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International audience; Yttrium, Titanium and Yttrium-Titanium getter thin films were elaborated on silicon by co-evaporation in ultra-high vacuum. Y-Ti films exhibit nanometric crystallites size (18-35 nm) leading to a very high grain boundary density, which is a favorable microstructure for an activation at low temperature. The yttrium content in Y-Ti alloys influences grain size, resistance against room temperature oxidation and gettering performance for oxygen. Y-Ti films with an yttrium content higher than 30 % show strong oxygen sorption during annealing at low temperature (< 300 °C). After 1 h of annealing at 250 °C, it was estimated that the yttrium-based getter films can trap between 0.2 and 0.5 µmol of oxygen per cm 2 , while no oxygen sorption was detected for a single metal titanium film. This make Y-Ti getter alloys attractive candidates for the packaging of MEMS under vacuum with a low bonding temperature.

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International audience; Chronic stimulation by infectious pathogens or self-antigen glucosylsphingosine (GlcSph) can lead to monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). Novel assays such as the multiplex infectious antigen microarray (MIAA) and GlcSph assays, permit identification of targets for >60% purified monoclonal immunoglobulins (Igs). Searching for additional targets, we selected 28 purified monoclonal Igs whose antigen was not represented on the MIAA and GlcSph assays; their specificity of recognition was then analyzed using microarrays consisting of 3760 B-cell epitopes from 196 pathogens. The peptide sequences PALTAVETG and PALTAAETG of the VP1 coat proteins of human poliovirus 1/3 and coxsackievirus B1/B3, respectively, were specifically recognized by 6/28 monoclonal Igs. Re-analysis of patient cohorts showed that purified monoclonal Igs from 10/155 MGUS/SM (6.5%) and 3/147 MM (2.0%) bound to the PALTAVETG or PALTAAETG epitopes. Altogether, PALTAV/AETG-initiated MGUS are not rare and few seem to evolve toward myeloma.

Endothelial cells drive the formation of new blood vessels in physiological and pathological contexts such as embryonic development, wound healing, cancer and ocular diseases. Once formed, all vessels of the vasculature system present an endothelial monolayer (the endothelium), lining the luminal wall of the vessels, that regulates gas and nutrient exchange between the circulating blood and tissues, contributing to maintaining tissue and vascular homeostasis. To perform their functions, endothelial cells integrate signalling pathways promoted by growth factors, cytokines, extracellular matrix components and signals from mechanosensory complexes sensing the blood flow. New evidence shows that endothelial cells rely on specific metabolic pathways for distinct cellular functions and that the integration of signalling and metabolic pathways regulates endothelial-dependent processes such as angiogenesis and vascular homeostasis. In this review, we provide an overview of endothelial functions and the recent advances in understanding the role of endothelial signalling and metabolism in physiological processes such as angiogenesis and vascular homeostasis and vascular diseases. Also, we focus on the signalling pathways promoted by the transmembrane protein Neuropilin-1 (NRP1) in endothelial cells, its recently discovered role in regulating mitochondrial function and iron homeostasis and the role of mitochondrial dysfunction and iron in atherosclerosis and neurodegenerative diseases.

Inflammatory cytokines play a major role in myeloproliferative neoplasms (MPNs) as regulators of the MPN clone and as mediators of clinical symptoms and complications. Firstly, we investigated the effect of JAK2V617F on 42 molecules linked to inflammation. For JAK2V617F-mutated patients, the JAK2V617F allele burden (%JAK2V617F) correlated with the levels of IL-1&beta, IL-1R&alpha, IP-10 and leptin in polycythemia vera (PV), and with IL-33 in ET, for all other molecules, no correlation was found. Cytokine production was also studied in the human megakaryocytic cell line UT-7. Wild-type UT-7 cells secreted 27/42 cytokines measured. UT-7 clones expressing 50% or 75% JAK2V617F were generated, in which the production of IL-1&beta, IP-10 and RANTES was increased, other cytokines were not affected. Secondly, we searched for causes of chronic inflammation in MPNs other than driver mutations. Since antigen-driven selection is increasingly implicated in the pathogenesis of blood malignancies, we investigated whether proinflammatory glucosylsphingosine (GlcSph) may play a role in MPNs. We report that 20% (15/75) of MPN patients presented with anti-GlcSph IgGs, distinguished by elevated levels of 11 cytokines. In summary, only IL-1&beta, and IP-10 were linked to JAK2V617F both in patients and in UT-7 cells, other inflammation-linked cytokines in excess in MPNs were not. For subsets of MPN patients, a possible cause of inflammation may be auto-immunity against glucolipids.

International audience; A process able to produce at wafer scale patterned electrodes on the vertical sidewalls of trenches is described and investigated in detail. It is based on metal evaporation at oblique incidence through a shadow mask made in a dry photoresist film. A full model of the deposition and patterning process is established in order to map the shape as well as the thickness and density of patterned electrodes with or without wafer rotation. In the case of wafer rotation, the modelling is based on the analogy of each shadow mask edge with the gnomon of a sundial. The final electrode shape is then computed from the trajectories followed by the shadows of the gnomons. Offset of the substrate tilt axis with respect to substrate plane, and position on the wafer surface, are considered in the analysis, as well as the variation of film density with incidence angle. Advantages and limitations of the proposed process are discussed. It is shown that sidewall electrodes isolated or connected to top or bottom electrodes can be simply achieved by a suitable sizing and alignment of the shadow mask but that close electrodes on a given sidewall cannot be mutually isolated when the substrate is rotated. The patterning process is demonstrated in the case of Au/Cr electrodes on the sidewalls of through wafer trenches made in GaAs by deep reactive ion etching.

Chronic stimulation by infectious or self-antigens initiates subsets of monoclonal gammopathies of undetermined significance (MGUS), smoldering multiple myeloma (SMM), or multiple myeloma (MM). Recently, glucosylsphingosine (GlcSph) was reported to be the target of one third of monoclonal immunoglobulins (Igs). In this study of 233 patients (137 MGUS, 6 SMM, 90 MM), we analyzed the GlcSph-reactivity of monoclonal Igs and non-clonal Igs. The presence of GlcSph-reactive Igs in serum was unexpectedly frequent, detected for 103/233 (44.2%) patients. However, GlcSph was targeted by the patient&rsquo, s monoclonal Ig for only 37 patients (15.9%), for other patients (44 MGUS, 22 MM), the GlcSph-reactive Igs were non-clonal. Then, the characteristics of patients were examined: compared to MM with an Epstein-Barr virus EBNA-1-reactive monoclonal Ig, MM patients with a GlcSph-reactive monoclonal Ig had a mild presentation. The inflammation profiles of patients were similar except for moderately elevated levels of 4 cytokines for patients with GlcSph-reactive Igs. In summary, our study highlights the importance of analyzing clonal Igs separately from non-clonal Igs and shows that, if autoimmune responses to GlcSph are frequent in MGUS/SMM and MM, GlcSph presumably represents the initial pathogenic event for ~16% cases. Importantly, GlcSph-initiated MM appears to be a mild form of MM disease.

L’ouverture de la guerre de Succession d’Autriche au front maritime (1744) a conduit de nombreux armateurs et gens de mer basques a se convertir a la course dans l’espoir de trouver emploi, gloire et fortune. A partir du moment ou ils s’aventurent dans ces croisieres, les acteurs de ce fait social sont inevitablement confrontes a une « loterie corsaire » (Andre Lespagnol) qui leur impose des mutations d’ordre professionnel, financier ou encore physique. L’etude des carrieres de trois equipages corsaires basques, analysees en amont et en aval de leurs croisieres, temoigne d’une activite synonyme d’ascensions et accelerations professionnelles durant la guerre. Mais le retour a la paix (1748) rebat les cartes et laisse entrevoir que les avantages acquis en temps de guerre sont souvent temporaires et illusoires.

Cancer therapy is currently a major challenge within the research community, especially in reducing the side effects of treatments and to develop new specific strategies against cancers that still have a poor prognosis. In this context, alternative strategies using biotechnologies, such as marine peptides, have been developed based on their promise of effectivity associated with a low toxicity for healthy cells. The purpose of the present paper is to investigate the active mechanism of two peptides that were isolated from the epigonal tissue of the lesser spotted dogfish Scyliorhinus canicula L., identified NFDTDEQALEDVFSKYG (K092A) and EAPPEAAEEDEW (K092B) on the in vitro growth inhibition of ZR-75-1 mammary carcinoma cells and MDA-Pca-2b prostate cancer cells. The effects of the peptides on cell proliferation and cell death mechanisms were studied by the flow cytometry and immunofluorescence microscopy approaches. The results have shown the onset of both K092A- and K092B-induced early cytoskeleton changes, and then cell cycle perturbations followed by non-apoptotic cell death. Moreover, impedance perturbation and plasma membrane perforation in ZR-75-1 K092A-treated cell cultures and autophagy inhibition in MDA-Pca-2b K092B-treated cells have been observed. In conclusion, these two bioactive peptides from dogfish exhibit antineoplastic activity on the human prostate and breast cancer cells in vitro.

International audience; This paper reports on progress in the analysis of time-domain optical coherence tomography (OCT) applied to the dimensional metrology of through-silicon vias (TSVs), which are vertical interconnect accesses in silicon, enabling three-dimensional (3D) integration in microelectronics, and estimates the deviations from earlier, simpler models. The considered TSV structures are 1D trenches and circular holes etched into silicon with a large aspect ratio. As a prerequisite for a realistic modeling, we work with spectra obtained from reference interferograms measured at a planar substrate, which fully includes the dispersion of the OCT apparatus. Applying a rigorous modal approach, we estimate the differences to a pure ray tracing technique. Accelerating our computations, we focus on the relevant fundamental modes and apply a Fabry–Perot model as an efficient approximation. Exploiting our results, we construct and present an iterative procedure based on the minimization of a merit function, which concludes TSV heights reliably, accurately, and rapidly from measured interferograms.

Cancer therapy is currently a major challenge within the research community, especially in reducing the side effects of treatments and to develop new specific strategies against cancers that still have a poor prognosis. In this context, alternative strategies using biotechnologies, such as marine peptides, have been developed based on their promise of effectivity associated with a low toxicity for healthy cells. The purpose of the present paper is to investigate the active mechanism of two peptides that were isolated from the epigonal tissue of the lesser spotted dogfish Scyliorhinus canicula L., identified NFDTDEQALEDVFSKYG (K092A) and EAPPEAAEEDEW (K092B) on the in vitro growth inhibition of ZR-75-1 mammary carcinoma cells and MDA-Pca-2b prostate cancer cells. The effects of the peptides on cell proliferation and cell death mechanisms were studied by the flow cytometry and immunofluorescence microscopy approaches. The results have shown the onset of both K092A- and K092B-induced early cytoskeleton changes, and then cell cycle perturbations followed by non-apoptotic cell death. Moreover, impedance perturbation and plasma membrane perforation in ZR-75-1 K092A-treated cell cultures and autophagy inhibition in MDA-Pca-2b K092B-treated cells have been observed. In conclusion, these two bioactive peptides from dogfish exhibit antineoplastic activity on the human prostate and breast cancer cells in vitro.

Transition metals alloys are the most studied getter films for wafer-level vacuum packaging of MEMS. In this work we investigated yttrium and YxTiy alloys films that could possibly overcome the limitations of usual getter materials, i.e. reversible sorption of hydrogen and low sorption ability for hydrocarbon gases. As a preliminary step towards this objective, properties of (co-)evaporated yttrium and YxTiy films were analyzed by SEM, EDS, XPS and in-situ sheet resistance measurements before, after and/or during annealing in vacuum. As deposited and annealed films have a small grain size and a columnar structure. It is shown that yttrium and YxTiy films can be activated after 1 hour of annealing in vacuum at 250 °C if the Y-content is larger than ∼9 %. These results are promising for the use of Y-based films as low temperature getters for vacuum packaging.

The purpose of the present paper is to investigate the mechanism of action of a pyroglutamate-modified peptide (pE-K092D) on in vitro growth inhibition of MDA-Pca-2b prostate cancer cells. This peptide was derived from a peptide previously isolated from the testis of the lesser spotted dogfish and identified as QLTPEALADEEEMNALAAR (K092D). The effect of the peptide on cell proliferation and cell death mechanisms was studied by flow cytometry. Cellular morphology and cytoskeleton integrity of peptide-treated cells were observed by immunofluorescence microscopy. Results showed the onset of peptide induced early cytoskeleton perturbation, inhibition of autophagy, inhibition of cell proliferation and, at the end, non-apoptotic cell death mechanisms (membrane destabilization and necrosis). All those mechanisms seem to contribute to MDA-Pca-2b growth inhibition by a main cytostatic fate.

International audience; Gettering properties of thin films of pure yttrium and yttrium-based alloys have been studied for application to MEMS vacuum packaging at the wafer level. Thin films of Y, Zr-Y, Ti-Y and V-Y were co-evaporated under ultra-high vacuum. It is demonstrated that the sheet resistance measured by 4-probes technique before and after activation at 250°C gives a good estimation of the oxygen sorption ability determined by NRA. Pure yttrium has been found to be highly reactive after deposition (sheet resistance increases by 40% after 1 month in air) but poorly efficient in oxygen trapping after activation. Conversely, the sorption ability of Y-V, Y-Zr and Y-Ti alloys is extremely high and increases with the yttrium content in the film. The bests results for sorption are obtained with Y-V (2.7 10 22 atom/cm 3 for Y44V56).

Context: Metastatic disease is responsible for the majority of endocrine cancer deaths. New therapeutic targets are urgently needed to improve patient survival rates. Objective: The proto-oncogene PTTG1-binding factor (PBF/PTTG1IP) is overexpressed in multiple endocrine cancers and circumstantially associated with tumor aggressiveness. This study aimed to understand the role of PBF in tumor cell invasion and identify possible routes to inhibit its action. Design, Setting, Patients, and Interventions: Thyroid, breast, and colorectal cells were transfected with PBF and cultured for in vitro analysis. PBF and cortactin (CTTN) expression was determined in differentiated thyroid cancer and The Cancer Genome Atlas RNA-seq data. Primary Outcome Measure: Pro-invasive effects of PBF were evaluated by 2D Boyden chamber, 3D organotypic, and proximity ligation assays. Results: Our study identified that PBF and CTTN physically interact and co-localize, and that this occurs at the cell periphery, particularly at the leading edge of migrating cancer cells. Critically, PBF induces potent cellular invasion and migration in thyroid and breast cancer cells, which is entirely abrogated in the absence of CTTN. Importantly, we found that CTTN is over-expressed in differentiated thyroid cancer, particularly in patients with regional lymph node metastasis, which significantly correlates with elevated PBF expression. Mutation of PBF (Y174A) or pharmacological intervention modulates the PBF: CTTN interaction and attenuates the invasive properties of cancer cells. Conclusion: Our results demonstrate a unique role for PBF in regulating CTTN function to promote endocrine cell invasion and migration, as well as identify a new targetable interaction to block tumor cell movement., This study identifies a novel interaction between proto-oncogene PBF and cortactin which opens up new therapeutic avenues for blocking tumour cell movement in endocrine cancer.

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The different studies dealing with the problem of benzodiazepines (BZD) misuse highlight the difficulty of applying guidelines in terms of BZD prescriptions in general practice. Physicians’ conditions of practice, the health system organization, as well as patients and doctors’ representations can explain it. The objective of our study is to evaluate the impact of an online tutorial proposal on the prescription of benzodiazepines by general practitioners. Two groups have been compared in this observational study: a 100-physician group from Gironde who have been introduced to the online tutorial by a delegate and a second group of 1435 physicians who have not. They were matched on the age, sex and installation medium. The evolution of the prescriptions of BZD (anxiolytics and hypnotics), in total number of boxes given by the CPAM, was observed between a period before the visit (November 2016-April 2017) and a period after (November 2017-April 2018). The CPAM provided the data. GP’s changes in opinions and practices after the online tutorial training offer were analyzed, as well as if they were satisfied by the tutorial. Our results show that prescribers in the "intervention" group prescribed fewer boxes (339) than the comparison group (406, i.e. +19.8 %) before the tutorial was made available. There was an increase in the average number of boxes prescribed by the prescribers of the "intervention" group after this one (382 b/p versus 339 b/p i.e. +12.7 %), remaining lower than in the non-introduced group, while we can notice a stability of prescriptions in the comparison group (407 b/p versus 406 b/p i.e. +0.2 %). The results show a positive but modest, non-significant impact of the SBIRT training on the perceptions of GPs. Difficulties related to the patient seem to remain the main problem encountered by general practitioners, whether in terms of patient demand or refusal to reduce existing consumption. Reminding hygienic-dietary rules proves to be the most important contribution of the tutorial as alternatives to prescriptions. SBIRT offers a simplified mechanism for routine screening, with short-term intervention. It provides information on the existence of validated alternatives for use disorders that can be implemented in primary care, and resources to obtain specialized care if needed., Les différentes études s’intéressant au problème du mésusage de benzodiazépines (BZD) mettent en évidence la difficulté pour appliquer les recommandations de bonne pratique en termes de prescriptions de BZD en médecine générale. Les conditions d’exercice des praticiens, l’organisation du système de santé, les représentations des patients et des médecins peuvent notamment l’expliquer. L’objectif de notre étude est d’évaluer l’impact d’une proposition de tutoriel en ligne sur la prescription des benzodiazépines par les médecins généralistes (MG). Il s’agit d’une étude observationnelle comparant les prescriptions d’un groupe de 100 MG girondins visités par une Déléguée Santé Prévention pour leur présenter le tutoriel en ligne à celles d’un groupe de 1435 MG girondins non visités, appariés sur l’âge, le sexe, et le milieu d’installation. L’évolution des prescriptions de BZD (anxiolytiques et hypnotiques), en nombre global de boîtes remboursées par la CPAM, a été observée entre une période avant la visite (novembre 2016-avril 2017) et une période après (novembre 2017-avril 2018). Les données de remboursement étaient fournies par la CPAM. Le travail a aussi étudié l’évolution des opinions et pratiques déclarées des médecins généralistes après la proposition de formation au tutoriel en ligne ainsi que leur satisfaction sur le tutoriel. Il ressort de nos résultats que les prescripteurs du groupe « intervention » prescrivaient moins de boîtes en moyenne (339) que le groupe de comparaison (406, soit +19,8 %) avant la mise à disposition du tutoriel. Il y a eu une augmentation du nombre de boîtes prescrites en moyenne par les prescripteurs du groupe « intervention » après celle-ci (382 b/p versus 339 b/p soit +12,7 %), restant moindre que dans le groupe non visité même si l’écart se réduit de façon nette, alors qu’on observe une stabilité des prescriptions dans le groupe de comparaison (407 b/p versus 406 b/p soit +0,2 %). Les résultats montrent un impact favorable mais modeste, non significatif, de la formation RPIB sur les perceptions des médecins généralistes. Les difficultés en lien avec le patient semblent rester le problème principal rencontré par les médecins généralistes, que ce soit en termes de demande de la part du patient ou de refus de diminuer une consommation déjà existante. L’apport le plus important du tutoriel dans les alternatives à la prescription se révèle être le rappel des règles hygiéno-diététiques. Le RPIB offre un mécanisme simplifié de dépistage systématique, par une intervention à court terme. Il permet d’informer sur l’existence d’alternatives validées pour les troubles de l’usage pouvant être mises en œuvre en soins primaires, et sur les ressources pour obtenir des soins spécialisés si besoin.

International audience; We report on progress in Time-Domain OCT (optical coherence tomography) applied to TSV (vertical interconnect accesses in silicon, enabling stacking of devices). Transitioning from the common scalar approach to an electromagnetic one, and combining it with a damped least squares approach, we enhance the accuracy of TSV height measurements.

La loi du 4 janvier 2002 relative aux musées de France a consacré la vocation de service public des musées, issus d’une tradition historique qui implique que ceux-ci sont à majorité gérés par des personnes publiques. Or, si l’État s’est toujours imposé comme l’autorité référente en matière de musée, il existe aujourd’hui plus de 1 200 musées gérés par les collectivités territoriales. Ces dernières se sont investies très tôt dans ce domaine, dans le cadre de relations parfois conflictuelles avec l’État. La loi de 2002 se pose alors comme l’aboutissement de la volonté de l’État d’imposer son contrôle sur les musées territoriaux. Cependant, ce contrôle doit être appréhendé dans le cadre du principe constitutionnel de libre administration des collectivités territoriales. Cet article est un extrait de la thèse relative aux collectivités territoriales et à leurs musées, parues aux PUAM en 2015. Il met en lumière les interrogations qui découlent de la nécessité de concilier les principes de la décentralisation avec les impératifs légaux de gestion des collections. The law of 4 January 2002 on the museums of France established the public service mission of museums, which emerged from a historical tradition that means that they are predominantly managed by public legal entities. However, although the State has always established itself as the reference authority in museum matters, more than 1,200 museums are currently managed by local authorities. They became involved in this area at a very early stage and have sometimes had conflictual relationships with the State. The law of 2002 is, therefore, the fulfilment of the State’s desire to exert its control over local museums. However, this control must be understood within the scope of the constitutional principle of the free administration of local authorities. This article is an excerpt from the thesis on local authorities and their museums, which was published by the PUAM in 2015. It highlights the issues arising from the need to balance the principles of decentralisation with the legal requirements of collections management.

Electrostatically actuated microelectromechanical systems (MEMS) devices integrating a surface micromachined silicon nanowire were batch processed to investigate motion detection with a nanowire piezoresistive gauge. In the proposed implementation, the nanogauge is indirectly coupled to the MEMS structure through an intermediate coupling spring. This design allows an arbitrary choice of MEMS motion detection range and a resolution improvement of in situ nanowire gauge factor measurements. Using this approach, it is demonstrated that an in-plane MEMS displacements up to 180 nm with a noise level down to 0.7 A/Hz1/2 can be achieved. MEMS resonance measurement in air and in vacuum by this method is also demonstrated. Results are compared with ex situ measurements of MEMS displacement by optical microscopy and by integrated capacitive detection.

Depuis le debut des annees 80, naissance des premiers systemes miniaturises associant des microsystemes electromecaniques (MEMS) en technologie silicium et de l’optique, les fonctions optiques realisees, les technologies de fabrication et d’integration employees et les applications potentielles des microsystemes electromecaniques optiques (MEMS optiques) et des microsystemes optoelectromecaniques (MOEMS) se sont tres largement etendues et diversifiees. Des contributions a ces evolutions sont illustrees ici par quelques exemples de projets en cours dans notre laboratoire.

The Energy End-use Efficiency and Energy Services Directive (ESD) of the European Union requires the member states to define and attain an overall target of at least 9% annual energy savings between 2008 and 2016. Even if this target is indicative, this is the first international framework mandating countries to report on their energy savings results and prove achievement of their targets. The directive thus also required the development of harmonised calculation methods that can be used by member states for this proof and reporting. Existing literature covers most of the usual issues related to energy savings evaluation, but mostly looking at single, given energy efficiency programmes or policies. The evaluation objective for the ESD implementation is different, as it aims at accounting for the whole energy savings achieved in a country. Moreover, one of the main difficulties is the diversity in history and experience on this topic among the member states. In this context, the European project EMEEES has worked out an integrated system of bottom-up and top-down methods for the measurement of energy savings. The paper presents the overview of its final results. The proposals, inter alia, include 20 bottom-up and 14 top-down case applications of general evaluation methods. They enable more than 90% of the potential energy savings to be measured and reported. They were used as a starting point by the European Commission to develop the methods recently recommended to the member states. Furthermore, the paper briefly discusses the importance of the quantity to be measured—all or additional energy savings—and the effect of measures implemented before the entering into force of the ESD (‘early action’), and what this meant for the methods to be developed. It compares the main elements of calculation needed to ensure consistent results between bottom-up and top-down methods at the overall national level. Finally, general conclusions are drawn about what could be the next steps in developing an evaluation system that enables a high degree of comparability of results between different countries.

Interdiffusion in gold/titanium films with titanium evaporated on silicon at different oblique angles (0°, 30°, 50°, and 70°) and gold evaporated under normal incidence is investigated using a scanning electron microscope and in-situ sheet resistance measurements for the optimization of the films' effective gettering ability during and after a low-temperature thermal activation. Films have a tilted columnar structure and a porosity increasing with the deposition angle in agreement with calculated values. The oxygen effective gettering ability, characterized by energy-dispersive X-ray spectroscopy, increases with the deposition angle. It is shown that the gold/titanium film with titanium deposited with an oblique angle of 50° is an optimized condition to obtain the largest sorption capacity after 1 h thermal activation at temperatures lower or equal to 300 °C. This film has a low initial residual stress that becomes highly tensile if thermal activation is performed above 300 °C.