MRI Registration for Human Hip Kinematics

Measurement of joint kinematics can provide knowledge to help improve joint prosthesis design, as well as identify joint motion patterns that may lead to joint degeneration or injury. More investigation into how the hip translates in live human subjects during high amplitude motions is needed. This work presents a design of a non-invasive method using the registration between images from conventional Magnetic Resonance Imaging (MRI) and open MRI to calculate three dimensional hip joint kinematics. The method was tested on a single healthy subject in three different poses. MRI protocols for the conventional gantry, high-resolution MRI and the open gantry, lowresolution MRI were developed. The scan time for the low-resolution protocol was just under 6 minutes. High-resolution meshes and low resolution contours were derived from segmentation of the high-resolution and low-resolution images, respectively. Low-resolution contours described the poses as scanned, whereas the meshes described the bones’ geometries. The meshes and contours were registered to each other, and joint kinematics were calculated. The segmentation and registration were performed for both cortical and sub-cortical bone surfaces. A repeatability study was performed by comparing the kinematic results derived from three users’ segmentations of the sub-cortical bone surfaces from a low-resolution scan. The root mean squared error of all registrations was below 1.92mm. The maximum range between segmenters in translation magnitude was 0.95mm, and the maximum deviation from the average of all orientations was 1.27◦. This work demonstrated that this method for non-invasive measurement of hip kinematics is promising for measuring high-range-of-motion hip motions in vivo.

A valorização da função do objecto de design em contexto museológico : lógicas expositivas - a museologia do design industrial

The design objects give us a testimony of those who imagined, designed, developed, manufactured and used them. Each object, intentionally or not, portrays its own story, all the visible details are part of a decision taken by someone at some time of its chronology. The act of collecting objects, as well as private collections are the basis for the creation of museums as we know them today. Musealization - taking objects into a museum - means that one is restoring, preserving, enhancing some objects compared to others. And when restoring these objects, one is restoring their symbolic capacity, i.e. the fact that they tell a story, means you are restoring its message. In a museum, although out of context and deprived of most of the functions to which they had been designed for, the objects acquire other function(s), preserving their importance. Design museums give us the possibility to have a closer view of the objects, rather than just look at them, along with the pedagogical function. Thus presents a proposal for museography regarding industrial design, which is based on the appreciation of the function of anonymous design objects, based on expository logic, that takes the visitor to see, instead of just looking at objects, offering the possibility of interaction with the same, increasing the relationship between human being - object - museum, including groups with special needs, which are often forgotten in these exhibitions. This dissertation is a reflection and a projectual intervention on the design object in a museum, clarifying the concepts of object and museum, covering issues regarding the relevance of design museums, and culminating in the presentation of a museography project, where the function of an object prevails

First steps toward harmonized human biomonitoring in Europe : demonstration project to perform human biomonitoring on a European scale

'Reproduced with permission from Environmental Health Perspectives'

Regulation of lipocalin prostaglandin-D synthase expression by interleukin-1β in human chondrocytes

L'arthrose est une maladie multifactorielle complexe. Parmi les facteurs impliqués dans sa pathogénie, les certains prostaglandines exercent un rôle inflammatoire et d’autres un rôle protecteur. La prostaglandine D2 (PGD2) est bien connue comme une PG anti-inflammatoire, qui est régulée par l’enzyme «Lipocalin prostaglandine D-synthase». Avec l’inflammation de l'arthrose, les chondrocytes essaient de protéger le cartilage en activant certaines voies de récupération dont l'induction du gène L-PGDS. Dans cette étude, nous étudions la voie de signalisation impliquée dans la régulation de l'expression du (L-PGDS) sur les chondrocytes traités avec différents médiateurs inflammatoires. Le but de projet: Nous souhaitons étudier la régulation de la L-PGDS dans le but de concevoir des approches thérapeutiques qui peuvent activer la voie intrinsèque anti-inflammatoire. Méthode et conclusions: In vivo, l'arthrose a été suivie en fonction de l’âge chez la souris ou chirurgicalement suivant une intervention au niveau des genoux de souris. Nous avons confirmé les niveaux d’expression de L-PGDS histologiquement et par immunohistochimie. In vitro, dans les chondrocytes humains qui ont été traités avec différents médiateurs de l'inflammation, nous avons observé une augmentation de l’expression de la L-PGDS dose et temps dépendante. Nous avons montré, in vivo et in vitro que l’inflammation induit une sécrétion chondrocytaire de la L-PGDS dans le milieu extracellulaire. Enfin, nous avons observé la production de différentes isoformes de la L-PGDS en réponse à l'inflammation.

Design and synthesis of constrained azacyclic pyrrolidine analogues of FTY720 as anticancer agents & metal coordination-controlled and bifunctional catalysis toward tertiary β-Ketols

Cette thèse se compose en deux parties: Première Partie: La conception et la synthèse d’analogues pyrrolidiniques, utilisés comme agents anticancéreux, dérivés du FTY720. FTY720 est actuellement commercialisé comme médicament (GilenyaTM) pour le traitement de la sclérose en plaques rémittente-récurrente. Il agit comme immunosuppresseur en raison de son effet sur les récepteurs de la sphingosine-1-phosphate. A fortes doses, FTY720 présente un effet antinéoplasique. Cependant, à de telles doses, un des effets secondaires observé est la bradycardie dû à l’activation des récepteurs S1P1 et S1P3. Ceci limite son potentiel d’utilisation lors de chimiothérapie. Nos précédentes études ont montré que des analogues pyrrolidiniques dérivés du FTY720 présentaient une activité anticancéreuse mais aucune sur les récepteurs S1P1 et S1P3. Nous avons soumis l’idée qu’une étude relation structure-activité (SARs) pourrait nous conduire à la découverte de nouveaux agents anti tumoraux. Ainsi, deux séries de composés pyrrolidiniques (O-arylmethyl substitué et C-arylmethyl substitué) ont pu être envisagés et synthétisés (Chapitre 1). Ces analogues ont montré d’excellentes activités cytotoxiques contre diverses cellules cancéreuses humaines (prostate, colon, sein, pancréas et leucémie), plus particulièrement les analogues actifs qui ne peuvent pas être phosphorylés par SphK, présentent un plus grand potentiel pour le traitement du cancer sans effet secondaire comme la bradycardie. Les études mécanistiques suggèrent que ces analogues de déclencheurs de régulation négative sur les transporteurs de nutriments induisent une crise bioénergétique en affamant les cellules cancéreuses. Afin d’approfondir nos connaissances sur les récepteurs cibles, nous avons conçu et synthétisé des sondes diazirine basées sur le marquage d’affinité aux photons (méthode PAL: Photo-Affinity Labeling) (Chapitre 2). En s’appuyant sur la méthode PAL, il est possible de récolter des informations sur les récepteurs cibles à travers l’analyse LC/MS/MS de la protéine. Ces tests sont en cours et les résultats sont prometteurs. Deuxième partie: Coordination métallique et catalyse di fonctionnelle de dérivés β-hydroxy cétones tertiaires. Les réactions de Barbier et de Grignard sont des méthodes classiques pour former des liaisons carbone-carbone, et généralement utilisées pour la préparation d’alcools secondaires et tertiaires. En vue d’améliorer la réaction de Grignard avec le 1-iodobutane dans les conditions « one-pot » de Barbier, nous avons obtenu comme produit majoritaire la β-hydroxy cétone provenant de l’auto aldolisation de la 5-hexen-2-one, plutôt que le produit attendu d’addition de l’alcool (Chapitre 3). La formation inattendue de la β-hydroxy cétone a également été observée en utilisant d’autres dérivés méthyl cétone. Étonnement dans la réaction intramoléculaire d’une tricétone, connue pour former la cétone Hajos-Parrish, le produit majoritaire est rarement la β-hydroxy cétone présentant la fonction alcool en position axiale. Intrigué par ces résultats et après l’étude systématique des conditions de réaction, nous avons développé deux nouvelles méthodes à travers la synthèse sélective et catalytique de β-hydroxy cétones spécifiques par cyclisation intramoléculaire avec des rendements élevés (Chapitre 4). La réaction peut être catalysée soit par une base adaptée et du bromure de lithium comme additif en passant par un état de transition coordonné au lithium, ou bien soit à l’aide d’un catalyseur TBD di fonctionnel, via un état de transition médiée par une coordination bidenté au TBD. Les mécanismes proposés ont été corroborés par calcul DFT. Ces réactions catalytiques ont également été appliquées à d’autres substrats comme les tricétones et les dicétones. Bien que les efforts préliminaires afin d’obtenir une enantioselectivité se sont révélés sans succès, la synthèse et la recherche de nouveaux catalyseurs chiraux sont en cours.

The nuclear safety framework in the European Union after Fukushima. Egmont Paper No. 73, December 2014

Summary. On 11 March 2011, a devastating earthquake struck Japan and caused a major nuclear accident at the Fukushima Daiichi nuclear plant. The disaster confirmed that nuclear reactors must be protected even against accidents that have been assessed as highly unlikely. It also revealed a well-known catalogue of problems: faulty design, insufficient back-up systems, human error, inadequate contingency plans, and poor communications. The catastrophe triggered the rapid launch of a major re-examination of nuclear reactor security in Europe. It also stopped in its tracks what had appeared to be a ‘nuclear renaissance’, both in Europe and globally, especially in the emerging countries. Under the accumulated pressure of rising demand and climate warming, many new nuclear projects had been proposed. Since 2011 there has been more ambivalence, especially in Europe. Some Member States have even decided to abandon the nuclear sector altogether. This Egmont Paper aims to examine the reactions of the EU regarding nuclear safety since 2011. Firstly, a general description of the nuclear sector in Europe is provided. The nuclear production of electricity currently employs around 500,000 people, including those working in the supply chain. It generates approximately €70 billion per year. It provides roughly 30% of the electricity consumed in the EU. At the end of 2013, there were 131 nuclear power reactors active in the EU, located in 14 countries. Four new reactors are under construction in France, Slovakia and Finland. Secondly, this paper will present the Euratom legal framework regarding nuclear safety. The European Atomic Energy Community (EAEC or Euratom) Treaty was signed in 1957, and somewhat obscured by the European Economic Community (EEC) Treaty. It was a more classical treaty, establishing institutions with limited powers. Its development remained relatively modest until the Chernobyl catastrophe, which provoked many initiatives. The most important was the final adoption of the Nuclear Safety Directive 2009/71. Thirdly, the general symbiosis between Euratom and the International Atomic Energy Agency (IAEA) will be explained. Fourthly, the paper analyses the initiatives taken by the EU in the wake of the Fukushima catastrophe. These initiatives are centred around the famous ‘stress tests’. Fifthly, the most important legal change brought about by this event was the revision of Directive 2009/71. Directive 2014/87 has been adopted quite rapidly, and has deepened in various ways the role of the EU in nuclear safety. It has reinforced the role and effective independence of the national regulatory authorities. It has enhanced transparency on nuclear safety matters. It has strengthened principles, and introduced new general nuclear safety objectives and requirements, addressing specific technical issues across the entire life cycle of nuclear installations, and in particular, nuclear power plants. It has extended monitoring and the exchange of experiences by establishing a European system of peer reviews. Finally, it has established a mechanism for developing EU-wide harmonized nuclear safety guidelines. In spite of these various improvements, Directive 2014/87 Euratom still reflects the ambiguity of the Euratom system in general, and especially in the field of nuclear safety. The use of nuclear energy remains controversial among Member States. Some of them remain adamantly in favour, others against or ambivalent. The intervention of the EAEC institutions remains sensitive. The use of the traditional Community method remains limited. The peer review method remains a very peculiar mechanism that deserves more attention.

Quantifying epistemic actions in human-computer interaction

As digital systems move away from traditional desktop setups, new interaction paradigms are emerging that better integrate with users’ realworld surroundings, and better support users’ individual needs. While promising, these modern interaction paradigms also present new challenges, such as a lack of paradigm-specific tools to systematically evaluate and fully understand their use. This dissertation tackles this issue by framing empirical studies of three novel digital systems in embodied cognition – an exciting new perspective in cognitive science where the body and its interactions with the physical world take a central role in human cognition. This is achieved by first, focusing the design of all these systems on a contemporary interaction paradigm that emphasizes physical interaction on tangible interaction, a contemporary interaction paradigm; and second, by comprehensively studying user performance in these systems through a set of novel performance metrics grounded on epistemic actions, a relatively well established and studied construct in the literature on embodied cognition. The first system presented in this dissertation is an augmented Four-in-a-row board game. Three different versions of the game were developed, based on three different interaction paradigms (tangible, touch and mouse), and a repeated measures study involving 36 participants measured the occurrence of three simple epistemic actions across these three interfaces. The results highlight the relevance of epistemic actions in such a task and suggest that the different interaction paradigms afford instantiation of these actions in different ways. Additionally, the tangible version of the system supports the most rapid execution of these actions, providing novel quantitative insights into the real benefits of tangible systems. The second system presented in this dissertation is a tangible tabletop scheduling application. Two studies with single and paired users provide several insights into the impact of epistemic actions on the user experience when these are performed outside of a system’s sensing boundaries. These insights are clustered by the form, size and location of ideal interface areas for such offline epistemic actions to occur, as well as how can physical tokens be designed to better support them. Finally, and based on the results obtained to this point, the last study presented in this dissertation directly addresses the lack of empirical tools to formally evaluate tangible interaction. It presents a video-coding framework grounded on a systematic literature review of 78 papers, and evaluates its value as metric through a 60 participant study performed across three different research laboratories. The results highlight the usefulness and power of epistemic actions as a performance metric for tangible systems. In sum, through the use of such novel metrics in each of the three studies presented, this dissertation provides a better understanding of the real impact and benefits of designing and developing systems that feature tangible interaction.

Establishment of a confluent monolayer model with human primary trophoblast cells: novel insights into placental glucose transport

STUDY HYPOTHESIS Using optimized conditions, primary trophoblast cells isolated from human term placenta can develop a confluent monolayer in vitro, which morphologically and functionally resembles the microvilli structure found in vivo. STUDY FINDING We report the successful establishment of a confluent human primary trophoblast monolayer using pre-coated polycarbonate inserts, where the integrity and functionality was validated by cell morphology, biophysical features, cellular marker expression and secretion, and asymmetric glucose transport. WHAT IS KNOWN ALREADY Human trophoblast cells form the initial barrier between maternal and fetal blood to regulate materno-fetal exchange processes. Although the method for isolating pure human cytotrophoblast cells was developed almost 30 years ago, a functional in vitro model with primary trophoblasts forming a confluent monolayer is still lacking. STUDY DESIGN, SAMPLES/MATERIALS, METHODS Human term cytotrophoblasts were isolated by enzymatic digestion and density gradient separation. The purity of the primary cells was evaluated by flow cytometry using the trophoblast-specific marker cytokeratin 7, and vimentin as an indicator for potentially contaminating cells. We screened different coating matrices for high cell viability to optimize the growth conditions for primary trophoblasts on polycarbonate inserts. During culture, cell confluency and polarity were monitored daily by determining transepithelial electrical resistance (TEER) and permeability properties of florescent dyes. The time course of syncytia-related gene expression and hCG secretion during syncytialization were assessed by quantitative RT-PCR and enzyme-linked immunosorbent assay, respectively. The morphology of cultured trophoblasts after 5 days was determined by light microscopy, scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Membrane makers were visualized using confocal microscopy. Additionally, glucose transport studies were performed on the polarized trophoblasts in the same system. MAIN RESULTS AND THE ROLE OF CHANCE During 5-day culture, the highly pure trophoblasts were cultured on inserts coated with reconstituted basement membrane matrix . They exhibited a confluent polarized monolayer, with a modest TEER and a size-dependent apparent permeability coefficient (Papp) to fluorescently labeled compounds (MW ∼400-70 000 Da). The syncytialization progress was characterized by gradually increasing mRNA levels of fusogen genes and elevating hCG secretion. SEM analyses confirmed a confluent trophoblast layer with numerous microvilli, and TEM revealed a monolayer with tight junctions. Immunocytochemistry on the confluent trophoblasts showed positivity for the cell-cell adhesion molecule E-cadherin, the tight junction protein 1 (ZO-1) and the membrane proteins ATP-binding cassette transporter A1 (ABCA1) and glucose transporter 1 (GLUT1). Applying this model to study the bidirectional transport of a non-metabolizable glucose derivative indicated a carrier-mediated placental glucose transport mechanism with asymmetric kinetics. LIMITATIONS, REASONS FOR CAUTION The current study is only focused on primary trophoblast cells isolated from healthy placentas delivered at term. It remains to be evaluated whether this system can be extended to pathological trophoblasts isolated from diverse gestational diseases. WIDER IMPLICATIONS OF THE FINDINGS These findings confirmed the physiological properties of the newly developed human trophoblast barrier, which can be applied to study the exchange of endobiotics and xenobiotics between the maternal and fetal compartment, as well as intracellular metabolism, paracellular contributions and regulatory mechanisms influencing the vectorial transport of molecules. LARGE-SCALE DATA Not applicable. STUDY FUNDING AND COMPETING INTERESTS This study was supported by the Swiss National Center of Competence in Research, NCCR TransCure, University of Bern, Switzerland, and the Swiss National Science Foundation (grant no. 310030_149958, C.A.). All authors declare that their participation in the study did not involve factual or potential conflicts of interests.

Design and synthesis of constrained azacyclic pyrrolidine analogues of FTY720 as anticancer agents & metal coordination-controlled and bifunctional catalysis toward tertiary β-Ketols

Cette thèse se compose en deux parties: Première Partie: La conception et la synthèse d’analogues pyrrolidiniques, utilisés comme agents anticancéreux, dérivés du FTY720. FTY720 est actuellement commercialisé comme médicament (GilenyaTM) pour le traitement de la sclérose en plaques rémittente-récurrente. Il agit comme immunosuppresseur en raison de son effet sur les récepteurs de la sphingosine-1-phosphate. A fortes doses, FTY720 présente un effet antinéoplasique. Cependant, à de telles doses, un des effets secondaires observé est la bradycardie dû à l’activation des récepteurs S1P1 et S1P3. Ceci limite son potentiel d’utilisation lors de chimiothérapie. Nos précédentes études ont montré que des analogues pyrrolidiniques dérivés du FTY720 présentaient une activité anticancéreuse mais aucune sur les récepteurs S1P1 et S1P3. Nous avons soumis l’idée qu’une étude relation structure-activité (SARs) pourrait nous conduire à la découverte de nouveaux agents anti tumoraux. Ainsi, deux séries de composés pyrrolidiniques (O-arylmethyl substitué et C-arylmethyl substitué) ont pu être envisagés et synthétisés (Chapitre 1). Ces analogues ont montré d’excellentes activités cytotoxiques contre diverses cellules cancéreuses humaines (prostate, colon, sein, pancréas et leucémie), plus particulièrement les analogues actifs qui ne peuvent pas être phosphorylés par SphK, présentent un plus grand potentiel pour le traitement du cancer sans effet secondaire comme la bradycardie. Les études mécanistiques suggèrent que ces analogues de déclencheurs de régulation négative sur les transporteurs de nutriments induisent une crise bioénergétique en affamant les cellules cancéreuses. Afin d’approfondir nos connaissances sur les récepteurs cibles, nous avons conçu et synthétisé des sondes diazirine basées sur le marquage d’affinité aux photons (méthode PAL: Photo-Affinity Labeling) (Chapitre 2). En s’appuyant sur la méthode PAL, il est possible de récolter des informations sur les récepteurs cibles à travers l’analyse LC/MS/MS de la protéine. Ces tests sont en cours et les résultats sont prometteurs. Deuxième partie: Coordination métallique et catalyse di fonctionnelle de dérivés β-hydroxy cétones tertiaires. Les réactions de Barbier et de Grignard sont des méthodes classiques pour former des liaisons carbone-carbone, et généralement utilisées pour la préparation d’alcools secondaires et tertiaires. En vue d’améliorer la réaction de Grignard avec le 1-iodobutane dans les conditions « one-pot » de Barbier, nous avons obtenu comme produit majoritaire la β-hydroxy cétone provenant de l’auto aldolisation de la 5-hexen-2-one, plutôt que le produit attendu d’addition de l’alcool (Chapitre 3). La formation inattendue de la β-hydroxy cétone a également été observée en utilisant d’autres dérivés méthyl cétone. Étonnement dans la réaction intramoléculaire d’une tricétone, connue pour former la cétone Hajos-Parrish, le produit majoritaire est rarement la β-hydroxy cétone présentant la fonction alcool en position axiale. Intrigué par ces résultats et après l’étude systématique des conditions de réaction, nous avons développé deux nouvelles méthodes à travers la synthèse sélective et catalytique de β-hydroxy cétones spécifiques par cyclisation intramoléculaire avec des rendements élevés (Chapitre 4). La réaction peut être catalysée soit par une base adaptée et du bromure de lithium comme additif en passant par un état de transition coordonné au lithium, ou bien soit à l’aide d’un catalyseur TBD di fonctionnel, via un état de transition médiée par une coordination bidenté au TBD. Les mécanismes proposés ont été corroborés par calcul DFT. Ces réactions catalytiques ont également été appliquées à d’autres substrats comme les tricétones et les dicétones. Bien que les efforts préliminaires afin d’obtenir une enantioselectivité se sont révélés sans succès, la synthèse et la recherche de nouveaux catalyseurs chiraux sont en cours.

Driver expectancy in highway design and traffic operations. Final report.

Mode of access: Internet.

Highway geometric design consistency related to driver expectancy. Volume I: executive summary. Final report.

Federal Highway Administration, Environmental Division, Washington, D.C.

Highway geometric design consistency related to driver expectancy. Volume II: research report. Final report.

Federal Highway Administration, Environmental Division, Washington, D.C.

Highway geometric design consistency related to driver expectancy. Volume III: procedures for determining geometric design consistency. Final report.

Federal Highway Administration, Environmental Division, Washington, D.C.

Decision sight distance for highway design and traffic control requirements. Final report.

Federal Highway Administration, Office of Research, Washington, D.C.

Preliminary human factors guidelines for automated highway system designers. Volume I: guidelines for AHS designers.

Federal Highway Administration, Washington, D.C.