Discordant Increases in CD4+ T Cells in Human Immunodeficiency Virus-Infected Patients Experiencing Virologic Treatment Failure: Role of Changes in Thymic Output and T Cell Death

Some patients infected with human immunodeficiency virus (HIV) who are experiencing antiretroviral treatment failure have persistent improvement in CD4+ T cell counts despite high plasma viremia. To explore the mechanisms responsible for this phenomenon, 2 parameters influencing the dynamics of CD4+ T cells were evaluated: death of mature CD4+ T cells and replenishment of the CD4+ T cell pool by the thymus. The improvement in CD4+ T cells observed in patients with treatment failure was not correlated with spontaneous, Fas ligand-induced, or activation-induced T cell death. In contrast, a significant correlation between the improvement in CD4+ T cell counts and thymic output, as assessed by measurement of T cell receptor excision circles, was observed. These observations suggest that increased thymic output contributes to the dissociation between CD4+ T cell counts and viremia in patients failing antiretroviral therapy and support a model in which drug-resistant HIV strains may have reduced replication rates and pathogenicity in the thymu

UX-FFE Model : An Experimentation of a new innovation process dedicated to a mature industrial company

Most of mature companies, operating through a certain form of repeat business in producing incremental innovations, have lost their ability to conduct radical or breakthrough innovations. While this is not necessarily a bad strategy for short-term sustainability, this is more questionable for future growth and long-term sustainability. Hence, we present in this paper a new innovation model, named UX-FFE because it combines both User eXperience and Fuzzy Front-End approaches. It is intended to tackle economical and social challenges of a successful innovation process. Beyond the systemic processes, like the FFE, addressing the economic stake of a company, our model includes an UX-based process in order to address also the social stake. Then, we explain how this new innovation model was concretely implemented, through the use of several techniques and tools, within a mature industrial company. Finally, we unveil the results of this innovation process experiment for evaluating its potential to overcome both economical and social challenges.Company SOURIAU ESTERLIN

UX-FFE Model : An Experimentation of a new innovation process dedicated to a mature industrial company

Most of mature companies, operating through a certain form of repeat business in producing incremental innovations, have lost their ability to conduct radical or breakthrough innovations. While this is not necessarily a bad strategy for short-term sustainability, this is more questionable for future growth and long-term sustainability. Hence, we present in this paper a new innovation model, named UX-FFE because it combines both User eXperience and Fuzzy Front-End approaches. It is intended to tackle economical and social challenges of a successful innovation process. Beyond the systemic processes, like the FFE, addressing the economic stake of a company, our model includes an UX-based process in order to address also the social stake. Then, we explain how this new innovation model was concretely implemented, through the use of several techniques and tools, within a mature industrial company. Finally, we unveil the results of this innovation process experiment for evaluating its potential to overcome both economical and social challenges.Company SOURIAU ESTERLIN

Reduced expression of monocyte CD200R is associated with enhanced proinflammatory cytokine production in sarcoidosis

In sarcoidosis, the proinflammatory cytokines interferon gamma, tumour necrosis factor and interleukin-6 are released by monocyte-derived macrophages and lymphocytes in the lungs and other affected tissues. Regulatory receptors expressed on monocytes and macrophages act to suppress cytokine production, and reduced expression of regulatory receptors may thus promote tissue inflammation. The aim of this study was to characterise the role of regulatory receptors on blood monocytes in patients with sarcoidosis. Cytokine release in response to stimulation of whole blood was measured in healthy controls and Caucasian non-smoking patients with sarcoidosis who were not taking disease modifying therapy. Expression of the regulatory molecules IL-10R, SIRP-α/β, CD47, CD200R, and CD200L was measured by flow cytometry, and functional activity was assessed using blocking antibodies. Stimulated whole blood and monocytes from patients with sarcoidosis produced more TNF and IL-6 compared with healthy controls. 52.9% of sarcoidosis patients had monocytes characterised by low expression of CD200R, compared with 11.7% of controls (p < 0.0001). Patients with low monocyte CD200R expression produced higher levels of proinflammatory cytokines. In functional studies, blocking the CD200 axis increased production of TNF and IL-6. Reduced expression of CD200R on monocytes may be a mechanism contributing to monocyte and macrophage hyper-activation in sarcoidosis

Towards radical innovations in a mature company: an empirical study on the UX-FFE model

Publication dans le cadre d'une thèse Cifre entre le LAMPA et Esterline.The ability to successfully conduct radical innovations is mandatory for mature industrial companies that want to remain competitive in the global market. This ability relies on several ingredients, namely: (1) the structuring of the innovation process; (2) managerial principles; (3) methodological tools; (4) the presence of a culture of innovation. This paper reports about the impact of applying the User eXperience-Fuzzy Front End (UX-FFE) model, which brings together the systemic innovation process with the social, economical, and methodological aspects on the outcomes of the innovation process. Firstly, it appears that the operational performance of the upstream innovation process relies on the quality of the social context, intrinsic to the group of co-creators, corresponding to the reported perceived experience. Secondly, the UX-FFE model application, therefore, allows optimizing the upstream innovation process performance. Indeed, we argue that the evaluation of the co-creators perceived experience brings new opportunities to optimize the operational performance of the upstream innovation process. The first part of this paper presents deeper a theoretical model, named UX-FFE, which combines a UX approach with an upstream innovation process (FFE). The main interest of this UX-FFE model is that it allows evaluating the social aspect of the upstream innovation process, which may be detrimental to the success of radical innovation projects in mature companies. The second part presents the results of previous experiments that validated the model. The results allow the design of an instrument dedicated to the evaluation of the user experience of co-creators in the ideation stage. Finally, the third part reports about the experimentation of the UX-FFE in a mature company. Results present the impact of the co-creators’experience on the performance of radical innovation projects.Esterlin

Modèle UX-FFE : Expérimentation de la phase de validation d'un nouveau processus d'innovation dédié à une entreprise industrielle mature

Le modèle UX-FFE est un modèle qui associe les approches « User eXperience » et « Fuzzy Front End » dans le but de répondre aux enjeux économiques et sociaux d’une entreprise industrielle mature. Ce papier présente une proposition de structuration de la phase de validation du modèle. Ensuite, nous verrons comment cette proposition a concrètement été expérimentée en milieu industriel. Les résultats montrent que notre proposition facilite l’introduction d’innovations de rupture et a une influence sur la qualité de l’expérience utilisateur tout au cours de la phase de validation du modèle UX-FFE, donc au cours du processus amont d’innovation. Enfin, cet article prévient aussi qu’une nouvelle approche de la mesure de la performance des processus d’innovation est envisageable.Société Souriau Esterlin

Variation in RNA Virus Mutation Rates across Host Cells

It is well established that RNA viruses exhibit higher rates of spontaneous mutation than DNA viruses and microorganisms. However, their mutation rates vary amply, from 10−6 to 10−4 substitutions per nucleotide per round of copying (s/n/r) and the causes of this variability remain poorly understood. In addition to differences in intrinsic fidelity or error correction capability, viral mutation rates may be dependent on host factors. Here, we assessed the effect of the cellular environment on the rate of spontaneous mutation of the vesicular stomatitis virus (VSV), which has a broad host range and cell tropism. Luria-Delbrück fluctuation tests and sequencing showed that VSV mutated similarly in baby hamster kidney, murine embryonic fibroblasts, colon cancer, and neuroblastoma cells (approx. 10−5 s/n/r). Cell immortalization through p53 inactivation and oxygen levels (1–21%) did not have a significant impact on viral replication fidelity. This shows that previously published mutation rates can be considered reliable despite being based on a narrow and artificial set of laboratory conditions. Interestingly, we also found that VSV mutated approximately four times more slowly in various insect cells compared with mammalian cells. This may contribute to explaining the relatively slow evolution of VSV and other arthropod-borne viruses in nature

Une vision multidimensionnelle des typologies d'innovation pour identifier et concevoir une démarche d'innovation

Quels que soient les auteurs majeurs, la première partie de cet article confirme qu’il ressort une valeur universelle portée par une innovation, celle d’une nouveauté associée à une réussite commerciale.Nous rappellerons la vision pionnière de Schumpeter qui tend vers une caractérisation générale de l’innovation jusqu’à une échelle internationale portée par le manuel d’Oslo.Nous verrons comment ces visions croisées ont permis de faire émerger un nouvel agencement des typologies pour lequel nous proposons un modèle synthétique.Cette synthèses’est basée sur le système de caractérisation originale proposé par Garcia et Calantone, mais en considérant cette fois les innovations radicales, réellement nouvelles et incrémentales non pas comme des typologies mais comme des niveaux d’intensité. De plus, nous apporterons des compléments qui renforcent les notions de discontinuités, fondations de leur modèle. Enfin, et toujours dans un souci de clarification et de compréhension, il nous a semblé utile de représenter les domaines de validité de ces différentes typologies d’innovations par des équations booléennes, en complément des travaux de Garcia et Calantone. La mise en exergue des différentes variables, composantes de chaque typologie, favorise ainsi l’ajustement voire le choix de la meilleure typologie en fonction de l’objectif visé. A l’inverse, notre formalisation croisée peut faciliter la reconnaissance de l’origine d’un résultat à partir de son observation

Changes in Human Immunodeficiency Virus Type 1 Populations after Treatment Interruption in Patients Failing Antiretroviral Therapy

ABSTRACT Mutations in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase and protease that confer resistance to antiretroviral agents are usually accompanied by a reduction in the viral replicative capacity under drug-free conditions. Consequently, when antiretroviral treatment is interrupted in HIV-1-infected patients harboring drug-resistant virus, resistant quasi-species appear to be most often replaced within several weeks by wild-type virus. Using a real-time PCR-based technique for the selective quantification of resistant viral sequences in plasma, we have studied the kinetics of the switch from mutant to wild-type virus and evaluated the extent to which minority populations of resistant viruses not detected by genotyping persist in these individuals. Among 12 patients with viruses expressing the V82A or L90M resistance mutation who had undergone a 3-month interruption of therapy and for whom conventional genotyping had revealed an apparent total reconversion to wild-type virus, minority populations expressing these mutations, representing 0.1 to 21% of total virus, were still detectable in 9 cases. Kinetic studies demonstrated that viruses expressing resistance mutations could be detected for &gt;5 months after the discontinuation of treatment in some patients. Most of the minority resistant genomes detected more than 3 months after the interruption of therapy carried only part of the mutations present in the resistant viruses prior to treatment interruption and appeared to result from the emergence of existing strains selected at earlier stages in the development of drug resistance. Thus, following the interruption of treatment, viral populations containing resistance mutations can persist for several months after the time when conventional genotyping techniques detect only wild-type virus. These populations include viral strains with only some of the resistance mutations initially present, strains that presumably express better fitness under drug-free conditions.</jats:p