Digitized by Kansas Correctional Industries

Cancer is the second most common cause of death in the United States behind heart disease. While current treatments such as surgery, chemotherapy, and radiation therapy are effective and widely used, medicine is moving towards more targeted and personalized therapies. Immunotherapy is one such treatment that utilizes the patient’s own immune system to target and eliminate tumor cells. It allows for the patient’s adaptive immune system to bypass the self-tolerance mechanisms used by the cancerous cells and be activated against the cancer. Two such self-tolerant mechanisms that are co-opted by tumor cells are the interactions between CTLA-4 and T lymphocytes and the interactions between PD-1 and PD-L1. Blocking these interactions allows for the recruitment of CTLs to the site of the tumor and subsequent attack. CTLA-4 and PD-1 are inhibitory costimulators that play a role in the suppression of the adaptive immune system. The interaction of these receptors with their respective ligands leads to self-tolerance, and is a common mechanism used as a protective measure against autoimmune reactions. Monoclonal antibodies against these two receptors and ligand have been tested in clinical trials and have shown efficacy against ovarian cancers, non-small cell lung carcinomas, colon cancers, and melanomas. By targeting the inhibitory signals, these monoclonal antibodies expose cancer cells as being “non-self” thus prompting the immune system to attack. Now, studies are focusing on combination therapies, which combine chemotherapeutics or other monoclonal antibodies with PD-1 and CTLA-4 inhibitors to enhance the effectiveness of the drug. However, drawbacks and side effects to the therapy range from fatigue and nausea to development of autoimmune diseases. It brings forward that future studies will need a panel of predictive biomarkers to identify the best candidates for the immunotherapy. While there are many obstacles, such as a lower than expected efficacy of the immunotherapy, the progress made has important implications in the development of personalized medicine.

Toll-like receptor 4 (TLR4) is an important vertebrate innate immune receptor. TLR4 recognizes both endogenous and exogenous danger signals to trigger an NF-kB dependent inflammatory response. While exogenous danger signal recognition is an essential part of pathogen response by the innate immune system, endogenous danger signal recognition by TLR4 can lead to chronic and pathological inflammation. Understanding the differences in recognition of these two types of danger signals would allow for independent modulation of pathogen and host triggered inflammatory response through TLR4. Here, we examine the evolution of activation of TLR4 by two agonists, pathogen-derived lipopolysaccharide and host-produced S100A9. We show that these two types of signals evolved earlier than previously thought. We identified TLR4 cofactors MD-2 and CD14 in amphibians and fish, and validated that zebrafish TLR4 can recognize LPS. By contrast, we find that S100 activation evolved in the ancestor of amniotes. We identified an ortholog of S100A9 in birds and reptiles capable of activating TLR4. Using comparative immunology, we found that the requirements for LPS and S100A9 activation are different. In addition to our evolutionary studies, we used molecular approaches to probe if zinc binding to S100A9 is necessary for TLR4 activation. We found that activation of TLR4 by S100A9 occurs even in the absence of zinc. Finally, we describe how our evolutionary approach led to mechanistic hypotheses regarding TLR4 activation by both LPS and S100A9. This has led to ongoing projects in the Harms lab. This dissertation includes previously published and unpublished co-authored material. / 2021-04-30

Choruses, sung by the Kansas State University Chamber Choir; Jess Wade, piano; the author, conductor; with historical and critical analysis of the works. / Digitized by Kansas Correctional Industries

Selon Benjamin Constant, l’indépendance individuelle est le premier des besoins modernes. Mais, il semble que la sécurité dans les jouissances privées soit primordiale. Pour réaliser la liberté politique de chacun des individus, il a été mis en place, à partir de processus constitutionnels et du principe de la séparation des pouvoirs, des régimes représentatifs. A contrario de Constant, Alexis de Tocqueville fait procéder la démocratie de l’articulation entre la liberté et l’égalité. Ainsi, chez les deux, s’observe un passage de l’individu sujet à l’individu citoyen. Aujourd’hui, Pierre Rosanvallon affirme que la citoyenneté est plus qu’une « dette », elle est aussi un plaisir spirituel. Cependant, à partir des deux auteurs précités, Constant et Tocqueville, et de l’évaluation qu’ils font d’une tradition qui prend son origine dans les idées de Montesquieu et de Rousseau, on s’interrogera sur les concepts de liberté individuelle et de liberté politique, ainsi que ceux d’individualisme et d’égoïsme, jusqu’aux discours contemporains sur la démocratie en Chine (depuis le mouvement du 4 mai 1919). / According to Benjamin Constant, individual independence is the first modern need. Nevertheless in private uses, the security appears to be essential. To achieve political liberty of each individual, representative regimes were established based on constitutional processes and the principle of separation of powers. Unlike Constant, Tocqueville defines democracy by the relationship between liberty and equality. Therefore, for both of them there’s a passage from the individual subject to the individual citizen. Nowadays, Pierre Rosanvallon argues that citizenship is more than a “debt”, but also becomes a spiritual pleasure. However, based on the two pre-cited authors, Constant and Tocqueville, and their assessment of a tradition that originates in the ideas of Montesquieu and Rousseau, we question the concepts of individual liberty and political liberty, as well as those of individualism and democracy, up to the contemporary discourses on democracy in China (since the movement of May 4th, 1919).

La dernière décennie a vu s'établir la démocratisation des interfaces tactiles. De nombreux logiciels jusque là réservés aux ordinateurs de bureau offrent désormais une version qui se contrôle du bout des doigts. Cependant, l'expressivité limitée de la modalité tactile restreint drastiquement le nombre de fonctionnalités disponibles. La recherche explore donc différentes pistes pour augmenter cette expressivité notamment par l'identification des doigts. Alors que la littérature se focalise principalement sur les méthodes d'identification des doigts, cette thèse vise à mieux en comprendre l'utilisation afin de guider la conception de techniques d'interaction.Nous réalisons d'abord une revue des technologies existantes, présentons nos prototypes et évaluons l'utilisation de la reconnaissance des empreintes digitales, qui nous semble la solution la plus prometteuse en vue d'une intégration dans des systèmes commerciaux. Par la réalisation d'expériences contrôlées, nous étudions ensuite les différences de performances et de préférences entre les doigts, l'influence de l'identification des doigts sur la stratégie de réalisation de tâches. Nous explorons également comment intégrer cette information au sein des techniques d'interaction existantes et aider les utilisateurs à appréhender le riche vocabulaire offert. / During the last decade, touch interfaces have become more and more ubiquitous. A lot of software applications initially designed for desktop computers have now a tactile counterpart. However, the limited expressiveness of the touch modality restricts drastically the amount of features available on touch applications. Researchers have been exploring different tracks on how to augment this expressiveness, notably through finger identification. While the literature mainly focuses on tackling the technological challenge, this dissertation aims at better understanding its use in order to provide guidelines for designing interaction techniques.We first summarize existing technologies, present our prototypes and evaluate the use of fingerprint recognition, that we perceive as the most promising solution with the aim of being integrated in consumer devices. Through controlled experiments, we study the differences of performance and preference between fingers, the influence of finger identification on user strategies to complete tasks. We also explore how to integrate this new information along existing interaction techniques and help users grasp the rich vocabulary provided. Our works lead to guidelines for designing interaction techniques leveraging finger identification that we implement in three different interaction contexts (tabletops, tablets and smartphones) through Adoiraccourcix, an interaction technique combining command selection and parameter manipulation.

No description available.

Tese de mestrado integrado. Engenharia Civil (especialização em Via de Comunicação). Faculdade de Engenharia. Universidade do Porto. 2008

Cupins are a large superfamily of enzymatic and non-enzymatic members that contain a conserved β-barrel domain, or double-stranded β-helix (DSBH) fold. The cupin superfamily is one of the most functionally diverse groups of proteins known to exist. The vast majority of cupins contain a mononuclear metal binding site at the core of the DSBH fold capable of binding different metal ions. One of the largest cupin subfamilies is known as the Fe(II)/α-ketoglutarate (αKG)-dependent dioxygenases. Prolyl 4-hydroxylases (P4Hs) belong to the group of Fe(II)/αKG-dependent dioxygenases and catalyze the formation of 4R-hydroxyproline (Hyp) from various proline-containing substrates. The formation of Hyp is an important post-translational modification to many different proteins involved in essential biochemical pathways. Abnormalities in these pathways can lead to diseases such as cancer, fibrosis, respiratory issues, scurvy, and stroke. An Fe(II)/αKG-dependent prolyl hydroxylase from Bacillus anthracis (BaP4H) was investigated to understand its substrate recognition ability and catalytic properties. Novel crystal structures were solved that revealed conformational changes upon substrate binding and key interactions of various ligands in the active site for different catalytic steps. Although the majority of cupin family enzymes catalyze a reaction using iron as an essential cofactor, other metal cofactors can allow the diverse biological transformations carried out by this group of enzymes. A class of enzymes known as dimethylsulfoniopropionate (DMSP) lyases uses different metal ions to catalyze the formation of acrylate and dimethylsulfide (DMS) from DMSP. DMSP is one of the most prevalent and significant molecules to the life and biogeochemistry of the oceans. The products DMS and acrylate are environmentally significant and industrially valuable. DMSP is predominantly catabolized by marine bacteria and can serve different functions. One of the most abundant bacteria in the ocean, Pelagibacter, was determined to contain a DMSP lyase DddK. The DddK catalyzed DMSP lyase activity in the presence of different metal ions has shown that it catalytically prefers Ni(II) compared to other transition metal ions examined. Spectroscopic, site-directed mutagenesis, and crystallographic studies illustrate central residues responsible for metal ion binding and possible roles in transition state stabilization. A greater mechanistic understanding of DMSP lyases will lead to more impactful information about global environmental climate regulation.

Alors que le développement industriel des technologies CMOS-SOI aborde le cap des longueurs de grille inférieures à 30nm, l’optimisation du module source/drain est identifié comme l’un des verrous technologiques fondamentaux afin d’atteindre le niveau de performance spécifié dans la feuille de route ITRS. Afin d’adresser cette difficulté, une solution consiste à remplacer le module de jonction source/drain conventionnel par un contact métallique de type Schottky dont la hauteur de barrière doit être modulée à la baisse afin de réduire la résistance spécifique de contact. La mise en œuvre des techniques de ségrégation de dopants à basse température a été identifiée comme une technique efficace de réduction de barrière Schottky. D’autre part, l’application de contraintes mécaniques est également connue pour induire une réduction de barrière Schottky par levée de dégénérescence aux minima de bandes. L’objet principal de cette thèse est donc d’étudier la possibilité de cumuler ces deux effets, en particulier dans le cas d’un substrat SOI en tension biaxiale. Les caractérisations morphologiques et électriques réalisées au cours de cette thèse montrent que l’utilisation du siliciure de platine est judicieuse de part sa faible hauteur de barrière Schottky aux trous (250meV). Nous avons également démontré que l’utilisation simultanée des deux méthodes d’abaissement de barrière précédemment citées permet de réduire ce paramètre de 145 meV. Ce travail de thèse a démontré que l’intégration du siliciure de platine combiné à l’utilisation de la ségrégation de dopant et de substrat contraint permettait d’obtenir des jonctions Schottky de type p et n à faible hauteur de barrière. / While the CMOS-SOI technologies development is reaching the sub 30-nm gate length era, the Source/Drain module optimization is identified as a one of the biggest challenge to be solved in order to satisfy the ITRS specification. For the sake of addressing this difficulty, one solution consists in replacing the conventional Source/Drain junction module by Schottky contacts. However, the Schottky Barrier Height has to be lowered in order to reduce the contact resistance to the minimum. The dopant segregation implementation has been identified as an efficient method to reduce the Schottky Barrier Height. The mechanical stress is also known to induce a Schottky Barrier height lowering due to degeneracy breaks at silicon sub bands minima. The main objective of this thesis is to assess the possibility of cumulating these two effects, in particular in the case of a biaxialy strained substrate. Morphological and electrical characteristics showed that the use of platinum silicide is relevant for the low Schottky Barrier Height to hole (250meV). In addition, we demonstrated that the combined implementation of the two aforementioned Schottky Barrier height lowering methods leads to a reduction equal to 145meV. This thesis work illustrates that platinum silicide integration combined with the use of dopant segregation and advanced strained substrates provide Schottky junctions with a low barrier height for both p- and n-type.