying and cool washing is more important than efficient appliances. Spatial LCI with country-specific data is a promising method, necessary for the challenges of globalized production-consumption chains. We recommend inventory reporting of final energy forms, such as electricity, and modular LCA databases, which would allow the easy modification of underlying energy infrastructure.

Cinema and the Work of Doré

According to Ray Harryhausen, a special effects expert in the film industry, "Gustave Doré would have made a great director of photography . . . He saw things from the point of view of the camera." Doré's work has had a permanent impact on the imaginative realm of film since its very early days. In return, the silver screen has etched Doré into the 20th century imagination. Almost every film about the Bible since The Life and Passion of Jesus Christ produced by Pathé in 1902 refers to his illustrations, and every film adaptation of Dante or Don Quixote has used him as a model, from Georg Wilhelm Pabst and Orson Welles to Terry Gilliam. All films dealing with life in London in the Victorian era by directors ranging from David Lean, to Roman Polanski and Tim Burton draw on the visions in London: a pilgrimage for their sets. A large number of dream fantastical or phantasmagorical scenes take their inspiration from Doré's graphic world, beginning with Georges Méliès' A Trip to the Moon in 1902. In the realm of cartoons and animation, Walt Disney owes a huge debt to Doré. Doré primal forests, from Atala in particular, were also used in the various versions of King Kong from 1933 to the 2005 film by Peter Jackson, who had already drawn on Doré for The Lord of the Rings. Jean Cocteau was also indebted to the illustrations for Perrault's Fairy Tales for his Beauty and the Beast (1945), as was George Lucas for the character Chewbacca in Star Wars (1977) and even the Harry Potter film series. Through his influence on film history, Doré shaped the mass culture imagination.

Shelf life and sensory assessment of tilapia quenelle during frozen storage

The objective of this work was to evaluate the shelf life and sensory attributes of tilapia quenelle. Treatments consisted of two types of packages - polyethylene zipper (retort pouch) (QA) and polyethylene waxed paper box (QB) - stored at -18ºC for 120 days. Tilapia quenelle was stable for all parameters established by Brazilian legislation. Average values of the evaluated attributes in different packages, during storage, showed no significant difference, except for the "refrigeration" flavor. However, during the storage period, there were significant differences for sensory attributes, as "moist appearance", fish and product aroma, and off flavors of "mud" and "refrigeration". Preserving product quality as for its sensory attributes, during storage, shows that tilapia quenelle is a convenience product and contributes to the increase of fish consumption.

Using tools to help cost estimating and pricing: examination of costing model's and cost breakdown's workability and their capability to cooperative work

Tämä diplomityö käsittelee työkaluja, jotka on suunniteltu kustannusten ennakointiin ja hinnan asetantaan. Aluksi on käyty läpi perinteisen ja toimintoperusteisen kustannuslaskennan perusteita. Näiden menetelmien välisiä eroja on tarkasteltu ja toimintoperusteisen kustannuslaskennan paremmin sopivuus nykypäivän yrityksille on perusteltu. Toisena käsitellään hinnoittelu. Hinnan merkitys, hinnoittelumenetelmät ja päätös lopullisesta hinnasta on käyty läpi. Hinnoittelun jälkeen esitellään kustannusjärjestelmät ja kustannusten arviointi. Nämä asiat todistavat, että tarkat kustannusarviot ovat elintärkeitä yritykselle. Tuotteen kustannusarviointi, hinnan asetanta ja tarjoaminen ovat erittäin merkityksellisiä asioita ottaen huomioon koko projektin elinkaaren ja tulevat tuotot. Nykyään on yleistä käyttää työkaluja kustannusarvioinnissa ja joskus myös hinnoittelussa. Työkalujen luotettavuus on tiedettävä, ennenkuin työkalut otetaan käyttöön. Myös työkalujen käyttäjät täytyy perehdyttää hyvin. Muuten yritys todennäköisesti kohtaa odottamattomia ja epämiellyttäviä yllätyksiä.

La flexibilité du temps de travail: entre autonomie et contraintes. Une étude de cas en Suisse.

Flexitime : between autonomy and constraints. A case study in SwitzerlandBy looking at how a new regulation is translated into everyday practices, this dissertation explores through a specific case study the degree of autonomy gained by wage-earners with the introduction of flexible working schedules. The guiding hypothesis is that by introducing procedural rules, flexitime opens the space for more daily negotiations, therefore reinforcing the effects of power relations inherent to employment relationships. The goal is to understand, through a sociological approach, how employees experience a form of working time that transfers responsibility for time management to them, and howthey integrate work-related constraints with their life outside the workplace. The first part of the dissertation sets up the context of the case study. It offers a definition of flexibility by situating it in the broader history of work time, as well as in relation to various organizational forms and cultural transformations. An international literature review and a focus on the Swiss case are offered. In the second part, the focus is narrowed to a specificSwiss firm specialized in mail-order, where a system of individualized management of annual work time has been introduced. By combining a quantitative and qualitative approach, it is possible to analyze determinants of the practices internal to the firm anddeterminants related to employees themselves, as well as the way in which employees articulate these two orders of constraints. The results show that the implementation of flexible working time is not affecting daily negotiation practices so much as it is creating a set of informal rules. The autonomy ofwage-earners is expressed first and foremost through their capacity to produce, negotiate, and legitimate these rules. The intraindividual level has proven to be central for the social regulation of flexible working time. It is not so much a question of legitimation, but rather the process of institutionalization nurtured by the energy invested by wage-earners in their personal quest for a compromise between their various roles, identities, and aspirations. It is this individualized regulation that is ensuring the success of the system under study.

Life cycle analysis and life cyle impact assessment methodologies: a state of the art

Life cycle analysis (LCA) is a comprehensive method for assessing the environmental impact of a product or an activity over its entire life cycle. The purpose of conducting LCA studies varies from one application to another. Different applications use LCA for different purposes. In general, the main aim of using LCA is to reduce the environmental impact of products through guiding the decision making process towards more sustainable solutions. The most critical phase in an LCA study is the Life Cycle Impact Assessment (LCIA) where the life cycle inventory (LCI) results of the considered substances related to the study of a certain system are transformed into understandable impact categories that represent the impact on the environment. In this research work, a general structure clarifying the steps that shall be followed ir order to conduct an LCA study effectively is presented. These steps are based on the ISO 14040 standard framework. In addition, a survey is done on the most widely used LCIA methodologies. Recommendations about possible developments and suggetions for further research work regarding the use of LCA and LCIA methodologies are discussed as well.

Applying the principles of life cycle assessment and costing in process modeling to examine profit-making capability

Static process simulation has traditionally been used to model complex processes for various purposes. However, the use of static processsimulators for the preparation of holistic examinations aiming at improving profit-making capability requires a lot of work because the production of results requires the assessment of the applicability of detailed data which may be irrelevant to the objective. The relevant data for the total assessment gets buried byirrelevant data. Furthermore, the models do not include an examination of the maintenance or risk management, and economic examination is often an extra property added to them which can be performed with a spreadsheet program. A process model applicable to holistic economic examinations has been developed in this work. The model is based on the life cycle profit philosophy developed by Hagberg and Henriksson in 1996. The construction of the model has utilized life cycle assessment and life cycle costing methodologies with a view to developing, above all, a model which would be applicable to the economic examinations of complete wholes and which would require the need for information focusing on aspects essential to the objectives. Life cycle assessment and costing differ from each other in terms of the modeling principles, but the features of bothmethodologies can be used in the development of economic process modeling. Methods applicable to the modeling of complex processes can be examined from the viewpoint of life cycle methodologies, because they involve the collection and management of large corpuses of information and the production of information for the needs of decision-makers as well. The results of the study shows that on the basis of the principles of life cycle modeling, a process model can be created which may be used to produce holistic efficiency examinations on the profit-making capability of the production line, with fewer resources thanwith traditional methods. The calculations of the model are based to the maximum extent on the information system of the factory, which means that the accuracyof the results can be improved by developing information systems so that they can provide the best information for this kind of examinations.

Warlike outlines of the securitarian state. Life control and the exclusion of people

Present book collects some of the thoughts developed during the 5 years (2004-2009) of work in the frame of the CHALLENGE project, "The Changing Landscape of European Liberty and Security". The project has related academic knowledge and research with the analysis of the policies and practices of the member States of the European Union [EU] around the couple liberty and security

Spatially varying selection shapes life history clines among populations of Drosophila melanogaster from sub-Saharan Africa.

Clines in life history traits, presumably driven by spatially varying selection, are widespread. Major latitudinal clines have been observed, for example, in Drosophila melanogaster, an ancestrally tropical insect from Africa that has colonized temperate habitats on multiple continents. Yet, how geographic factors other than latitude, such as altitude or longitude, affect life history in this species remains poorly understood. Moreover, most previous work has been performed on derived European, American and Australian populations, but whether life history also varies predictably with geography in the ancestral Afro-tropical range has not been investigated systematically. Here, we have examined life history variation among populations of D. melanogaster from sub-Saharan Africa. Viability and reproductive diapause did not vary with geography, but body size increased with altitude, latitude and longitude. Early fecundity covaried positively with altitude and latitude, whereas lifespan showed the opposite trend. Examination of genetic variance-covariance matrices revealed geographic differentiation also in trade-off structure, and QST -FST analysis showed that life history differentiation among populations is likely shaped by selection. Together, our results suggest that geographic and/or climatic factors drive adaptive phenotypic differentiation among ancestral African populations and confirm the widely held notion that latitude and altitude represent parallel gradients.

Opening The Fortress : the work of public gaze on the Swiss asylum reality

The Fortress (La Forteresse) is a 2008 documentary film by Fernand Melgar that reports the Swiss asylum reality from a distant but committed point of view. The documentary describes the life of asylum seekers awaiting in a federal centre the decision to grant them-or not-refugee status. It subtly raises the issue of the role that "textual realities", grasped from the spectator's point of view, play in the production of public discourses. Most of all, it subtly poses the question of the (Swiss) spectator as an actor of the asylum policy, in the context of a semi-direct democracy. After evoking the notion of sensible experience for linking spectatorship to politics, we look at how the documentary invites its model spectator to accept the film's moral premises. Furthermore, focusing on the Swiss public sphere, we deliver an account of the reception by empirical spectators, notably by a group of leftist activists that tend to subvert Melgar's intentions. This two-fold analysis leads us to exhibit that, in a context of discursive struggles, The Fortress generates an original space of deliberation and experience, which appeals to the public to exercise their political agency on asylum policy without being constricted by an antagonist framework.

Quality of life after pulmonary embolism: Prospective validation of the German version of the PEmb-QoL questionnaire.

BACKGROUND: The Pulmonary Embolism Quality of Life questionnaire (PEmb-QoL) is a 40-item questionnaire to measure health-related quality of life in patients with pulmonary embolism. It covers six 6 dimensions: frequency of complaints, limitations in activities of daily living, work-related problems, social limitations, intensity of complaints, and emotional complaints. Originally developed in Dutch and English, we prospectively validated a German version of the PEmb-QoL. METHODS: A forward-backward translation of the English version of the PEmb-QoL into German was performed. German-speaking consecutive adult patients aged ≥18 years with an acute, objectively confirmed pulmonary embolism discharged from a Swiss university hospital (01/2011-06/2013) were recruited telephonically. Established psychometric tests and criteria were used to evaluate the acceptability, reliability, and validity of the German PEmb-QoL questionnaire. To assess the underlying dimensions, an exploratory factor analysis was performed. RESULTS: Overall, 102 patients were enrolled in the study. The German version of the PEmb-QoL showed a good internal consistency (Cronbach's alpha ranging from 0.72 to 0.96), item-total (0.53-0.95) and inter-item correlations (>0.4), and test-retest reliability (intra-class correlation coefficients 0.59-0.89) for the dimension scores. A moderate correlation of the PEmb-QoL with SF-36 dimension and summary scores (0.21-0.83) indicated convergent validity, while low correlations of PEmb-QoL dimensions with clinical characteristics (-0.16-0.37) supported discriminant validity. The exploratory factor analysis suggested four underlying dimensions: limitations in daily activities, symptoms, work-related problems, and emotional complaints. CONCLUSION: The German version of the PEmb-QoL questionnaire is a valid and reliable disease-specific measure for quality of life in patients with pulmonary embolism.

Early life host-microbe interactions : implications for the development of asthma

Plus de 300 millions de personnes dans le monde souffrent de l'asthme. L'asthme est une maladie inflammatoire chronique des voies respiratoires caractérisée par des symptômes variables et récurrents, une obstruction bronchique réversible et des bronchospasmes. Les symptômes communs incluent une respiration sifflante, de la toux, une oppression thoracique et de la dyspnée. Normalement, la maladie commence à se manifester pendant l'enfance. Pourtant, facteurs génétiques héréditaires et événements environnementaux survenant au cours de la petite enfance sont responsables de sa manifestation, indiquant que le développement de la maladie est lié à des événements qui se produisent bien avant son déclenchement. L'infection respiratoire virale aiguë constitue un de ces facteurs environnementaux jouant un rôle prépondérant. Un des virus les plus communs est le virus respiratoire syncytial (VRS), qui infecte presque tous les enfants avant l'âge de 2 ans. Ce virus, s'il infecte des tout-petits, peut en effet provoquer une bronchiolite aiguë, un phénomène qui a été épidémiologiquement lié à l'apparition d'asthme plus tard dans la vie. Dans le premier chapitre de cette thèse, nous avons étudié, chez la souris, comment une infection avec le VRS influe sur l'asthme allergique. Nous avons constaté que seule l'infection des souris à l'état de nouveau-né prédispose à un asthme allergique plus sévère chez l'adulte. En effet, si des souris adultes étaient infectées, elles étaient protégées contre l'apparition des symptômes asthmatiques. Cela nous a mené à investiguer les mécanismes immunitaires spécifiques durant cette courte période du début de la vie. Deux événements se produisent en parallèle au cours de la petite enfance: (1) Le système immunitaire, qui est encore immature immédiatement après la naissance, commence à se développer pour être en mesure de jouer son rôle protecteur contre les agents infectieux. (2) Le corps, y compris les poumons, est colonisé par des bactéries commensales, qui vivent en symbiose avec leur hôte humain. Chez l'adulte, ces bactéries sont connues pour influencer notre système immunitaire, l'éduquant à générer des réponses immunitaires adéquates et efficaces. Dans la deuxième partie de cette thèse, nous avons voulu déterminer si ces bactéries symbiotiques étaient impliquées dans l'éducation du système immunitaire du nouveau-né et quelles conséquences cela pourrait avoir sur les réponses immunitaires engendrées par ce dernier. Pour étudier l'effet de ces bactéries symbiotiques, nous avons utilisé des souris stériles, en d'autres termes des souris qui n'hébergent pas ces bactéries symbiotiques. En comparant ces souris stériles à des souris qui abritent une flore microbienne normale, nous avons constaté que les bactéries symbiotiques sont vitales pour la bonne éducation du système immunitaire du nouveau-né. Nous avons démontré que le contact direct des cellules immunitaires avec la flore microbienne dans les poumons modifie le phénotype de ces cellules immunitaires, ce qui change probablement leur réaction au cours de réponses immunitaires. Nous avons donc vérifié si l'éducation immunitaire induite par cette microflore est importante pour prévenir les maladies pulmonaires telles que l'asthme allergique, affections qui sont causées par une réaction excessive du système immunitaire envers des agents inoffensifs. En effet, nous avons observé que le processus de maturation du système immunitaire néonatal, lequel a été déclenché et façonné par la flore microbienne, est important pour éviter une réaction asthmatique exagérée chez la souris adulte. Ce phénomène est dû aux lymphocytes T régulateurs. Ces cellules, dont la présence est induite dans les poumons, ont des capacités immunosuppressives et atténuent donc les réponses immunitaires pour prévenir une inflammation excessive. En conclusion, nous avons montré dans cette thèse que la colonisation par des bactéries symbiotiques tôt dans la vie est un événement décisif pour la maturation du système immunitaire et pour prévenir le développement de l'asthme. Dans l'avenir, il serait intéressant de découvrir quelles bactéries sont présentes dans les poumons du nouveau-né et lesquelles sont directement impliquées dans ce processus de maturation immunitaire. Une prochaine étape serait alors de favoriser la présence de ces bactéries au début de la vie au moyen d'un traitement avec des agents pré- ou probiotiques, ce qui pourrait éventuellement contribuer à une prévention précoce du développement de l'asthme. -- L'asthme est une maladie chronique inflammatoire des voies respiratoires affectant près de 300 millions d'individus dans le monde. Bien que les traits caractéristiques du phénotype asthmatique s'établissent généralement pendant l'enfance, la prédisposition au développement de la maladie est intimement liée à des événements survenant durant la petite enfance, comme le sont par exemple les infections virales respiratoires aiguës. Les mécanismes par lesquels ces événements provoquent un dysfonctionnement immunitaire et, par conséquent, conduisent au développement de l'asthme n'ont pas encore été entièrement décelés. La dysbiose du microbiote des voies respiratoires a été récemment associes au phénotype asthmatique, touisTcis, la cuûoboiatioî! d un lien cause à effet entre la dysbiose microbienne et l'apparition des symptômes asthmatiques reste à être démontrée. Dans cette thèse, nous avons étudié le rôle que joue la colonisation microbienne des voies respiratoires au cours de la petite enfance dans la maturation du système immunitaire ainsi que dans la protection contre l'inflammation pulmonaire de type allergique. Nous avons de surcroît développé un modèle expérimental pour comprendre comment les infections virales respiratoires interfèrent avec ce processus. Dans la première partie de cette thèse, nous avons évalué l'effet d'infections causées par le virus respiratoire syncytial (VRS) sur le développement de l'asthme. En accord avec des études épidémiologiques, nous avons constaté qu'une infection au VRS lors de la période néonatale exacerbait les réponses pulmonaires allergiques ultérieures. Par contraste, une infection à l'âge adulte avait un effet protecteur. Nous avons ainsi démontré que l'influence d'une infection à VRS sur l'issue et la sévérité de l'asthme respiratoire était strictement dépendante de l'âge. Ces résultats nous ont conduit à émettre l'hypothèse que des différences dans le phénotype homéostatique des cellules immunitaires pourraient être responsables de ces disparités liées à l'âge. Par conséquent, dans la deuxième partie de cette thèse, nous avons suivi et caractérisé le processus de maturation des cellules immunitaires dans les poumons du nouveau-né en condition d'homéostasie. Nous avons découvert que leur phénotype change de façon dynamique pendant le développement néonatal et que la colonisation par des microbes était déterminante pour la maturation des cellules immunitaires dans les poumons. Dans la dernière partie de cette thèse, nous avons démontré comment le microbiote pulmonaire éduque le développement immunitaire durant la période néonatale l'orientant de manière à induire une tolérance face aux aéroallergènes. Nous avons découvert que la colonisation microbienne des voies respiratoires provoque une expression transitoire de PD-L1 sur les cellules dendritiques (CD) pulmonaires du type CD11b+ dans les deux premières semaines de la vie. Cet événement engendre par la suite la génération de lymphocytes T régulateurs (TREG) dans les poumons, lesquels sont responsables de la protection contre une réponse inflammatoire allergique exagérée chez la souris adulte. Par conséquent, nous proposons un rôle pivot de la maturation immunitaire induite par le microbiote pulmonaire dans l'établissement de la tolérance aux aéroallergènes. En conclusion, les résultats présentés dans cette thèse fournissent de nouveaux indices révélant comment des événements se produisant lors de la petite enfance peuvent façonner les réponses du système immunitaire dirigées contre les allergènes et soulignent le rôle central joué par le microbiote pulmonaire dans l'édification d'une réponse immunitaire équilibrée. En résumé, notre travail met en évidence le microbiote pulmonaire comme étant une cible potentielle pour la prévention de certaines maladies respiratoires. -- Asthma is a chronic inflammatory disorder of the respiratory tract and affects approximately 300 million individuals world-wide. Although the asthmatic phenotype commonly establishes during childhood, predisposition towards disease development has been linked to events in early infancy, such as severe respiratory viral infections. However, the mechanisms by which these events cause immune dysfunction and, therefore, lead to the development of asthma have yet to be fully deciphered. Dysbiosis of the airway microbiota has recently been associated with the asthmatic phenotype; however, conclusive evidence for a causal link between microbial dysbiosis in the ail ways and asthma development is still missing. In this thesis we investigated the role of early-life microbial airway colonization in immune maturation and the protection against allergic airway inflammation and established an experimental model to address how respiratory viral infections interfere in this process. In the first part of this thesis we evaluated the effect of Respiratory syncytial virus (RSV) infections on the development of asthma. In concurrence with epidemiological studies, we found that neonatal infection exacerbated subsequent allergic airway inflammation. In contrast, adult infection was protective in the same context. Thus, we could demonstrate that the influence of RSV infection on subsequent allergic airway responses was strictly age-dependent. These findings led us to the hypothesis that differences in the homeostatic phenotype of immune cells could be responsible for the age-related disparities seen within the context of RSV. Therefore, in a second part of this thesis, we followed the process of homeostatic immune cell maturation in the neonatal lung. Immune cell phenotypes changed dynamically during neonatal development. We discovered that the colonization with microbes was central to the maturation of immune cells in the lung. In the last part of this thesis, we demonstrated how microbiota-driven immune development during the neonatal period induces tolerance against aeroallergens. We discovered that microbial colonization led to a transient programmed death-ligand (PD-L) 1 expression on CD11b+ pulmonary dendritic cells (DCs) during the first two weeks of life. This in turn induced regulatory T (TREG) cells in the lung, which were responsible for the protection against exaggerated allergic airway inflammation in adult mice. Thus, we propose a key role for microbiota-driven immune maturation in the establishment of tolerance towards aeroallergens. In conclusion, the results presented in this thesis provide new insights into how early-life events shape pulmonary immune responses towards allergens and suggest the airway microbiota as a key player in establishing a balanced immune response. Overall, our work highlights the airway microbiota as potential target for disease prevention.

The Life-World and Its Multiple Realities: Alfred Schütz's Contribution to the Understanding of the Experience of Illness

Alfred Schütz original contribution to the social sciences refers to his analysis of the structure of the "life-world". This article aims to invigorate interest in the work of this author, little known in the field of health psychology. Key concepts of Schütz' approach will be presented in relation to their potential interest to the understanding of the experience of illness. In particular, we develop the main characteristics of the everyday life and its cognitive style, that is, its finite province of meaning. We propose to adopt this notion to define the experience of chronic or serious illness when the individual is confronted to the medical world. By articulating this analysis with literature in health psychology, we argue that Schütz's perspective brings useful insight to the field, namely because of its ability to study meaning constructions by overcoming the trap of solipsism by embracing intersubjectivity. The article concludes by outlining both, the limitations and research perspectives brought by this phenomenological analysis of the experiences of health and illness.