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We present evidence for redshift quantization in the Lyman -a forest of several QSOs. The Ly -a data are at redshifts z from 1.89 to 3.74, and the theory of redshift quantization proposed by Cocke (1983, 1085) is used to scale the quantization interval (24.15 km s -') to these high redshift. The sealing depends on the deceleration parameter qo, and the quantization is present at a statistical significance of greater than 99% for qo = 1/2. This may be taken as confirming the inflationary model of the early history of the universe. The significance of the quantization is highest at go rs 0.48, and the width of the peak is about 0.03 . The result can also be seen as providing confirmatory evidence for both the theory of the redshift quantization and the above value of qo, but at a significance of only 03 %. The scenario proposed for the relativistic generalization of the theory is that of fermion wavefunctione and quantum operators in a background Riemannian spacetime satisfying Einstein's field equations.

Class of 2017 Abstract / Objectives: Evaluate thymoquinone (TQ) and thymol (THY) inhibitory activities against α-glucosidase enzyme by using an in vitro assay and determine the IC50 (concentration of TQ/THY to inhibit 50% of maximum enzyme activity). Methods: Various concentrations of thymoquinone and thymol were incubated, separately, with one concentration of the substrate - p-nitrophenol-α-D-glucopyranoside (PNPG) (<<Km) in presence of α-glucosidase enzyme. A positive and a negative control consisting of acarbose, and buffer, respectively, were included in the incubation as well. The incubation time was set at 30 min in a 37 °C controlled water bath. The enzyme activity was determined by detecting and quantitating the levels of p-nitrophenol using a spectrophotometer set at 405 nm. The percent inhibition exhibited by any studied drug was calculated as shown in equation 1. % inhibition = Absorbance Substrate Alone – Absorbance of Substrate + Inhibitor Absorbance Substrate Alone Results: Results of the in vitro incubation of thymoquinone, thymol and acarbose revealed “statistically” significant inhibition of -glucosidase (p<0.05). At 400 g/ml, thymoquinone inhibited the enzyme activity by ~52 % whereas the enzyme inhibition by thymol and acarbose were calculated to be ~84% and 57%, respectively. IC50 were tentatively determined although the maxima inhibitions of the inhibitors were not reached fully. IC50s were calculated as 234 μg/ml, 304 μg/ml and 157 μg/ml for each of thymoquinone, thymol and acarbose, respectively. Conclusions: Thymoquinone and thymol do exhibit antagonistic pharmacological activity against α-glucosidase.

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Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Biochemical Sciences Candidate: Bc. Markéta Marešová Supervisor: Ing. Petra Matoušková, Ph.D. Title of diploma thesis: Effect of alpha-humulene on adhesion of breast cancer cell line MDA-MB-231 α-humulene is a sesquiterpene contained in the essential oil of Chinese Bayberry (Myrica rubra), which has various biological effects. The aim of this thesis was to study the cell adhesion of tumor cell line MDA-MB-231, and the effects of α-humulene on expression of cell adhesion molecules. Furthermore, the cytotoxic effect of α-humulene on this cell line was verified. Effect of α-humulene on cell proliferation was evaluated by neutral red uptake test (NRU test) and by xCelligence system. Cell adhesion was also continuously monitored by xCelligence. Expression ganges of cell adhesion molecules upon α-humulene treatment were determined by Western blotting and by quantitative polymerase chain reaction on the protein and mRNA levels, respectively. The proliferation of the cells was significantly affected by α-humulene after 24 hour treatment (IC50 13.6 µg/ml). α-humulene alone caused slightly increased cell adhesion. Adhesion molecules EpCAM and β-cathenin were almost unaffected. Level of ICAM1 mRNA was increased after 12 hours and...

Le développement de nouvelles stratégies d’immunothérapie représente de nos jours un enjeu majeur de santé publique. Dans ce contexte, les lymphocytes T Natural Killer invariant (iNKT) exercent de puissantes activités immuno-modulatrices. Ces cellules ont la particularité de reconnaitre par l’intermédiaire de leur récepteur T (TCR), des (glyco) lipides, présentés par la molécule CD1d exprimée par les cellules présentatrices d’antigènes (APC), notamment les cellules dendritiques (DC). Initialement découvert à partir d’une éponge marine pour ses activités anti-métastatiques, l’alpha-galactosylcéramide (a-GalCer ou KRN) induit rapidement une sécrétion massive, par les cellules iNKT, de cytokines immunomodulatrices telles l’IFN-g, conduisant à la transactivation de nombreuses cellules immunitaires, notamment les cellules Natural Killer (NK), les DC ou encore les lymphocytes Tgd. Cette propriété unique permet aux cellules iNKT de contrôler, chez la souris, le développement des réponses immunes, notamment la réponse anti-tumorale. Face à ces résultats encourageants, des essais cliniques chez l’homme ont été réalisés mais les résultats se sont avérés décevants. Actuellement, il existe deux stratégies pour cibler un antigène à une population cellulaire particulière : 1) le ciblage passif, basé sur la taille des particules ou leur composition et 2) le ciblage actif, basé sur les fortes interactions anticorps/antigène ou ligand/récepteur. Nous avons testé les deux types de ciblages et avons utilisé le même polymère pour constituer nos vecteurs : le PLGA ou poly(lactic coglycolic acid). Dans une première étude (ciblage passif), nous avons comparé l’efficacité de l’encapsulation de l’a-GalCer dans des particules de tailles différentes: des nano (NP) et microparticules (MP). L’a-GalCer vectorisé dans les NP et les MP est endocyté par les DC (voie des clathrines) et active les cellules iNKT in vitro et in vivo mais ne peuvent empêcher leur anergie. Ces résultats décevants nous ont conduits à opter pour le ciblage actif des DC. Dans un premier temps, étant donné les études controversées sur le rôle des DC dans l’anergie des cellules iNKT, nous avons revisité l’implication de ces dernières dans la primo-activation/anergie des cellules iNKT. Nous confirmons ainsi le rôle primordial de DC dans la primo-activation des cellules iNKT mais surtout, nous montrons qu’elles n’induisent pas leur anergie. Représentant une population hétérogène, nous montrons que parmi les DC, les DC CD8a+ sont de puissantes activatrices des cellules iNKT. Nos résultats nous ont ainsi menés à délivrer spécifiquement l’a-GalCer aux DC CD8a+. Pour cela, nous avons greffé sur les NP de PLGA un anticorps anti-DEC205, récepteur lectinique fortement exprimé par les DC CD8a+. In vitro et in vivo, les NP/DEC205/a-GalCer induisent une plus forte activation des cellules iNKT comparativement à l’a-GalCer libre. De même, la co-délivrance d’a-GalCer et d’ovalbumine (OVA) au sein des DC CD8a+ améliore les propriétés adjuvantes de l’a-GalCer en induisant des réponses humorale et cellulaire (lymphocytes T CD8+) spécifiques de l’OVA plus importantes comparativement à la délivrance des deux composés sous leur forme libre. Finalement, de façon intéressante, nous montrons que suite à une primo-activation par les NP/DEC205/a-GalCer, les cellules iNKT sont capables de répondre de nouveau à une seconde stimulation, traduisant l’absence d’anergie des cellules iNKT. En conclusion, nos résultats indiquent que la délivrance spécifique de l’a-GalCer aux DC CD8a+ amplifie la primo-activation des cellules iNKT tout en évitant la mise en place du phénomène d’anergie et ouvrent de nombreuses perspectives dans le cadre de thérapies anti-tumorales et anti-infectieuses. / Nowdays, the development of new immunotherapy strategies represent a major issuein public health. In this context, the invariant Natural Killer T lymphocytes (iNKT) have strongimmunomodulatory properties. This cell population recognizes (glycol)lipid presented by theCD1d molecule expressed by antigen presenting cell (APC) as dendritic cells (DC). Initiallyfound in a marine sponge for its anti-metastatic activities, alpha-galactosylceramide (-GalCer or KRN) induces a massive cytokine production (IFN-, IL-4, IL-17) by iNKT cells.This cytokine burst lead to downstream activation of numerous immune cells like naturalkiller cell (NK), DC or CD8+ T cells. Through this property, iNKT cells regulate numerousimmune responses, including anti-tumoral response. Based on encouraging results in themouse model, -GalCer has been used in anti-tumour therapy in human. Although the drugwas well tolerated, no or moderate clinical responses were observed in patients repeatedlyinoculated with -GalCer. As observed in the mouse system, one potential explanation forthis disappointing observation may lie in the induction of a long-term anergy of human iNKTcells, thus preventing cytokine release upon a recall stimulation. Although controversial,various studies suggest that this phenomonen should be due to a lack of delivery of -GalCer into dendritic cells (DC) and so its presentation by non adequate antigen presentingcell (APC) as B cells. The objective of our work was to optimize -GalCer activity by avoidingiNKT anergy using vectorisation approach. Actually, there are 2 strategies using nanotechnologies to target an antigen to a specific cell population: 1) passive targeting based on the size of the particles, their composition and their surface charge and 2) active targeting based on the strong interactions between an antibody and its antigen or a ligand and its receptor. We have tested the two strategies and therefore we use the same composition of our particles: PLGA or poly(lactic co glycolic acid). This biodegradable and biocompatible molecule is already used in therapy.In a first study (passive targeting), we compared the efficiency of -GalCer encapsulation inparticles with different size: nano (NP) and microparticle (MP). Vectorised -GalCer in NPand MP rapidly activates iNKT cells in vitro. Both type of particles are uptake by DC via aclathrin dependent mechanism. In in vivo approaches, NP/-GalCer and MP/-GalCeractivate iNKT cells but unfortunately could not prevent iNKT cell anergy. These disappointingresults led us to use an active targeting. In first time, because of controversial role of DC iniNKT anergy, we have revisited the role of DC in iNKT primo-activation and anergy. Weconfirm the primordial role of DC in iNKT primo-activation but especially we show that DC donot induce iNKT anergy. DC are heterogeneous and we show that among DC, CD8a+ DCsubpopulation are potent iNKT cells activation. Our results led us to deliver specifically a-GalCer to CD8+ DC. For this, anti-DEC205 antibodies were covalently linked to the surfaceof PLGA NP, DEC205 being highly expressed by CD8+ DC. In vitro and in vivo,NP/DEC205/-GalCer induce a stronger iNKT cell activation relative to free -GalCer (or NPIgG/-GalCer). Moreover, -GalCer and ovalbumin co-delivery in CD8+ DC improve -GalCer adjuvanticity leading to more important humoral and cellular responses. Interestingly,after a primo-activation by NP/DEC205/-GalCer, iNKT cells are able to respond to secondstimulation thus avoiding iNKT cell anergy.In conclusion, our results indicate that specific -GalCer delivery to CD8+ DC improve iNKT cells primo-activation and avoid anergy phenomenon. These findings open several perspectives in anti-tumoral and anti-infectious therapies.

Les mécanismes impliqués dans l’activation de foyers ectopiques dans les veines thoraciques, source de fibrillation auriculaire (FA) chez l’Homme, sont encore méconnus. Nous avons montré que la noradrénaline peut induire une activité automatique sur la veine pulmonaire (VP) mais pas sur l’oreillette gauche (OG) chez le Rat. Au cours de cette étude, nous avons montré : 1) un potentiel de membrane de repos dépolarisé dans la VP et la veine cave supérieure (VCS) par rapport à l’OG ainsi que la présence d’une activité automatique en salves sur la VP ; 2) une dépolarisation due à la stimulation des récepteurs α1-adrénergiques (α1-AR) plus importante sur la VP que sur les deux autres tissus qui induit une inexcitabilité de la VP et la VCS ; 3) la présence d’une activité déclenchée favorisée par la stimulation des β1-AR sur la VCS ; 4) une diminution liée à l’âge de l’incidence de l’activité automatique catécholaminergique et des réponses à la stimulation des α1-AR sur la VP ainsi que la présence d’une activité déclenchée sous stimulation des α1-AR sur la VP chez les animaux âgés. Nous avons donc pu mettre en évidence des différences fonctionnelles entre le myocarde des veines thoraciques et le tissu atrial. Cependant, la relation entre l’activité automatique observée sur la VP du Rat et la FA reste encore à établir. / The mechanisms involved in the activation of ectopic foci within the thoracic veins, cause of atrial fibrillation (AF) in man, are still unknown. We shown that norepinephrine (NE) can induce an automatic activity in pulmonary vein (PV) but not in left atrium (LA) of the Rat. In this study, we shown: 1) a depolarised resting membrane potential in PV and superior vena cava (SVC) compared with LA and the occurence of an automatic activity in repetitive bursts in PV; 2) a depolarisation due to α1-adrenergic receptors (α1-AR) stimulation more pronounced in PV than the other two tissues, which induce an inexcitability of the PV and the SVC; 3) the occurence of a triggered activity facilitated by the simulation of β1-AR in SVC; 4) a decrease with age of the incidence of the catecholaminergic automatic activity and responses to the stimulation of α1-AR in PV and the occurence of a triggered activity under stimulation of α1-adrenergic in PV of old animals. Therefore, we have shown some functionnal differences between the myocardium of thoracic veins and atrial tissu. Nevertheless, the relationship between automatic activity observed in Rat PV and AF remains to establish.

Entwicklung eines experimentellen Systems zur Untersuchung der subzellulärenLokalisierung der Alpha-Methylacyl-CoA-Racemase (AMACR) (Methode der retroviralen Transfektion von transformierten, embryonalen Mausfibroblasten) / Development of a experimental system for the investigation of the subcellular localisation of alpha-methylacyl-CoA racemase (amacr) (retroviral transfection of mouse fibroblasts)

Alpha matting is an important topic in areas of computer vision. It has various applications, such as virtual reality, digital image and video editing, and image synthesis. The conventional approaches for alpha matting perform unsatisfactorily when they encounter complicated background and foreground. It is also difficult for them to extract alpha matte accurately when the foreground objects are transparent, semi-transparent, perforated or hairy. Fortunately, the rapid development of deep learning techniques brings new possibilities for solving alpha matting problems. In this thesis, we propose a residual convolutional grid network for alpha matting, which is based on the convolutional neural networks (CNNs) and can learn the alpha matte directly from the original image and its trimap. Our grid network consists of horizontal residual convolutional computation blocks and vertical upsampling/downsampling convolutional computation blocks. By choosing different paths to pass information by itself, our network can not only retain the rich details of the image but also extract high-level abstract semantic information of the image. The experimental results demonstrate that our method can solve the matting problems that plague conventional matting methods for decades and outperform all the other state-of-the-art matting methods in quality and visual evaluation. The only matting method performs a little better than ours is the current best matting method. However, that matting method requires three times amount of trainable parameters compared with ours. Hence, our matting method is the best considering the computation complexity, memory usage, and matting performance.