A partir de 2002, grâce à l'introduction du concept de la Qualité par la Conception (en anglais Quality by Design : QbD) par l'agence américaine des produits alimentaires et médicamenteux, l'industrie pharmaceutique a intensifié les efforts et les investissements pour permettre une libération en temps réel des lots commerciaux. Le QbD propose que la qualité soit construite dès la conception initiale du médicament plutôt que d'être évaluée à la fin de sa fabrication. Ainsi, avec l'initiative QbD, les tests de contrôle de la qualité de médicaments, réalisés après la fabrication des comprimés, peuvent être éliminés si les paramètres qui les influencent sont contrôlés.En effet, ces tests de contrôle qualité dits traditionnels requièrent en général plusieurs heures pour leurs préparations et leurs réalisations. Tel est le cas du test de dissolution. Ce test est très consommateur de ressources matérielles et humaines. La réalisation de stratégies de contrôle pour les tests de dissolution basée sur une approche QbD pourrait être bénéfique pour l'industrie pharmaceutique.À travers ce travail, nous avons pu :• proposer différentes stratégies novatrices de contrôle du test de dissolution de comprimés pharmaceutiques sur la base des principes du QbD,• apporter un nouvel éclairage sur la compréhension des phénomènes impliqués dans la dissolution de comprimés pharmaceutiques.Les résultats de ce projet de recherche ont permis 1) la mise en évidence des paramètres critiques influençant le test de dissolution, 2) l'élaboration et l'évaluation de modèles statistiques pour les combinaisons de variation de paramètres selon un plan d'expérience préalablement conçu, 3) la corrélation du test de dissolution à des paramètres critiques de procédés de fabrication et d'attributs de matériaux grâce aux technologies d'analyse de procédés. / With the introduction in 2002 of the concept of Quality by Design (QbD) by the Food and Drug Administration, the pharmaceutical industry intensified efforts and investments to reach real time release of commercial batches, reducing time between manufacturing and availability to the patient. QbD proposes that quality should be built in the initial design of a product rather than being assessed at the end of the tablet manufacturing. Thus, with the QbD initiative, quality control tests of tablets like dissolution testing performed after tablets manufacturing could be removed if the parameters impacting them are controlled.Indeed, quality control tests such as traditional dissolution tests generally require several hours for their preparation and their realizations. Dissolution tests are very consuming of time, material, equipment and human resources. The elimination of these tests through a QbD approach could be beneficial for the pharmaceutical industry.Thanks to this work, it was possible to :• propose different innovative strategies to control the dissolution test of pharmaceutical tablets based on the principles of Quality by Design,• have a better understanding of this quality control test.The main results relies on 1) the identification of critical parameters influencing the dissolution test, 2) the development and evaluation of statistical models for the combination of variation of parameters according to an experimental design, 3) the correlation of dissolution test to critical manufacturing process parameters and attributes of materials through process analysis technology.

Toutes les cellules libèrent plusieurs types de vésicules extracellulaires (VEs) qui transportent protéines, lipides et acides nucléiques. Ces vésicules de petite taille se retrouvent dans tous les fluides biologiques tel que le sang et la lymphe et interagissent avec les cellules environnantes. Le système lymphatique constitue une voie de prédilection pour la mobilisation des accepteurs de cholestérol à partir de la paroi artérielle. Nous avons démontré dans un modèle murin qu’une dysfonction lymphatique précède la formation de la plaque d’athérome et que cette dysfonction touche a priori la capacité de contraction des vaisseaux collecteurs. À la base de toutes ces observations, nous avons émis l’hypothèse que les VEs contribuent à la dysfonction lymphatique liée à l’athérosclérose. Pour répondre à ceci, nous avons mis en place un projet translationnel composé de deux groupes de sujets sains, sans maladie cardiovasculaire, qui se distinguent par la présence d’antécédents familiaux d’accidents cardiovasculaires prématurés chez un parent du premier degré. Nous avons quantifié plusieurs sous-types d’intérêt de VEs en circulation à partir du plasma exempt de plaquettes, par cytométrie en flux ultraspécialisés dans la détection de petites particules (> 100 nm) combiné à d’autres techniques complémentaires standardisées. Ensuite, nous avons évalué la fonction lymphatique grâce à l’imagerie par proche infrarouge après injection du vert indocyanine (ICG). Nos résultats préliminaires sont prometteurs quant aux rôles des VEs et de la dysfonction lymphatique dans le développement de l’athérosclérose et corroborent avec nos observations faites chez la souris. Les sujets avec antécédents familiaux de maladie cardiovasculaire (MCV) présentent des signes de dysfonction lymphatique avant même l’apparition de plaques d’athérome subcliniques. La réponse mécano-sensible de leurs vaisseaux collecteurs paraît défectueuse et est observable de concert avec un profil de VEs qui présument une atteinte lymphatique. Ces résultats restent à être confirmer avec le recrutement de sujets additionnels et l'évaluation de la corrélation avec le score de risque polygénique de développer une MCV, dans l’objectif ultime de faire des VEs et de la fonction lymphatique de nouveaux biomarqueurs dans l’identification précoce des MCV. / All cell types release extracellular vesicles (EVs) that carry different types of cellular cargo, such as proteins, lipids and nucleic acids. These small vesicles are found in all biological fluids including blood and lymph and can interact with neighboring cells. The lymphatic system is a preferred route for the mobilization of cholesterol from the arterial wall. We have demonstrated in a mouse model that lymphatic dysfunction precedes the development of atherosclerosis and that that this dysfunction affects the contraction capacity of the collecting vessels. Based on these observations, we hypothesized that EVs contribute to atherosclerosis-associated lymphatic dysfunction. Therefore, we have initiated a translational study involving two groups of healthy subjects that differ in their risk of cardiovascular disease (CVD). We quantified several subtypes of circulating EVs on platelet-free plasma by ultraspecialized flow cytometry in the detection of small particles (> 100 nm) combined to other state-of-the art complementary techniques. Next, we assessed the lymphatic function using near-infrared imaging and injection of indocyanine green (ICG). Our preliminary results are promising for the role of EVs and lymphatic dysfunction in the development of atherosclerosis and corroborate with our observations made in mice. Individuals at high risk of CVD have signs of lymphatic dysfunction even before the onset of subclinical atherosclerosis. The mechano-sensitive response of their collecting vessels appears to be defective and is observable in concert with a profile of EVs that presume lymphatic damage. These results remain to be confirmed with the recruitment of additional subjects and the assessment of the correlation with the polygenic risk score of developing a CVD, in the hope of making these specific EV subsets and lymphatic function new biomarkers in the early detection of CVD.

No description available.

Suite à la découverte d’environ 2000 naines brunes au cours des deux dernières décennies, on commence à bien comprendre la physique de ces objets de masse intermédiaire entre les étoiles et les planètes. Malgré tout, les modèles d’atmosphère et d’évolution de ces objets peu massifs peinent toujours à reproduire fidèlement leurs caractéristiques pour les âges les plus jeunes. Ce travail propose la caractérisation de quatre compagnons de masse sous-stellaire (8-30 MJup) en orbite à grande séparation (300-900 UA) autour d'étoiles jeunes (5 Ma) de la région de formation Upper Scorpius. De nouveaux spectres (0,9-2,5 um) et de nouvelles mesures photométriques (YJHKsL') sont présentés et analysés, dans le but de déterminer la masse, température effective, luminosité et gravité de surface de ces compagnons, tout en évaluant la fidélité avec laquelle les spectres synthétiques tirés de deux modèles d’atmosphère récents reproduisent les spectres observés. / Following the discovery of about 2000 brown dwarfs over the past two decades, we begin to understand the physics of these objects of mass intermediate between stellar and planetary masses. Nevertheless, the atmosphere and evolution models for these low-mass objects are still struggling to reproduce their characteristics at young ages. This work presents the characterization of four sub-stellar mass (8-30 MJup) companions orbiting at large separation (300-900 AU) around young stars (5 Myr) in the Upper Scorpius formation region. New spectra (0,9-2,5 um) and new photometric measurements (YJHKsL') are presented and analyzed in order to determine the mass, effective temperature, luminosity and surface gravity of these companions, while assessing the fidelity with which the synthetic spectra from two recent atmosphere models reproduce the observed spectra.

Suite à la découverte d’environ 2000 naines brunes au cours des deux dernières décennies, on commence à bien comprendre la physique de ces objets de masse intermédiaire entre les étoiles et les planètes. Malgré tout, les modèles d’atmosphère et d’évolution de ces objets peu massifs peinent toujours à reproduire fidèlement leurs caractéristiques pour les âges les plus jeunes. Ce travail propose la caractérisation de quatre compagnons de masse sous-stellaire (8-30 MJup) en orbite à grande séparation (300-900 UA) autour d'étoiles jeunes (5 Ma) de la région de formation Upper Scorpius. De nouveaux spectres (0,9-2,5 um) et de nouvelles mesures photométriques (YJHKsL') sont présentés et analysés, dans le but de déterminer la masse, température effective, luminosité et gravité de surface de ces compagnons, tout en évaluant la fidélité avec laquelle les spectres synthétiques tirés de deux modèles d’atmosphère récents reproduisent les spectres observés. / Following the discovery of about 2000 brown dwarfs over the past two decades, we begin to understand the physics of these objects of mass intermediate between stellar and planetary masses. Nevertheless, the atmosphere and evolution models for these low-mass objects are still struggling to reproduce their characteristics at young ages. This work presents the characterization of four sub-stellar mass (8-30 MJup) companions orbiting at large separation (300-900 AU) around young stars (5 Myr) in the Upper Scorpius formation region. New spectra (0,9-2,5 um) and new photometric measurements (YJHKsL') are presented and analyzed in order to determine the mass, effective temperature, luminosity and surface gravity of these companions, while assessing the fidelity with which the synthetic spectra from two recent atmosphere models reproduce the observed spectra.

Il y a de plus en plus d'indications que les trous noirs super-massifs ont joué un rôle important dans l'évolution des galaxies, en particulier au moment de la formation des galaxies les plus massives à haut décalage spectral vers le rouge (z ~ 2 - 3). Nous nous sommes attachés à quantifier les effets sur le milieu interstellaire des galaxies hôtes que peuvent avoir les jets des radio-galaxies, d'une part, et les importantes luminosités bolometriques des quasars, d'autre part. Pour cela, nous avons étudié la cinématique du gaz ionisé dans 12 radio-galaxies modérément puissantes et dans 11 quasars (6 avec une détection en radio et 5 sans jet détectable) à grand décalage spectral vers le rouge avec le spectro-imageur proche infra-rouge SINFONI du VLT, qui nous donnait accès aux raies d'émission normalement sitées dans le domaine visible. Afin d'évaluer la capacité du NAG à stopper la formation d'étoiles, nous avons cherché des traces de leur rétroaction dans ces galaxies, comme de vents de gaz s'échappant de la galaxie hôte. Dans notre échantillon de radio-galaxies modérément puissantes, nous observons des dispersions de vitesse presque aussi importantes que dans les plus puissantes (avec une FWHM ~ 1000 km/s), mais les quantités de gaz ionisé observées y sont inférieures d'un ordre de grandeur (Mion gas ~ 10^8 - 10^9 Msun) et les gradients de vitesse sont plus faibles (Δv < 400 km/s), quand ils sont observés. Dans notre échantillon de quasars, nous devions d'abord soustraire la composante large des raies d'émission avant de pouvoir étudier leur composante étroite, celle susceptible d'être étendue spatialement. Nous détectons des régions d'émission véritablement étendue autour de quatre des six sources avec une détection en radio et autour d'une seule des cinq sans détection radio. Nous estimons qu'il y a moins de gaz ionisé dans ces sources que dans notre échantillon de radio-galaxies (avec Mion gas ~ 10^7 - 10^8 Msun) et la cinématique de ce gaz est aussi plus calme, similaire à ce qui est observé autour de certains quasars proches. Enfin, de nouvelles observations de deux radio-galaxies particulières nous ont révélé que l'une d'entre elles est entourée de quatorze galaxies-companions et qu'elle se trouve donc dans une partie sur-dense de l'Univers. Nous expliquons donc la morphologie inhabituelle du gaz ionisé présent autour de ces deux radio-galaxies par des cycles répétés d'activité du NAG, en analogie à ce qui est observé dans les amas de galaxies proches, qui sont d'excellents exemples de rétroaction du NAG dans l'Univers local. / There is growing evidence that supermassive black holes may play a crucial role for galaxy evolution, in particular during the formation of massive galaxies at high redshift (z ~ 2 - 3). Our work focuses on quantifying the effects of jets of radiogalaxies and of large bolometric luminosities of quasars on the interstellar gas in their host galaxies. To this end, we studied the kinematics of the ionized gas in 12 moderately powerful radio galaxies and 11 quasars (6 radio-loud and 5 radio-quiet) at high redshifts with rest-frame optical imaging spectroscopy obtained at the VLT with SINFONI. We searched for outflows and other signatures of feedback from the supermassive black holes in the centers of these galaxies to evaluate if the AGN may plausibly quench star formation. In our sample of moderately powerful radiogalaxies, we observe velocity dispersions nearly as large as those observed in the most powerful ones (with FWHM ~ 1000 km/s), but the quantity of ionized gas is decreased by one order of magnitude (Mion gas ~ 10^8 - 10^9 Msun) and velocity gradients tend to be less dramatic (Δv < 400 km/s), when they are observed. In our sample of quasars, we had to carefully subtract the broad spectral component of emission lines to have access to its narrow, and spatially extended, component. We detect truly extended emission line regions in 4/6 sources of our radio-loud subsample and in 1/5 source of our radio-quiet subsample. We estimate that masses of ionized gas in these sources are smaller than in our sample of high-redshift radiogalaxies (with Mion gas ~ 10^7 - 10^8 Msun) and kinematics tend to be more quiescent, akin to what is observed in local quasars. Finally, detailed observations of two outliers among our sample of high-redshift radiogalaxies revealed that one of them is closely surrounded by 14 companions galaxies, hence lying in an overdensity. We therefore interpret the presence and morphology of ionized gas around these galaxies as evidence for repeated cycles ouf AGN outbursts, akin to what can be observed in local clusters of galaxies, which are prime examples of AGN feedback in the nearby Universe.

<p> </p> <p>Learning about ‘behavior’ has always been at the heart of my research endeavors. While my undergraduate work in evolution and ecology exposed me to the science behind why a behavior exists, in my graduate work, I intended to explore how to use something’s behavior to widen its applicability. In this thesis, <em>I will present three works that utilize some of the fundamental</em></p> <p><em>behaviors (i.e., properties) of elastin-like polypeptides (ELP) to improve existing protein purification methods or explore their applicability in bladder cancer imaging and immunotherapy. </em></p> <p>Bladder cancer has high recurrence rates (60-70 % annually) that necessitate multiple follow-up therapies making it one of the costliest cancers per patient. In this work, we have attempted to address two leading causes of the recurrence. First is a low sensitivity (62-84 %) and variable specificity (43-95 %) of white light cystoscopy used to diagnose and remove tumors. We aimed to address the heart of this problem, i.e., the non-specific mode of detection using white light. Only the trained eyes can discern abnormal from normal-appearing tissues even then, leaving up to 45% of tumors unresected to colonize and spread. <em>We developed and characterized near infrared dye-peptide-ligand conjugates (NIR-ELP-ligand) that undergo receptor-mediated binding and internalization to human bladder cancer cells in vitro and tissues ex vivo.</em> By using a molecular target-based probe in combination with NIR imaging, we can aid in improving the detection limit via selective binding to the tumor and reduction in background autofluorescence.</p> <p>Bacillus-Calmette Guérin (BCG) instillation in the bladder is the gold-standard</p> <p>immunotherapy used after surgical removal of bladder tumors. This was approved as a response to the inefficiency of surgery alone in improving cancer status. It has succeeded by reducing the recurrence rate to 30-50 %. But it comes with the complications of putting a live mycobacterium</p> <p>in the human body and giving a patient a urinary tract infection right after surgical tumor resection. <em>Thus, we aimed to deliver nucleic acid as immunotherapeutic cargo in a selective manner to elicit robust anti-tumor immune responses while minimizing the side effects due to its carrier.</em> Towards</p> <p>this goal, we have developed a highly modular and adaptable ELP-ligand fusion protein-based nucleic acid delivery carrier targeted toward bladder cancer. Before developing targeted peptide-based cancer imaging and nucleic acid delivery modalities, we addressed the Achilles heel of peptide-based approaches. The peptide and protein industry suffers</p> <p>through complex, time-consuming, inconsistent, and low-yielding purification methods. <em>We have developed a scalable, facile, and reproducible protein purification method that delivers ELP and ELP fusion proteins free of host cell proteins and nucleic acids and has low lipopolysaccharide</em></p> <p><em>content in just 3 h starting from a bacterial pellet. </em>Thus, for a coherent narrative, the thesis is structured as follows:</p> <p>1. Introduction</p> <p>2. ELP as a protein purification tag: Development of a rapid purification method for ELPs and ELP fusion proteins.</p> <p>3. ELP as a cancer imaging agent: Development of NIR-ELP-Ligand imaging probe targeting bladder cancer.</p> <p>4. ELP as a drug delivery agent: Utilizing ELP-ligand fusion protein in the formulation of targeted nucleic acid delivery carrier to bladder cancer.</p>

Measures of workload have been developed on the basis of the various definitions, some are designed to capture the multi-dimensional aspects of a unitary resource pool (Kahneman, 1973) while others are developed on the basis of multiple resource theory (Wickens, 2002). Although many theory based workload measures exist, others have often been constructed to serve the purpose of specific experimental tasks. As a result, it is likely that not every workload measure is reliable and valid for all tasks, much less each domain. To date, no single measure, systematically tested across experimental tasks, domains, and other measures is considered a universal measure of workload. Most researchers would argue that multiple measures from various categories should be applied to a given task to comprehensively assess workload. The goal for Study 1 to establish task load manipulations for two theoretically different tasks that induce distinct levels of workload assessed by both subjective and performance measures was successful. The results of the subjective responses support standardization and validation of the tasks and demands of that task for investigating workload. After investigating the use of subjective and objective measures of workload to identify a universal and comprehensive measure or set of measures, based on Study 2, it can only be concluded that not one or a set of measures exists. Arguably, it is not to say that one will never be conceived and developed, but at this time, one does not reside in the psychometric catalog. Instead, it appears that a more suitable approach is to customize a set of workload measures based on the task. The novel approach of assessing the sensitivity and comprehensive ability of conjointly utilizing subjective, performance, and physiological workload measures for theoretically different tasks within the same domain contributes to the theory by laying the foundation for improving methodology for researching workload. The applicable contribution of this project is a stepping-stone towards developing complex profiles of workload for use in closed-loop systems, such as human-robot team iv interaction. Identifying the best combination of workload measures enables human factors practitioners, trainers, and task designers to improve methodology and evaluation of system designs, training requirements, and personnel selection

No description available.

Roll-to-roll manufacturing of micro components based on advanced printing, structuring and lamination of ceramic tapes is rapidly progressing. This large-scale and cost-effective manufacturing process of ceramic micro devices is however prone to hide defects within the visually opaque tape stacks. To achieve a sustainable manufacturing with zero defects in the future, there is an urgent need for reliable inspection systems. The systems to be developed have to perform high-resolution in-process quality control at high speed. Optical coherence tomography (OCT) is a promising technology for detailed in-depth inspection and metrology. Combined with infrared screening of larger areas it can solve the inspection demands in the roll-to-roll ceramic tape processes. In this thesis state-of-art commercial and laboratory OCT systems, operating at the central wavelength of 1.3 µm and 1.7 µm respectively, are evaluated for detecting microchannels, metal prints, defects and delaminations embedded in alumina and zirconia ceramic layers at hundreds of micrometers beneath surfaces. The effect of surface roughness induced scattering and scattering by pores on the probing radiation, is analyzed by experimentally captured and theoretically simulated OCT images of the ceramic samples, while varying surface roughnesses and operating wavelengths. By extending the Monte Carlo simulations of the OCT response to the mid-infrared the optimal operating wavelength is found to be 4 µm for alumina and 2 µm for zirconia. At these wavelengths we predict a sufficient probing depth of about 1 mm and we demonstrate and discuss the effect of rough surfaces on the detectability of embedded boundaries. For high-precision measurement a new and automated 3D image processing algorithm for analysis of volumetric OCT data is developed. We show its capability by measuring the geometric dimensions of embedded structures in ceramic layers, extracting features with irregular shapes and detecting geometric deformations. The method demonstrates its suitability for industrial applications by rapid inspection of manufactured samples with high accuracy and robustness. The new inspection methods we demonstrate are finally analyzed in the context of measurement uncertainty, both in the axial and lateral cases, and reveal that scattering in the sample indeed affects the lateral measurement uncertainty. Two types of image artefacts are found to be present in OCT images due to multiple reflections between neighboring boundaries and inhomogeneity of refractive index. A wavefront aberration is found in the OCT system with a scanning scheme of two galvo mirrors, and it can be corrected using our image processing algorithm. / <p>QC 20140428</p> / Multilayer (FP7-NMP4-2007-214122)