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Ferroelectric liquid crystals (FLCs) have been investigated as the basis for a new type of liquid crystal display because of their fast switching times. In applications the layer contraction at the smectic A-smectic C transition is a severe problem that leads to buckling of the smectic layers and results in zigzag defects that drastically degrade the optical quality of FLC films. To solve this problem, researchers are focusing on a new class of liquid crystals with minimal smectic layer contraction at the SmA-SmC transition which is referred to as ‘de Vries-like’. In the first part of this thesis, we have developed a rational design strategy based on a concept of frustration between two structural elements, one promoting a SmA phase and another promoting a SmC phase. In this chapter, we show that one can further improve ‘de Vries-like’ properties by substituting the 2-phenylpyrimidine core in our first-generation siloxane-terminated mesogens with one stronger SmC-promoting core. We also address the hydrolytic instability of siloxane-terminated mesogens, by substituting the siloxane with a carbosilane end-group. As a result of this study, we found QL6-6 that forms a SmC phase at room temperature with ‘de Vries-like’ properties that are comparable to those of bona fide ‘de Vries-like’ liquid crystals. Next, the dialkoxy 2-phenyl-1,3,4-thiadiazole core which is a very powerful SmC promoting element was investigated. We prepared the analogue of QL6-6, compound QL13-6, which only forms a SmC phase despite having a chloro-terminated alkyl chain. Making a ‘de Vries-like’ liquid crystal without carbosilane terminal side-chain was also attempted, although ultimately unsuccessful. The terminal group effect on the ‘de Vries-like’ properties was also investigated. We prepared a series of mesogens derived from 2-phenylpyridine core with different end-groups to investigate whether the X-group might interact with the core in a bilayer structure. Finally, we inves¬tigated the effect of mixing ’de Vries-like’ liquid crystals with conventional smectic liquid crystals. We show that binary mix¬tures of ‘de Vries-like’ and conventional SmC meso¬gens with a molecular length ratio of 1.34 undergo a SmA-SmC phase transition with a maximum layer contraction ranging from 1.0 to 1.9% depending on the mixture composition. / Thesis (Ph.D, Chemistry) -- Queen's University, 2013-10-29 13:16:29.768

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Memoria para optar al Título Profesional de Químico Farmacéutico / Los fibroblastos cardíacos (FC), han sido denominados células centinelas del corazón, pues responden de manera variada y compleja ante cualquier elemento externo o interno a fin de mantener la homeostasis. Esta respuesta se lleva a cabo mediante una maquinaria conformada por una amplia red de receptores, entre ellos los receptores tipotoll y, en particular, el TLR4. La activación de este receptor ha mostrado mediar respuestas inflamatorias y fibróticas tanto en FC, como en otras células; en donde la expresión de proteínas de adhesión y reclutamiento de células del sistema inmune componen un eje vital en estos procesos. Por tanto se buscó determinar si la activación de TLR4 en el FC de ratas adultas genera una mayor adhesión de monocitos a través de un aumento en los niveles de E-selectina. La activación de TLR4 por LPS en FC, indujo un aumento en la expresión de Eselectina, situación que es revertida con el pre tratamiento con TAK-242 (inhibidor de TLR4). Adicionalmente, la activación de TLR4 generó un aumento en la adhesión de monocitos sobre los FC, mientras que la inhibición de TLR4 y las vías transduccionales ERK1/2, PI3K/Akt y NF-κB previo al estímulo con LPS, revirtió el aumento de adhesión de monocitos. De igual forma, el bloqueo de E-selectina, mediante el uso de un anticuerpo bloqueante, también revirtió el aumento de la adhesión, dando luces de que esta proteína de adhesión es fundamental para el reclutamiento de monocitos y por tanto para mediar la respuesta inflamatoria orquestada por el FC / Cardiac fibroblasts (CF) have been considered as sentinel cells, since they respond in a complex and diverse manner to external and internal stimulus, in orden to maintein homeostasis of the heart. This is mediated through a wide number of receptor, among then Toll-Like receptors, an particulary TLR4, play a critical role in cardiac inflammation. TLR4 activation has been involved in the regulation of inflammatory and fibrotic response both in CF and other cells; adhesion molecules and recruiment of immune cells are key elements of these process. Therefore we sought to evaluate whether TLR4 activation in CF obteined from adults rats increased monocyte adhesion trough increased levels of E-selectin. TLR4 activation by LPS in CF, induce increased in E-selectin expression, which was abolished when CF were pre treatment with TAK-242 (TLR4 inhibitor). In adittion, TLR4 activation increased monocyte adhesion to CF, whereas the inhibition of this receptor and releated signaling pathway ERK1/2, PI3K/Akt and NF-κB, previous LPS exposure reverse monocyte adhesion. Similarly, E-selectin blockade, by the use of blocking antibody, also blocked monocyte adhesion, which a yeast the importance of this adhesion molecule in monocyte recruitment and inflammatory response orchestrated by CF

Thesis advisor: Marc-Jan Gubbels / The apicomplexan parasite <italic>Toxoplasma gondii</italic> divides rapidly and asexually through a unique process of internal daughter budding. The physical infrastructure for this process is the cytoskeleton, which is composed of subpellicular microtubules, flattened vesicles (alveoli), and a meshwork of intermediate filament-like proteins. This meshwork is composed of a family of 14 inner membrane complex (IMC) proteins that were identified based on the presence of a repeat sequence shared across the Alveolata, the alveolin-repeat. All 14 proteins were cloned as YFP fusions to study their subcellular localization and antibodies were generated against several representative IMC proteins. Each IMC displays unique spatio-temporal dynamics throughout development, but four physically distinct localizations were identified: eight IMCs localize to the alveoli, four IMCs localize to a structure known as the basal complex, IMC11 localizes to the apical cap in mature parasites, and IMC15 localizes primarily to the centrosomes and early buds. IMC15 is of particular interest because its appearance before membrane occupation and recognition nexus 1 (MORN1) in the early bud suggests that it is the first cytoskeletal component to associate with the buds. A conditional knockdown of this protein using the destabilization domain (DD) reveals IMC15 has a strong affinity for the centrosomes that overcomes targeting of the DD fusion protein to the proteasome and the presence of IMC15 in the early bud may not be necessary for the division process. Conditional knockdowns using a tetracycline repressible promoter reveal that a minimal amount of IMC15 is sufficient for parasite survival. In order to further characterize IMC15, dominant negative constructs based on mutating putative palmitoylation sites or overexpression of deletion constructs are being pursued. Collectively, the IMC family is being incorporated into the temporal and spatial dynamics of cytoskeletal development through the creation of a comprehensive timeline of daughter bud assembly. These findings are contributing unprecedented detail to the cell division process. / Thesis (PhD) — Boston College, 2011. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.

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

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