L'objectif de ce travail est de développer et d'évaluer des approches méthodologiques pour la<p>prédiction de séquences cis-régulatrices. Ces approches ont été intégrées dans la suite logicielle<p>RSAT (Regulatory Sequences Analysis Tools). Ces séquences jouent un rôle important dans la<p>régulation de l'expression des gènes. Cette régulation, au niveau transcriptionnel, s'effectue à<p>travers la reconnaissance spécifique entre les facteurs de transcription et leurs sites de fixation<p>(TFBS) au niveau de l'ADN.<p>Nous avons développé et évalué une série d'outils bioinformatiques qui utilisent les matrices<p>position-poids pour prédire les TFBS ainsi que les modules cis-régulateurs (CRM). Nos outils<p>présentent l'avantage d'intégrer les différentes approches déjà proposées par d'autres auteurs tout<p>en proposant des fonctionnalités innovantes.<p>Nous proposons notamment une nouvelle approche pour la prédiction de CRM basé sur la<p>détection de régions significativement enrichies en TFBS. Nous les avons appelés les CRER (pour<p>Cis-Regulatory Elements Enriched Regions). Un autre aspect essentiel de toute notre approche<p>réside dans le fait que nous proposons des mesures statistiques rigoureuses pour estimer<p>théoriquement et empiriquement le risque associé aux différentes prédictions. Les méthodes de<p>prédictions de séquences cis-regulatrices prédisent en effet un taux de fausses prédictions<p>généralement élevé. Nous intégrons un calcul des P-valeurs associées à toutes les prédictions.<p>Nous proposons ainsi une mesure fiable de la probabilité de faux positifs.<p>Nous avons appliqué nos outils pour une évaluation systématique de l'effet du modèle de<p>background sur la précision des prédictions à partir de la base de données de TRANSFAC. Nos<p>résultats suggèrent une grande variabilité pour les modèles qui optimisent la précision des<p>prédictions. Il faut choisir le modèle de background au cas par cas selon la matrice considérée.<p>Nous avons ensuite évalué la qualité des matrices de tous les facteurs de transcription de<p>drosophile de la base de données ORegAnno, c'est à dire leur pouvoir de discrimination entre les<p>TFBS et les séquences génomiques. Nous avons ainsi collecté des matrices des facteurs de<p>transcription de drosophile de bonne qualité.<p>A partir des matrices de drosophile que nous avons collectées, nous avons entamé une analyse<p>préliminaire multi-genome de prédictions de TFBS et de CRM dans la région de lʼenhancer dorsocentral<p>(DCE) du complexe achaete-scute de drosophile. Les gènes de ce complexe jouent un<p>rôle important dans la détermination des cellules système nerveux périphérique de drosophile. Il a<p>été prouvé expérimentalement qu'il existe un lien direct entre le phénotype du système nerveux<p>périphérique et les séquences cis-régulateurs des gènes de ce complexe.<p>Les outils que nous avons développés durant ce projet peuvent s'appliquer à la prédiction des<p>séquences de régulation dans les génomes de tous les organismes. / Doctorat en Sciences / info:eu-repo/semantics/nonPublished

This​ ​essay​ ​examines​ ​the​ ​appearance​ ​of​ ​non-normative​ ​bodies​ ​in​ ​three​ ​films​ ​from​ ​the Marvel​ ​Cinematic​ ​Universe;​ ​​The​ ​Avengers​​ ​(2012),​ ​​Thor:​ ​The​ ​Dark​ ​World​​ ​(2013) ​and Avengers:​ ​Age​ ​of​ ​Ultron​​ ​(2015),​ ​in​ ​an​ ​attempt​ ​to​ ​find​ ​qualities​ ​that​ ​might​ ​suggest​ ​queer, non-binary​ ​or​ ​gender​ ​disruptive​ ​attributes,​ ​in​ ​addition​ ​to​ ​looking​ ​at​ ​how​ ​the​ ​movies handle​ ​them.​ ​Using​ ​a​ ​combination​ ​of​ ​feminist​ ​film​ ​theory,​ ​queer​ ​theory​ ​and​ ​discourse analysis,​ ​the​ ​Otherness​ ​of​ ​these​ ​bodies​ ​are​ ​put​ ​into​ ​contrast​ ​with​ ​the​ ​normative​ ​and hegemonic​ ​gender​ ​expressions​ ​employed​ ​by​ ​the​ ​protagonists,​ ​the​ ​heroes​ ​of​ ​the​ ​films. While​ ​the​ ​study​ ​finds​ ​several​ ​indications​ ​of​ ​transgressive​ ​bodies​ ​and​ ​'gender​ ​ambiguity' among​ ​the​ ​creatures​ ​and​ ​beings​ ​who​ ​play​ ​the​ ​part​ ​of​ ​inhuman​ ​threat,​ ​as​ ​well​ ​as​ ​the presence​ ​of​ ​discourses​ ​that​ ​paint​ ​them​ ​as​ ​threatening​ ​partly​ ​​because​​ ​of​ ​these​ ​qualities, they​ ​remain​ ​blurred​ ​and​ ​ill-defined,​ ​their​ ​queerness​ ​inferred​ ​rather​ ​than​ ​overt.​ ​The preferred​ ​reading,​ ​the​ ​analysis​ ​suggests,​ ​offers​ ​little​ ​in​ ​the​ ​way​ ​of​ ​identification,​ ​but​ ​all the​ ​more​ ​with​ ​regard​ ​to​ ​oppression.​ ​The​ ​way​ ​these​ ​bodies​ ​are​ ​treated​ ​in​ ​all​ ​three​ ​films implies​ ​that​ ​the​ ​tolerance​ ​for​ ​bodily​ ​deviance​ ​is​ ​virtually​ ​non-existent,​ ​and​ ​that​ ​a defining​ ​quality​ ​of​ ​masculine​ ​leadership​ ​is​ ​the​ ​ability​ ​to​ ​banish​ ​them​ ​from​ ​existence.

The thesis work delineates the rational design and successful syntheses of platinum (II) complexes for achieving light promoted dual action anticancer properties. The research work focuses on the syntheses, elaborate characterization including crystallization and mechanistic aspects of photodegradation processes. Theoretical studies were done to elucidate the properties of the excited states. The interaction of active Pt (II) species with DNA is also explored. The cellular studies include evaluation of the photo-induced cytotoxicities, mode of cell death, nature of reactive oxygen species (ROS), quantification of cellular Pt content and cellular and sub-cellular localization of the complexes. Chapter I provides an overview of the hallmarks of cancer and the current anticancer treatment modalities. It outlines the evolution of platinum based chemotherapeutic drugs, their mechanism of action and associated disadvantages. It also depicts the resurgence of metal complexes as photosensitizers for photoactivated chemotherapy, a selective tripartite strategy which permits light induced tumor destruction. Detailed literature reports of potential transition metal complexes showing light induced generation of ROS and controlled delivery of multiple drugs in tumor microenvironment are presented. The key challenges are the delivery and controlled activation of the clinically approved platinum (II) drugs. These prime objectives of the present investigation are depicted as a concluding segment of this introductory chapter. Chapter II includes the syntheses, characterization, evaluation of visible light induced cytotoxicity and interaction with DNA of novel ferrocenyl terpyridine appended platinum (II) complexes. Detailed mechanistic investigations revealed the important role of ferrocene in light triggered generation of reactive oxygen species. The effect of extensive conjugation on the photophysical properties of the complexes were also rationalized from theoretical calculations. The alteration in DNA binding affinities of the complexes on incorporation of a ferrocene unit in the platinum (II)terpyridines is also reflected. The work is the first report of the remarkable photocytotoxicity of platinum(II) complexes in visible light with nominal dark toxicity. Chapter III deals with novel ferrocenyl terpyridyl platinum(II) complexes having tumor targeting biotinylated acetylides which were synthesized for achieving selective photocytotoxicity only in cancer cells. An interesting observation was the red light promoted release of biotinylated acetylide ligands from platinum centre thereby generating mono-functional Pt(II) species. The possible covalent interactions of these platinum(II) species with DNA were also explored. These biotin complexes exhibit preferential cellular uptake in BT474 breast cancer cells over HBL-100 breast normal cells resulting in targeted photocytotoxicity in visible light. Chapter IV rationalizes design, syntheses and extensive characterization of 2-(phenylazo)pyridine based platinum(II) catecholates containing photosensitizers. The O^O donor ligand was chosen to release the more cytotoxic bi-functional platinum(II) species based on the prior knowledge of the labile Pt-O bonds. Interestingly, we observed glutathione triggered release of the catecholates imparting dual action anticancer properties to the molecules. Detailed mechanistic aspects indicated a possible reduction of the metal coordinated azo bond by cellular glutathione. The excellent photocytotoxicity in HaCaT and MCF-7 cells, cellular ROS generation and apoptosis, cellular Pt content and localization of these complexes are discussed. Chapter V addresses the advantages of navigating the platinum(II) complexes to mitochondrial DNA instead of genomic DNA. BODIPY appended platinum(II) catecholates were synthesized and the BODIPY core was modified to fine-tune the photophysical properties. The visible light induced growth inhibitory effects of the complexes and the mechanism of cell death in light exposed cells are explored. The novelty of this work is the mitochondria targeted remarkable photocytotoxicity as well as cellular imaging properties of the complexes making them ideal candidates for developing platinum based theranostic agents. Chapter VI presents the syntheses, characterization of unprecedented platinum(II) complexes of curcumin for dual action DNA crosslinking and photochemotherapeutic activities. The important feature of these Pt(II) prodrugs is the photorelease of curcumin from Pt(II) centre which results in controlled delivery of two potential anticancer agents. The visible light induced cytotoxicities of the complexes in HaCaT, BT474, T47D, Hep3B and HPL1D cells, their effect on the various cellular events, the interaction of the complexes with DNA and their cellular distribution in light and dark are explored. The appropriate references are provided at the end of each chapter and allocated as superscripts in the main text. The synthesized complexes are denoted by bold-faced numbers. Crystallography data of the complexes that are structurally characterized by single crystal X-ray crystallography are given in CIF format in the enclosed CD (Appendix-I). Due acknowledgements are provided for mentioned literature reports. Any omission is purely unintentional and is deeply regretted. INDEX WORDS: Platinum(II) complexes • Crystal structure • Visible light induced cytotoxicity • Cellular imaging • Photochemotherapeutic agents • DNA crosslink.

Understanding the functional impact of physical interactions between proteins and DNA on gene expression is important for developing approaches to correct disease-associated gene dysregulation. I conducted a systematic, functional genetic analysis of protein-DNA interactions in the promoter region of the yeast ribonucleotide reductase subunit gene RNR3. I measured the transcriptional impact of systematically perturbing the major transcriptional regulator, Crt1, and three X-box sites on the DNA known to physically bind Crt1. This analysis revealed interactions between two of the three X-boxes in the presence of Crt1, and unexpectedly, a significant functional role of the X-boxes in the absence of Crt1. Further analysis revealed Crt1- independent regulators of RNR3 that were impacted by X-box perturbation. Taken together, these results support the notion that higher-order X-box-mediated interactions are important for RNR3 transcription, and that the X-boxes have unexpected roles in the regulation of RNR3 transcription that extend beyond their interaction with Crt1.

京都大学 / 0048 / 新制・課程博士 / 博士(薬科学) / 甲第22750号 / 薬科博第124号 / 新制||薬科||14(附属図書館) / 京都大学大学院薬学研究科薬科学専攻 / (主査)教授 竹本 佳司, 教授 高須 清誠, 教授 大野 浩章 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

Title: Chiral recognition by mass spectrometry Author: Bc. Lenka Kosíková Department: Department of Organic Chemistry Supervisor: doc. Mgr. Jana Roithová, Ph.D. This work is focused on the use of mass spectrometry as the analytical method for chiral recognition in the gas phase. We have examined formation of complexes (S and R) isomers [dimethyl-2,2'-dihydroxy-1,1'binaphthalene-3,3'-dicarboxylate] with sodium. Chiral effect for the fomation of sodium dimers is 1,34±0,06 and that for formation of trimers 2,38±0,22 in favor of the formation of homochiral complexes. Part of the work is devoted to the preparation of isotopically labeled ester [(R)-(−)- di(D3-methyl)-2,2'-dihydroxy-1,1'binaphthalene-3,3'-dicarboxylate]. Mixing of equimolar amounts of D3-(R) and unlabeled (S) isomers leads to the artificial racemate, while we can still distinguish the enantiomers using mass spectrometry. Another part represents the study of the complex formation between (S and R) isomers of [dimethyl-2,2'-dihydroxy-1,1'binaphthalene-3,3'-dicarboxylate] with the metal complex [(S,S)-1,5-diaza-cis-decalin]Cu(OH)I depending on the molar ratios in the solution. I have showed that the molar concetration of the catalyst in the solution plays an important role in the complex formation and that the ESI source spectra of...

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

This diploma thesis is focused on the analysis of Russian foreign policy towards Kazakhstan and Ukraine. The actions of the external players, namely the US (NATO), the EU and China are discussed in order to see how these foreign entities can modify Russia's actions in its backyard. The current state of affairs demands a careful examination of Russian foreign policies. As Russia has demonstrated in Georgia, Ukraine, Syria, it is willing to protect its interests at any cost. Thus, it was decided to analyze whether the foreign involvement in Kazakhstan would provoke Russian aggression. The primary aim is to provide a complex examination of Russian involvement in Kazakhstan and Ukraine along with the increasing influence from external players. This thesis is expected to contribute to the existing research on Russian foreign policy by providing an essential background for future researches as well as by presenting previously incomparable cases. This work presents a significant historical background that provides a reader with the in- depth analysis of Russia's relations with Kazakhstan and Ukraine. Geopolitical, military, economic, social factors are analyzed to present a broader perspective of the regional interconnections. Thus, this work analyzes how Russia has established its dominance in the...

I takt med digitaliseringen skapas fler digitala nyhetssidor och därmed blir konkurrensen högre mellan nyhetskanaler. Eftersom nyhetsartiklar blir mer lättillgängliga är det intressant att se huruvida de inkluderar människor med alla olika könsidentiteter eller ej. Hbtq-personer har en högre risk för att känna psykisk ohälsa och i Sverige är det även fler transsexuella som övervägt att begå självmord under de senaste åren (Folkhälsomyndigheten, 2019). Studien undersöker därför om svenska nyhetsmedier väljer att upprätthålla samhällets diskurser om transpersoners utanförskap i samhället. Anledningen till att studien fokuserar på Sverige är för att landet anses vara ett inkluderande samhälle (Svenska Institutet, 2019). Därför studeras nyhetsmedia i form av Expressens nyhetsartiklar kring två valda fall.  Syftet med studien är att undersöka hur olika könsidentiteter blir representerade i nyhetsmedia och hur nyhetsurval sker. Detta görs med en kritisk diskursanalys och med hjälp av teoretiska utgångspunkter såsom nyhetsvärdering, det idealiska offret och genus och normer. Det empiriska material som behandlas är fyra artiklar om mordet på Emilia Lundberg och fyra artiklar från mordet på Wilma Andersson. Artiklarna väljs ut genom ett strategiskt urval och en tidslinje med fyra olika moment. Studien visar att transpersoner inte ses som lika nyhetsmässiga som cispersoner, transpersoner får mindre uppmärksamhet och ses som mindre idealiska offer. Transpersoner får varken samma uppmärksamhet, empati och representeras inte heller på ett likvärdigt sätt som cispersoner i nyhetsmedia. / In line with the digitalisation, the Internet's webpages increase and so does the competition between news media channels. Since it is getting easier to access news articles, it is interesting whether they include people with different gender identities or not. Hbtq people have a higher risk of feeling mental health issues and there are also more transsexuals in Sweden who intend to commit suicide in recent years (Folkhälsomyndigheten, 2019). The study therefore examines whether Swedish news media choose to erect society's discourses about transgender people's exclusion in society. Another reason why the study examines Sweden is because they are considered an inclusive society (Svenska Institutet, 2019). For those reasons, it will be interesting to examine Sweden's news media and Expressen's articles on two selected cases.  The purpose of the study is to investigate how different gender identities are represented in the news media and how news selection takes place. This will be done through a critical discourse analysis and theoretical starting points such as news evaluation, the ideal victim and gender and norms. The empirical material that is negotiated in the study is four articles about the murder case of Emilia Lundberg and four articles from the murder case of Wilma Andersson. The articles are chosen after four moments in terms of a timeline. The study shows that transgender people are not seen as newsworthy as cis people, transsexuals get less attention in the news, and they are seen as non-ideal victims. Transsexuals do not receive the same attention, empathy or get represented in an equivalent way as cispersons in the news.

Everyday need of modern society is a mass personal transit on a regular basis. For this purpose, mass transit systems exist which obey aforethought schedule. This thesis' goal is to examine the means of automatic search of connections from one place to another, implement such search, and to advance the search algorithm using the soft-computing paradigms. Minor goal would be a research of SQL language procedural capabilities, which could support mass pseudo-parallel computations.