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Balzano, Amodio Luca. "Design, synthesis, biological evaluation and binding studies of new small-molecule modulators of KDMs (lysine-specific demethylases)." Doctoral thesis, Universita degli studi di Salerno, 2017. http://hdl.handle.net/10556/2419.
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2014 - 2015JHDMs (JmjC-domain-containing histone demethylases) are the largest class of demethylase enzymes, contain a Jumonji C (JmjC) domain and catalyze lysine demethylation of histones through an oxidative reaction that requires Fe(II) ion and α-ketoglutarate (2OG) as cofactors. The misregulation of these enzymes, in particular JMJD2 subfamily, has being significantly implicated in cancer initiation and progression. Potent and specific inhibitors of these enzymes have not been identified yet, most of them inhibiting many other Fe(II)/2OG dependent oxygenases or being affected by undesirable characteristics. Here, we describe the discovery by high throughput screening (HTS) of a bunch of novel hit compounds active against KDM4s and the subsequent hit validation stage to select the most interesting ones for further derivatization. The use of a multiple combined approach of different in vitro techniques led us to select the hit EML586 as starting point for the development of novel optimized derivatives. The substitution of quinoxaline ring with more aliphatic portions gave derivatives such as EML678 and EML684, which demonstrate a better activity against hKDM4A compared to the starting hit compound. Furthermore, they induced a marked reduction in methylation of lysines H3K9 and H3K27 in a cell-based assay together with a marked arrest in the S phase of cell cycle. [edited by author]
Le JHDM (demetilasi istoniche contenenti il dominio JmjC) rappresentano la più numerosa classe di enzimi ad attività demetilasica, contengono il dominio Jumonji C (JmjC) e tramite esso sono in grado di catalizzare la rimozione del gruppo metile da residui di lisina istonici tramite una reazione ossidativa che utilizza lo ione Fe(II) e l’α-chetoglutarato (2OG) come cofattori. Un’attività aberrante di questi enzimi, in particolare della sottofamiglia JMJD2, sembra essere correlata in maniera significativa alla genesi e alla progressione di diverse forme tumorali. Non sono stati ancora identificati inibitori potenti e specifici per questa classe enzimatica, la gran parte delle molecole ad oggi note, infatti, è affetta da caratteristiche indesiderabili come scarsa permeabilità cellulare e mancanza di selettività verso gli altri enzimi Fe(II)/2OG dipendenti. In questo lavoro è descritta la scoperta tramite high throughput screening (HTS) di un gruppo di nuovi composti hit attivi contro KDM4 ed il successivo processo di validazione utilizzato per selezionare i derivati più interessanti per il futuro sviluppo. L’utilizzo di un approccio multiplo, combinato di differenti tecniche in vivo ha permesso di selezionare il composto EML586, punto di partenza per lo sviluppo di nuovi derivati ottimizzati. La sostituzione dell’anello chinossalinico con porzioni più alifatiche ha portato all’ottenimento dei derivati EML678 e EML684, che dimostrano una migliore attività inibitoria verso KDM4A umana rispetto al composto hit di partenza. Inoltre, tali derivati inducono una marcata riduzione del livello di metilazione delle lisine H3K9 e H3K27 in cellula insieme ad un evidente arresto del ciclo cellulare nella fase S. [a cura dell'autore]
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Schiller, Rachel Shamo. "Investigating the inhibitor and substrate diversity of the JmjC histone demethylases." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:1e7fd2a1-a9c3-48f7-8fa7-a041299d42f9.
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Epigenetic control of gene expression by histone post-translational modifications (PTMs) is a complex process regulated by proteins that can 'read', 'write' or 'erase' these PTMs. The histone lysine demethylase (KDM) family of epigenetic enzymes remove methyl modifications from lysines on histone tails. The Jumonji C domain (JmjC) family is the largest family of KDMs. Investigating the scope and mechanisms of the JmjC KDMs is of interest for understanding the diverse functions of the JmjC KDMs in vivo, as well as for the application of the basic science to medicinal chemistry design. The work described in this thesis aimed to biochemically investigate the inhibitor and substrate diversity of the JmjC KDMs, it led to the identification of new inhibitors and substrates and revealed a potential combinatorial dependence between adjacent histone PTMs. Structure-activity relationship studies gave rise to an n-octyl ester form of IOX1 with improved cellular potency and selectivity towards the KDM4 subfamily. This compound should find utility as a basis for the development of JmjC inhibitors and as a tool compound for biological studies. The rest of this thesis focused on the biochemical investigations of potential substrates and inhibitors for KDM3A, a JmjC demethylase with varied physiological functions. Kinetic characterisation of reported KDM3A substrates was used as the basis for evaluations of novel substrates and inhibitors. Further studies found TCA cycle intermediates to be moderate co-substrate competitive inhibitors of KDM3A. Biochemical investigations were carried out to study potential protein-protein interactions of KDM3A with intraflagellar transport proteins (IFTs), non-histone proteins involved in the formation of sperm flagellum. Work then addressed the exploration of novel in vitro substrates for KDM3 (KDM3A and JMJD1C) mediated catalysis, including: methylated arginines, lysine analogues, acetylated and formylated lysines. KDM3A, and other JmjC KDMs, were found to catalyse novel arginine demethylation reaction in vitro. Knowledge gained from studies with unnatural lysine analogues was utilised to search for additional novel PTM substrates for KDM3A. These results constitute the first evidence of JmjC KDM catalysed hydroxylation of an Nε-acetyllysine residue. The H3 K4me3 position seems to be required for acetyllysine substrate recognition, implying a combinatorial effect between PTMs. Preliminary results provide evidence that JMJD1C, a KDM3 protein previously reported to be inactive, may catalyse deacetylation in vitro. An additional novel reaction, observed with both KDM3A and JMJD1C, is deformylation of Nε-formyllysine residues on histone H3 fragment peptides. Interestingly, H3 K4 methylation was also observed to enhance the apparent deformylation of both KDM3A and JMJD1C catalysed reactions. Overall, findings in this thesis suggest that the catalytic activity of JmjC KDMs extends beyond lysine demethylation. In a cellular context, members of the KDM3 subfamily might provide a regulatory link between methylation and acylation marks. Such a link will further highlight the complex relationships between histone PTMs and the epigenetic enzymes that regulate them. The observed dependency of H3 K9 catalysis on H3 K4 methylation adds another layer of complexity to the epigenetic regulation by histone PTMs.
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Hookway, Edward. "The role of the lysine demethylases KDM5 and KDM6 in bone malignancies." Thesis, University of Oxford, 2016. https://ora.ox.ac.uk/objects/uuid:b591861f-985b-4722-8027-492e750f3ff7.
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Methylation of histone lysine residues functions as a dynamic, reversible mechanism for regulating gene expression and aberrations in this process have been linked with the development of cancer. Members of the lysine demethylase (KDM) family remove methyl marks from histones. KDM5B removes methyl marks from histone H3 lysine 4 (H3K4) whereas KDM6A and KDM6B remove methyl marks from histone H3 lysine 27 (H3K27). In this thesis, GSK-J4, an inhibitor of KDM5B, KDM6A and KDM6B, is shown to impair viability in a range of cancers affecting bone including multiple myeloma, Ewing sarcoma and chordoma. GSK-J4 induces a biphasic transcriptional response, characterized by an early, massive rise in the expression of a number of cysteine-rich metallothionein genes followed by induction of ATF4 via phosphorylation of eIF2α by GCN2. Induction of ATF4 leads to apoptosis in myeloma cells and cell cycle arrest in Ewing sarcoma. Ectopic overexpression of metallothioneins is shown to be sufficient to induce the ATF4 response. GSK-J4 is shown to alters cellular metabolism by impairing glutaminolysis. ChIPseq demonstrates a global increased H3K27me3 in response to treatment with GSK-J4 with a decrease in H3K4me3 around transcription start sites of genes not involved in the ATF4 response. Combined knockdown of KDM6A and KDM6B recapitulates the cellular response to GSK-J4 whereas inhibition of KDM5B is not sufficient to reproduce the effect. A model is presented suggesting that the increased requirement for incorporation of cysteine into protein due to the expression of metallothioneins leads to the presence of uncharged cysteinyl-tRNA molecules that are sensed by GCN2 leading to activation of an ATF4-driven integrated stress response.
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Chen, Runqiu, and 陳潤球. "Statistical validation of kidney deficiency syndromes (KDS) and the development of a KDS questionnaire in Hong Kong Chinese women aged 40-60 years." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43223813.
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Chen, Runqiu. "Statistical validation of kidney deficiency syndromes (KDS) and the development of a KDS questionnaire in Hong Kong Chinese women aged 40-60 years." Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B43223813.
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Ådahl, Hanna, and My Brännström. "The naked truth? : En kritisk diskursanalys om fast fashion-företaget NA-KD:s externa kommunikation." Thesis, Umeå universitet, Institutionen för kultur- och medievetenskaper, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-179312.
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The purpose of this study was to increase the understanding of how the Swedish fast fashion company NA-KD expressed its profile and how it could be linked to sustainability. The fashion industry is known for having big sustainability problems, and that is why the main focus of this study was the paradox between fast fashion and sustainability due to its conflict nature. To concretise the aim of the study, we formulated two questions: “What discourses can be found in NA-KD’s external communication?” and “What profile does the company express through their website?”. To analyse the company’s website we included relevant theories about the individualised consumer society, sustainable consumption and marketing communication. The used method for this study was Fairclough’s critical discourse analysis, which was a useful method to enable a critical perspective. Fairclough’s approach made it possible to examine how, and in what way, NA-KD expressed their external communication. The material consisted of ten texts found on the company’s website that were analysed closely and resulted in a number of findings. We found three discourses: the business discourse, the consumer discourse and the sustainability discourse. Those helped us to increase the understanding of the company’s profile, since we discovered a range of different tendencies. The main ones were that NA-KD constructed truth, encouraged more consumption, built relations with the consumer and expressed values and responsibility about sustainability. With those in mind, we concluded that it is doubtful that NA-KD’s sustainability communication is completely honest. They encouraged the consumer to buy more fast fashion clothing, which affects the environment negatively, at the same time as they communicated consciousness about the fashion industry’s impact on the environment. We also found that the communication was contradictory and misleading, hence that some information about their sustainability work does not comply with what is presented. Our main conclusion is therefore that NA-KD’s profile is ambiguous and difficult to establish.
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Khin, Khin Nyo Aree Jampaklay. "Access to health utilization among people aged 50 and older in KDSS is it equal /." Abstract, 2007. http://mulinet3.li.mahidol.ac.th/thesis/2550/cd404/4938533.pdf.
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Bader, Caroline, Eva-Louise Castefelt, and Louise Gunnarsson. "Influencers Marketing : En fallstudie om NA-KDs nyckel till en god tillväxt." Thesis, Högskolan i Borås, Akademin för textil, teknik och ekonomi, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:hb:diva-15381.
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Begreppet influencer blir mer och mer välkänt för varje dag. Begreppet syftar till ett yrke som vuxit fram i takt med internet. Även om det finns mycket information att tillgå kring fenomenet finns det många aspekter som fortfarande icke blivit belysta. Den information som finns att tillgå kring ämnet är inte heller i vetenskaplig tappning. Syftet med studien är att analysera och redogöra för hur influencer marketing kan påverka tillväxten för ett företag. Härtill studeras influencers inverkan på varumärkesbyggandet i relation till tillväxt. Följande kommer en fallstudie i samarbete med klädföretaget NA-KD presenteras. NA-KDs snabba tillväxt kommer förklaras med lämpligt teoretiska underlag och inte minst av medgrundaren själv. Det moderna sättet att marknadsföra via sociala medier med influencers kommer vidare att undersökas i ljuset av olika aspekter. Hur ett samarbete med en eller flera influencers ser ut kommer att undersökas med koppling till hur strategin har hjälpt NA-KD att växa under kort tid. Varumärkesutveckling och teorier kring ett företags tillväxt är två andra viktiga områden som kommer att studeras för att uppsatsen ska få en relevant och genomtänkt slutsats. Alla presenterade teorier kommer att kopplas till NA-KDs egna tillväxt. Metoden vald för följande uppsats är av den kvalitativa typen. Empiriinsamlingen kommer att bestå av en intervju med en medgrundare i fallföretaget, NA-KD. Vidare kommer företagets hemsida och Instagramkonton observeras, likaså kommer fyra utvalda influencers konton observeras. Även sekundär data så som NA-KDs årsredovisning samt en överskådlig presentation av ett par konkurrenter läggs fram. Efter analys av empirin trädde tydliga slutsatser fram. Kopplingar mellan influencer marketing och tillväxt blev ett klart faktum. Likaså blev samarbetet mellan företaget och person förtydligat. Det stod även klart att NA-KD ligger rätt i tiden och grundades när influencers redan vuxit fram och fått en stor inverkan.The term influencer is becoming more and more known for each day. The term aims at a profession that has emerged in line with the internet. Although there is much information available about the phenomenon, there are many aspects that have not yet been illuminated. The information available on the subject is also not of scientific sort. The purpose of the study is to analyze and explain how influencer marketing can affect the growth of a company. In addition, influencers affect the brand building. Following thesis will consist of a case study in collaboration with the clothing company NA- KD. The rapid growth of NA-KD will be explained by appropriate theoretical evidence, and not least by the co-founder himself. The modern way of marketing through social media with influencers will be investigated in light of various aspects. How cooperation with one or more influencers looks will be investigated in conjunction with how the strategy has helped NA-KD grow in a short period of time. Brand development and theories about a company's growth are two other important areas that will be studied in order for the thesis to have a relevant and well-reasoned conclusion. All theories presented will be linked to NA-KD’s own growth. The method chosen for the following thesis is of the qualitative type. The empirical collection will consist of an interview with a co-founder of the chosen company, NA-KD. Furthermore, the company's website and Instagram accounts will be observed, as well as four selected influencer's accounts that will also be observed. As well as secondary data such as the NA-KD annual report and a review of a few competitors will be presented. After analysis of the empiric data, clear conclusions emerged. Linkages between influencer marketing and growth became a clear fact. Likewise, cooperation between the companies and individuals was clarified. It was also clear that NA-KD was founded when influencers had already grown and had a major impact. Following thesis will be in Swedish.
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Tingare, Asmita. "The role of the KDM4 family histone 3 lysine 9 demethylases in hypertrophic remodelling of cardiac myocytes." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.648522.
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Santos, Bruno Marinho. "Extensões do metamodelo KDM para apoiar modernizações orientadas a aspectos de sistemas legados." Universidade Federal de São Carlos, 2014. https://repositorio.ufscar.br/handle/ufscar/593.
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Previous issue date: 2014-10-21Maintaining legacy systems is a complex and expensive activity for many companies. A recently proposal to solve this problem is Architecture-Driven Modernization (ADM), proposed by Object Management Group (OMG). The ADM consists of a set of concepts and standard metamodels that support systems modernization using models. The Knowledge Discovery Metamodel (KDM) is the main metamodel of ADM, it can represent many artifacts of a legacy system, such as source code, architecture, user interface, configuration files and business process. In general, legacy systems have crosscutting concerns, it can show source code problems like tangling and scattering, and it raises the maintenance costs. The aspect orientation is an alternative to improve crosscutting concerns modularization. Thus, in this dissertation is presented the term Aspect Oriented Modernization that uses the aspect oriented concepts in the ADM context. This modernization process consists in modularize legacy systems with aspects represented in model level. To achieve this goal, in this work were performed a lightweight and a heavyweight extension in the KDM metamodel, to analyze which one would present a better performance if used by Modernization Engineers. The evaluation of these extensions was performed by a case study that considered the modernization with aspects of a small-sized system. To evaluate the case study in both extensions, a set of comparison criteria were created to support the software engineers in choosing the best extension mechanism, according to their needs. In the context of this dissertation an experimental study were developed that aimed reproducing the scenarios that the modernization engineers had to perform maintenances and developing new refactorings in a aspect oriented KDM model. The experiment data considered the development time of the activities and the found number of errors. Finally, it was noticed that the extension mechanism to be choose will depend on the context that it will be applied, however, considering the approach studied here the best extension mechanism is the heavyweight one.
Manter sistemas legados é uma atividade complexa e onerosa para muitas empresas. Uma proposta recente para esse problema é a Modernização Dirigida à Arquitetura (Architecture-Driven Modernization - ADM), proposta pela OMG (Object Management Group). A ADM consiste em um conjunto de princípios e metamodelos padrões que apoiam a modernização de sistemas utilizando modelos. O Knowledge Discovery Metamodel (KDM) é o principal metamodelo da ADM, podendo representar diversos artefatos de um sistema, como código-fonte, arquitetura, interface de usuário, arquivos de configuração e processos de negócio. Em geral, sistemas legados possuem interesses transversais, apresentando problemas de entrelaçamento e espalhamento de código, o que eleva os custos de manutenção. A orientação a aspectos é uma alternativa para melhorar a modularização de interesses transversais. Mediante isso, neste trabalho é apresentado o termo Modernização Orientada a Aspectos que utiliza os conceitos da orientação a aspectos na ADM. Essa modernização consiste em remodularizar sistemas legados utilizando aspectos representados em nível de modelo. Para atingir esse objetivo, foi realizada uma extensão leve e outra pesada do metamodelo KDM, para analisar em qual das duas o desempenho dos engenheiros de modernização seria melhor. Para fazer a avaliação das extensões, foi realizado um estudo de caso levando em consideração a modernização com aspectos em um sistema de pequeno porte. Com o objetivo de avaliar o estudo de caso usando as duas extensões, foram desenvolvidos critérios de comparação que auxiliassem os engenheiros de software a escolher qual dos dois mecanismos de extensão utilizar em seu projeto. Foi feito também um estudo experimental que buscou reproduzir os cenários em que engenheiros de modernização tivessem que realizar manutenções e desenvolver novas refatorações em um modelo KDM orientado a aspectos. Os dados do experimento foram avaliados em relação ao tempo de desenvolvimento das atividades e quantidade de erros encontrados. Por fim, percebeu-se que o mecanismo de extensão a ser utilizado vai depender do contexto em que ele será aplicado, mas, para o domínio aqui estudado a extensão que melhor atendeu aos requisitos foi a pesada.
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Zhaunova, Liudmila. "Regulation of oocyte-specific chromatin organisation during prophase I by the histone demethylase Kdm5/Lid and other proteins." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/29007.
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In Drosophila oocytes, chromosomes undergo dynamic reorganisation during the prophase of the first meiotic division. This is essential to prepare chromatin for synapsis, recombination and consequent chromosome segregation. The progression of meiotic prophase I is well described, while the molecular mechanisms and regulation of these dramatic chromosomal reorganisations are not well understood. Histone modifying enzymes are major regulators of chromatin structure, however, our knowledge of their roles in meiotic prophase I is still limited. In this work, I investigated the role of the histone demethylase Kdm5/Lid, which removes one of the trimethyl groups at Lys4 of Histone 3 (H3K4me3). I showed that Kdm5/Lid is important for the assembly of the synaptonemal complex, pairing of homologous centromeres, and the karyosome formation. Additionally, Kdm5/Lid promotes crossing over and therefore ensures accurate chromosome segregation. Although loss of Kdm5/Lid dramatically increased the level of H3K4me3 in oocytes, catalytically inactive Kdm5/Lid rescued the above cytological defects. Thereby, I found that Kdm5/Lid regulates chromatin architecture in meiotic prophase I oocytes independently of its demethylase activity. To further identify the regulators of meiotic chromatin organisation during prophase I, I carried out a small-scale RNAi screen for karyosome defects. I found that depletion of ubiquitin ligase components, SkpA, Cul-3 and Ubc-6, disrupted the karyosome formation and the assembly of the synaptonemal complex. The success of the small-scale screen motivated me to initiate the genome-scale RNAi screen for karyosome defects. I found 40 new genes that, when depleted, strongly impaired karyosome morphology. Further studies are required to confirm and elucidate their role in chromatin organisation in oocytes. Overall, my findings have advanced our understanding of the regulation of chromatin reorganisation during oocyte development. Because of the conservation between Drosophila and human meiosis, this study provides novel insights into the regulation of meiotic progression in human oocytes.
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Armini, Monica. "Religionens plats i ett sekulärt politiskt landskap : Hur förhåller sig svensk kristdemokrati till det kristna över tid?" Thesis, Umeå universitet, Institutionen för idé- och samhällsstudier, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-184720.
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Detta arbete i religionsvetenskap har sökt finna svaret på hur svensk kristdemokrati harförändrats över tid med avseende på dess förhållande till begreppen kristen och kristendom.Källmaterialet har utgjorts av partiprogram, och dessa har undersökts för att ringa införekomst och kontext av ovan nämnda begrepp. Avsikten har varit att ta reda på partietsförhållningssätt till just det begrepp man en gång enades kring när man valde att ta sig anrikspolitiken — nämligen kristendomen. Dels görs en kvantitativ sammanställning, delsundersöks de sammanhang där orden används och om dessa har ändrats med åren. Följandearbete utgår från av KDS och KD utformade partiprogram från varje decennium sedan1960-talet och fram till 2015. Resultatet av studien visar att senare tiders KD har behållitkopplingen till det kristna i programtexterna, men att man har gått från en normativ kristenframtoning till en kristen etik av deskriptiv karaktär.2
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Zibetti, C. "ALTERNATIVE SPLICING AND PHOSPHORYLATION PROVIDE A MECHANISTIC BASIS FOR FUNCTIONAL SPECIALIZATION OF LSD1/KDM1 HISTONE DEMETHYLASE IN THE CENTRAL NERVOUS SYSTEM." Doctoral thesis, Università degli Studi di Milano, 2010. http://hdl.handle.net/2434/150261.
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Chromatin represents the physiological substrate of epigenetic regulation, underlying several biological processes, from replication and transcriptional activity to cell lineage commitment and adaptation in response to specific cues. In the central nervous system, chromatin integrates a plethora of converging signaling pathways, leading to short- and long-term changes in gene expression that are crucial for neuronal commitment, terminal differentiation and neuroplasticity throughout life. Although a variety of ubiquitously expressed chromatin-remodeling complexes assist tissue-specific transcription factors in mediating histotype-restricted transcriptional regulation, neuro restricted chromatin-remodeling factors have just been recently described.
Here, I report the identification of four mammal-specific variants of the histone demethylase LSD1 / KDM1 arising from combinatorial retention of two alternatively spliced exons, resulting in either ubiquitous isoforms or neuro-restricted ones, which are dynamically regulated during cortical development. The neuro-specific variants, whose functional diversification partly relies on the phosphorylation status, contribute to the acquisition of neurite morphology in an exclusive way.
The expression of LSD1 splice variants is particularly regulated during perinatal stages, with a progressive increase of LSD1 neuro-specific isoforms over the ubiquitous ones and the same LSD1 splice dynamics can be fairly recapitulated in cultured cortical neurons reflecting the early synaptic establishment. While LSD1 isoforms exhibit a comparable demethylase activity in vitro, the sole neuro-specific isoforms display an altered repressor activity on a reporter gene in cortical neurons, where their overexpression enhances neurite morphogenesis. Conversely, the imbalance of LSD1 isoforms that are devoid of the neurospecific exon elicits no morphogenic effect, indicating that the arousal of neuronal LSD1 isoforms pace-makes early neurite morphogenesis. The genome wide-location of LSD1 in cortical neurons by chromatin immunoprecipitation sequencing reveals its extensive role in the regulation of promoters related to developmental processes, pattern specification and forebrain organogenesis, as well as the control of cell fate decisions and calcium induced neuronal signaling, confirming its neurogenic implication.
Furthermore, for those genes where multiple binding locations can be found at short and long distance from the same transcriptional start site, a wide-range LSD1 regulatory role can be hypothesized, possibly related to enhancers function.
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Lopes, Daniel Barsi. "Juventude e cidadania: usos das mídias digitais na ONG Aldeia, em Fortaleza, e no projeto KDM, em Barcelona." Universidade do Vale do Rio dos Sinos, 2012. http://www.repositorio.jesuita.org.br/handle/UNISINOS/4156.
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FUNCAP - Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico
Esta pesquisa analisa os processos sociocomunicacionais tecidos pelos jovens quando eles deixam a condição de serem apenas audiência dos meios de comunicação e passam a ser, também, produtores de conteúdos midiáticos e gestores de políticas comunicacionais, através da atuação em projetos socioculturais que trabalham com a inserção cidadã de jovens em situação de exclusão, a partir dos usos das mídias digitais. Para dar conta disto, a pesquisa – de caráter qualitativo e desenvolvida sob uma perspectiva multimetodológica – realiza um estudo de dois casos específicos, nos quais se verificam essas relações entre as novas tecnologias da comunicação e as mobilizações coletivas. Os jovens informantes desta investigação participam da associação Aldeia, localizada em Fortaleza (Brasil), que trabalha com jovens moradores de periferia, em especial com rapazes e moças que vivem no Morro Santa Terezinha; e do projeto KDM, que se desenvolve em Barcelona (Espanha), e cujo foco de ação se volta para as relações de integração entre jovens migrantes e autóctonos. A pesquisa alicerça-se teoricamente a partir de determinados eixos: a construção social do conceito de juventude e a ambivalência que cerca esta faixa etária; a trajetória dos movimentos sociais e seu encontro com as questões identitárias e culturais; a concepção da comunicação cidadã, que se dá a partir da reconfiguração dos fluxos comunicacionais; a ampliação da noção de cidadania, para além dos direitos sociais, políticos e civis; e a centralidade das mídias digitais e suas relações com o exercício cidadão, potencializadas através da emergência dos receptores-produtores de comunicação. Três aspectos centrais são levantados com a investigação: 1) a complementaridade das mídias analógicas e digitais e das relações online e offline nas práticas cotidianas dos jovens pesquisados; 2) os sentidos de cidadania voltados para uma demanda de profissionalização e de inserção no mercado de trabalho; 3) a ausência de uma perspectiva mais crítica de leitura dos meios de comunicação e de análise das estruturas sociais, o que configura uma comunicação cidadã que não tem explorado todo o seu potencial de transformação das mídias e da sociedade.
This research analyzes the sociocommunicational processes produced by the young people when they leave the condition of being only part of the audience and start to be, as well, producers of mediatic content and managers of communicational policies, by acting in sociocultural projects that deal with citizenship insertion of young people in situation of social exclusion, through the use of digital medias. To achieve it, the research – qualitative and developed under a multimethodological perspective – studies two specific cases, where these relations between new communicational technologies and collective mobilizations can be identified. The protagonists of this investigation participate of Aldeia association, in Fortaleza (Brazil), that works with young inhabitants of unprivileged areas, specially with boys and girls that live in Morro Santa Terezinha; and of the Project KDM, developed in Barcelona (Spain), that focus the integration relations between young migrants and autochthonous. The research is theoretically based on determined axes: the social construction of the concept of youth and the ambivalence of this age group; the trajectory of social movements and its convergences with identity and cultural issues; the concept of citizen communication, by the reconfiguration of communicational flows; the extension of citizenship notions, beyond the social, political and civil rights; and the centrality of digital medias and its relations with the citizen exercise, potentiated through the emergency of communication receptors-producers. Three main aspects are presented with the investigation: 1) the complementarity of analogical and digital medias and the online and off-line relations in the daily practices of the researched young people. 2) The sense of citizenship turned to a demand of professionalization and insertion in the job market. 3) The lack of a more critical perspective on reading communicational means and analyzing social structures, which sets a citizen communication that doesn’t explore all its potential of transforming media and society.
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Durelli, Rafael Serapilha. "Uma abordagem para criação, reúso e aplicação de refatorações no contexto da modernização dirigida a arquitetura." Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/55/55134/tde-29092016-145938/.
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A Modernização Dirigida a Arquitetura (do inglês - Architecture-Driven Modernization (ADM)) é uma iniciativa do Object Management Group (OMG) no sentido de padronizar os tradicionais processos de reengenharia de software utilizando metamodelos. O metamodelo mais importante da ADM é o Knowledge Discovery Metamodel (KDM), cujo objetivo é representar todos artefatos de um determinado sistema, de forma independente de linguagem e plataforma. Um passo primordial durante processos de modernização de software é a aplicação de refatorações. No entanto, até o presente momento, há carência de abordagens que tratam das questões referentes a refatorações no contexto da ADM, desde a criação até a aplicação das mesmas. Além disso, atualmente, não existe uma forma sistemática e controlada de facilitar o reúso de refatorações que são específicas do KDM. Diante disso, são apresentados uma abordagem para criação e disponibilização de refatorações para o metamodelo KDM e um apoio ferramental que permite aplicá-las em diagramas de classe da UML. A abordagem possui dois passos: (i) o primeiro envolve passos que apoiam o engenheiro de modernização durante a criação de refatorações para o KDM; (ii) o segundo resume-se na especificação das refatorações por meio da criação de instâncias do metamodelo Structured Refactoring Metamodel (SRM) e posterior disponibilização delas em um repositório. O apoio ferramental, denominado KDM-RE, é composto por três plug-ins do Eclipse: (i) o primeiro consiste em um conjunto de Wizards que apoia o engenheiro de software na aplicação das refatorações em diagramas de classe UML; (ii) o segundo consiste em um módulo de propagação de mudanças, permitindo manter modelos internos do KDM sincronizados; (iii) o terceiro fornece apoio à importação e reúso de refatorações disponíveis no repositório. Além disso, o terceiro módulo também contém uma linguagem específica de domínio, a qual é utilizada para auxiliar o engenheiro de software a instanciar o metamodelo SRM. Foi realizado um experimento, buscando reproduzir os cenários em que engenheiros de software realizam refatorações em instâncias do metamodelo KDM. Os resultados mostraram que a abordagem, bem como o apoio ferramental podem trazer benefícios para o engenheiro de software durante a atividade de aplicação de refatorações em sistemas, representados pelo metamodelo KDM.Architecture Driven Modernization (ADM) is an initiative of the Object Management Group (OMG) whose main purpose is to provide standard metamodels that enable the conduction of modernization activities as reverse engineering and software transformation. In this context, the most important metamodel is the Knowledge Discovery Metamodel (KDM), whose objective is to represent software artifacts in a language- and platform-agnostic fashion. A fundamental step during software modernization is refactoring. However, there is a lack of approaches that address how refactoring can be applied in conjunction with ADM. In addition, few efforts have investigated how refactorings can be reused and systematically applied within the context of KDM representations. We propose an approach for creating and cataloging refactorings tailored to KDM. Our approach is twofold: (i) the first part comprises steps that help the software modernization engineer create KDM-compliant refactorings; (ii) the second part has to do with turning these refactoring descriptions into Structured Refactoring Metamodel (SRM) and making them available to be reused. To automate these activities, we developed a tool that makes it possible to apply refactorings to Unified Modeling Language (UML) class diagrams. Our tool, named KDM-RE, comprises three Eclipse plug-ins, which can be briefly described as follows: (i) a set of Wizards aimed at supporting the software modernization engineer during refactoring activities; (ii) a change propagation module that keeps the internal metamodels synchronized; and (iii) a plug-in that supports the selection and reuse of the refactorings available in the repository. Moreover, we developed a domain specific language to minimize the effort required to instantiate SRMs. We carried out an evaluation that simulates how software modernization engineers would go about refactoring KDM instances. Our results would seem to suggest that our approach, when automated by our tool, provides several advantages to software modernization engineers refactoring systems represented by KDMs.
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Granberg, Caroline. "Socioeconomic and sociodemographic differentials in pregnant women’s knowledge on prevention of mother-to-child HIV transmission in Kenya: A cross-sectional study from 2008-09 KDHS." Thesis, Uppsala universitet, Internationell mödra- och barnhälsovård (IMCH), 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-253890.
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Background: Human immunodeficiency virus (HIV) is a global public health issue. One way of transmission is through mother-to-child transmission (MTCT). There are ways to prevent this and one option is to give the mother special drugs during pregnancy, delivery or afterwards. Socioeconomic and sociodemographic factors can potentially affect the knowledge women have about prevention of mother-to-child transmission (PMTCT). Objective: The aim of this secondary analysis was to explore which socioeconomic and sociodemographic factors are associated with pregnant women’s knowledge about PMTCT. Methods: Secondary data obtained from Kenyan Demographic and Health Surveys from 2008-09 were used, n=524. Variables investigated were marital status, education level, HIV status, religion, type of residence, occupation and wealth quintile and their association to the outcome, knowledge about prevention of mother-to-child transmission. They were tested by means of logistic regression analysis. Results: Results showed that higher level of education and belonging to a higher level of wealth quintile were significantly associated with having knowledge about PMTCT. All categories for education showed a significant difference in the adjusted model I and for wealth quintile, only richer and richest category showed a significant difference, also in the adjusted model I. Over all, 74% did have knowledge about PMTCT. Conclusion: There are socioeconomic differentials in knowledge about PMTCT. Knowing which women have the least knowledge about PMTCT makes it is easier to know which women to target to be able to increase the knowledge among the population with high prevalence of HIV in low- and middle income countries.
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Fassauer, Georg Michael [Verfasser], Andreas [Akademischer Betreuer] Link, Andreas [Gutachter] Link, and Gerhard [Gutachter] Scriba. "Modulatoren epigenetischer Regulationsmechanismen: Medizinische Chemie neuer KDM4-Inhibitoren und Methodenentwicklung zur SFC-MS-Analytik von Ketaminmetaboliten / Georg Michael Fassauer ; Gutachter: Andreas Link, Gerhard Scriba ; Betreuer: Andreas Link." Greifswald : Ernst-Moritz-Arndt-Universität, 2018. http://d-nb.info/1170321658/34.
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Stenstad, Victoria. "Konsumenternas krav på varumärket: Prata med oss, ge oss erbjudanden och inspirera : En kvantitativ studie om svenska kvinnors konsumtionsvanor, upplevelser och åsikter kopplat till NA-KD’s innehåll på Instagram." Thesis, Högskolan i Gävle, Media- och kommunikationsvetenskap, 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:hig:diva-33267.
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The purpose of the study is to investigate the respondents’ consumption habits, experiences and opinions linked to NA-KD’s content on Instagram, to see which of the four communication models within PR (Grunig & Hunt 1984) that are reflected in their experiences, opinions and consumption. Method: The study is based on a quantitative web survey, which was answered by Swedish women, aged 16-35, who follows @nakdfashion on Instagram. They answered questions about their consumption of the content as well as their experiences and opinions on how NA-KD communicates with their followers. Result / analysis: The majority of respondents are "passive" consumers in the interaction with NA-KD on Instagram. The main reasons why they consume NA-KD's content are to get offers, coupons and to get inspiration. While their experiences reflects Grunig & Hunt’s asymmetric communication model, their opinions show more of the symmetric model. Conclusion: The respondents' experiences and opinions about how the communication takes place / should take place do not match. The result indicates an existing imbalance in power between transmitter and receiver in the communication process. In practice, the respondents do not seem to mind it as long as NA-KD meets their needs, which are mainly inspiration and offers.
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Di, Francesco Nathalie. "Early Childhood Educators' Knowledge of Developmental Milestones (KDM) and Appropriate Play Materials (KPM) in Relation to their Developmentally Appropriate Practices (DAP) in Child Care Centres in Quebec." Thèse, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/19959.
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The quality of early childhood education and care programs greatly impacts children’s development and well being. The classroom environment, program content and approach and early childhood educators’ characteristics are some of the elements that influence quality and thus have effects on young children’s development. Past research has indicated that early childhood education and care programs in Quebec have received on average low/minimal or mediocre ratings of quality and were also found to lack developmentally appropriate play materials (Drouin, Bigras, Fournier, Desrosiers, & Bernard, 2004; Goelman et al., 2006; Japel, Tremblay, & Cote, 2005).
The present study set out to explore elements that may influence the quality of child care classrooms in the province of Quebec. Early childhood educators’ knowledge and developmentally appropriate practice (DAP) were examined to determine the relationship between these elements. Early childhood educators’ knowledge of developmental milestones (KDM) and knowledge of appropriate play materials (KPM) were found to be weak but educators reported strong developmentally appropriate beliefs (BDAP) and practices (PDAP).
Results demonstrated positive correlations between early childhood educators’ declarative knowledge of developmental milestones (KDM), knowledge of appropriate play materials (KPM) and their beliefs and practices of developmentally appropriate practice (BDAP and PDAP). Educators’ levels of declarative KDM were positively correlated with their level of declarative KPM. In addition, educators’ BDAP was positively correlated with their level of declarative KPM, but their reported DAP was not linked to their level of KDM. Implications for the field of ECEC as well as early childhood education programs in CEGEPs and Universities in Quebec and across Canada are discussed in light of the study’s findings and limitations.
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Honda, Raphael Rodrigues. "Modelagem e cômputo de métricas de interesse no contexto de modernização de sistemas legados." Universidade Federal de São Carlos, 2014. https://repositorio.ufscar.br/handle/ufscar/587.
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Previous issue date: 2014-10-13Universidade Federal de Sao Carlos
Maintaining legacy systems is a complex and expensive activity for many companies. An alternative to this problem is the Architecture-Driven Modernization (ADM), proposed by the OMG (Object Management Group). ADM is a set of principles that support the modernization of systems using models. The Knowledge Discovery Metamodel (KDM) is the main ADM metamodel and it is able to represent various characteristics of a system, such as source code, configuration files and GUI. Through a reverse engineering process supported by tools is possible to extract knowledge from legacy source code and store it in KDM metamodel instances. Another metamodel that is important to this project is the Structured Metrics Metamodel (SMM) that allows the specification of metrics and also the representation of the measurements results performed on KDM models. When we decide to modernize a legacy system, an alternative that aims to improve concerns modularization of a system is the Aspect-Oriented Programming. Considering this alternative, the main goal of this project is to present an approach to defining and computing concern metrics in instances of KDM metamodel. This kind of measurement needs a prior concern mining that make notes on system components indicating concerns which it implements. To achieve the project objective, a complete approach to measure concerns using ADM models was developed, this approached is composed by an extension of KDM metamodel for representing Aspect- Oriented Software (AO-KDM), a concern metrics library in SMM format (CCML) developed in order to be parameterized by the Modernization Engineer. Therefore, the metrics defined in this project can be reused in other projects. Furthermore, we have developed a tool (CMEE) capable of handling parameterization annotations (notes about concerns made by the mining tools) that allows that models annotated by different mining tools could be measured by SMM metrics.
Manter sistemas legados é uma atividade complexa e cara para muitas empresas. Uma alternativa para este problema é a Modernização Dirigida à Arquitetura (Architecture- Driven Modernization - ADM), proposta pelo OMG (Object Management Group). A ADM consiste em um conjunto de princípios que apoiam a modernização de sistemas utilizando modelos. O Knowledge Discovery Metamodel (KDM) é o principal metamodelo da ADM e é capaz de representar diversas características de um sistema, como código-fonte, arquivos de configuração e de interface gráfica. Por meio de um processo de engenharia reversa apoiado por ferramentas é possível extrair conhecimento do código-fonte legado e armazená-lo em instâncias do metamodelo KDM. Outro metamodelo da ADM pertinente a este projeto é o Structured Metrics Metamodel (SMM) que torna possível a especificação de métricas e também a representação dos resultados de medições realizadas em modelos KDM. Quando decide-se modernizar um sistema legado, uma alternativa que procura melhorar o nível de modularização dos interesses de um sistema é a orientação a aspetos. Considerando essa alternativa, o objetivo deste projeto é apresentar uma abordagem para definição e aplicação de métricas de interesse em instâncias do metamodelo KDM. Esse tipo de medição precisa de uma mineração de interesses prévia, que realiza anotações nos componentes do sistema indicando qual interesse ele implementa. Para alcançar o objetivo do projeto, foi desenvolvida uma abordagem completa de medição de interesses utilizando modelos da ADM, composta por uma extensão do KDM para a representação de software orientado a aspectos (AO-KDM), uma biblioteca de métricas de interesses no formato SMM (CCML) desenvolvida com o intuito de ser parametrizável pelo Engenheiro de Modernização. Portanto, as métricas definidas neste projeto podem ser reusadas em outros projetos. Além disso, foi desenvolvida uma ferramenta de apoio computacional (CMEE) capaz de lidar com parametrização de anotações (anotações de interesses realizadas por ferramentas de mineração) que permite que modelos anotados com diferentes ferramentas de mineração possam ser medidos por métricas SMM.
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Boullosa, Allariz Beatriz. "Déshydratation naturelle et mécanisée de sédiments : étude des processus mis en jeu et applications." Thesis, Normandie, 2018. http://www.theses.fr/2018NORMC285/document.
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Les opérations de dragage génèrent d’importants volumes de sédiments à teneur en eau élevée qui sont difficilement transportables. Toute opération de valorisation ou stockage des sédiments implique de réduire la teneur en eau. Le séchage naturel et la déshydratation mécanisée des sédiments répondent à cette attente. Le séchage naturel des sédiments est la technique de déshydratation la plus économique et la meilleure du point de vue environnemental. Le temps de séchage peut être réduit par des moyens techniques adaptés (retournement, scarification) mis en action par l'application de critères d’aptitude au séchage naturel. Pour ce faire, le processus de séchage naturel a été reproduit à l’échelle du laboratoire à l’aide d’essais d’Égouttage et de Séchage et d’essais de Séchage et de Retrait couplés à des essais scissométriques. Ils ont porté sur neuf sédiments : sept sédiments de barrage, deux sédiments marins et une kaolinite. Une relation Su=f(IP) a été établie. Cette relation permet d’obtenir la cohésion non drainée Su à partir d’une mesure de teneur en eau. Elle permet aussi de définir ou cerner le moment le plus propice au retournement des sédiments à l’aide d’engins spécifiques sur site. Une autre méthode mécanique pour réduire le temps de séchage est suggérée. Il s'agit de pratiquer une scarification des sédiments à l’aide d’outils mobiles, voire robotisés, comme un rouleau scarificateur ou d'une rangée d'outils transportés par un treillis mobile adapté. En ce qui concerne la déshydratation mécanisée des sédiments, une nouvelle méthode de déshydratation en continu a été proposée à partir d'une presse à boues KDS®. Pour des raisons de conception et d'application, la presse à boues KDS® n’a jamais été utilisée pour déshydrater des sédiments. Un plan expérimental a été développé. Il est démontré que la presse KDS® est capable de déshydrater un sédiment fin sableux sans une maintenance démesurée. Des adaptations de la presse KDS® à la déshydratation de sédiments et des améliorations sont finalement proposéesDredging operations produce large amounts of sediments with high water content, that are difficult to handle. Storage management and future reuses need to reduce the water content of sediments. Natural and mechanical dewatering of sediments meet this need. The most economic and eco-friendly method of dewatering is natural dewatering. Dewatering period can be reduced with suitable technical means such as adapted plough or scarifier for sediments, operating under defined dewatering criteria. The natural dewatering process was investigated and reproduced at the laboratory scale by performing Natural dewatering test and Shrinkage test coupled with shear measurements (vane shear testing). Nine sediments have been considered: seven dam sediments, two marine sediments and a kaolinite clay. A relationship Su = f(IP) has been established. It allows to deduce the undrained shear strength Su from only a measurement of water content. It allows to state on the right moment to put in operation the specific tools for ploughing and returning over or scarifying sediments stored. These tools can move in the sediments (adapted plough) or roll on the sediments (scarifiying roller) or roll on banks of sediment storage basin. Another way to dewater high water content sediments concerns a mechanical device. Thus a new method of continuous dewatering has been investigated using a prototype machine patented and referenced as KDS® sludge press. This type of press was not adapted for dewater sediments. Full of dewatering tests have been undertaken and performed with this prototype concerning some of sediments (see natural dewatering testing) and sandy clayey mixtures. It has been shown that KDS® press is able to dehydrate sediments including fine sandy sediments without excessive maintenance. Some adaptations and improvements of KDS® press to dewatering sediments are finally suggested
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Wang, Zhuo. "Genetic studies of genes involved in the initiation of DNA replication in the fission yeast Schizosaccharomyces pombe." Wright State University / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=wright1284475548.
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Brunet, Johansson Albert. "Kristen värdegrund : En studie av Kristdemokratiska samhällspartiets utbildningspolitiska ställning i frågan om konfessionella friskolor åren 1984-1994." Thesis, Umeå universitet, Institutionen för idé- och samhällsstudier, 2018. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-157142.
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This study has investigated how the Swedish Christian Democratic Party (KDS) argued for the right of private actors to operate tax-funded schools outside of the public sector – charter schools. The hypothesis of this study was that KDS were openly positive to such a reform and saw it as a chance to run state-funded confessional schools.The study examined political texts produced by the party during a ten-year period, ranging from 1984 to 1994. The study’s methodological approach was one of a qualitative textual analysis, aided by a theoretical framework adapted from Samuel Moyn’s thesis in his book Christian Human Rights.The study concluded that there is empirical support to the thesis, and that KDS were very positive to a reform of the public school system in order to enable publicly funded private schools. There is less evidence to conclude that KDS intended for these schools to be confessional, although this study proposes that there is evidence to suggest as much.
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Dedeurwaerder, Sarah. "Biological and clinical relevance of epigenetic modifications in human breast cancers." Doctoral thesis, Universite Libre de Bruxelles, 2011. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209896.
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It is increasingly recognized by the scientific community that the field of epigenetics is a key step for a better understanding of human biology in both normal and pathological states. Its implication in cancer, and in particular in breast cancer, is now well accepted. Breast cancer, responsible for more than 450,000 deaths worldwide yearly, is a heterogenous disease at the histological and clinical levels as well as at the molecular level. Despite considerable efforts to develop new treatments and improve patient management, patients with a same “profile” of breast cancer can respond differently to therapies and have completely different clinical outcomes. There is therefore a critical need to improve our understanding of breast cancer biology and diversity, in order to find new markers that should provide a better management of patients and the development of new therapies. An increasing number of biologists, pathologists as well as clinicians are currently working towards these goals. During my PhD, we have conducted two studies in order to gain new insights into the contribution of epigenetics in breast cancer biology.In the first study, by performing large genome-scale DNA methylation profiling of numerous breast tumors as well as of normal breast tissues, we first revealed the existence of six groups of breast tumors based on their DNA methylation profiles. Three of these groups showed a strong association with the basal-like, HER2 and luminal A breast cancer subtypes, previously identified by gene expression profiling. Interestingly, the three other groups were found to be a mixture of several gene expression-based subtypes, thus revealing the capacity of DNA methylation profiling to improve breast tumor taxonomy. Second, our study suggests that the establishment of DNA methylation patterns of breast tumors might help to determine their cell type of origin. Finally, we also showed that DNA methylation profiling can reflect the cell type composition of the tumor microenvironment and that a signature of T cell tumoral infiltration is associated with a good prognosis in particular categories of breast cancer patients.
In the second study, we revealed the clinical relevance of the KDM5 histone demethylases in breast cancer. The expression of these histone demethylases was deregulated in the analyzed breast tumors as well as in the pre-invasive samples as compared to normal breast samples. This suggests that KDM5 enzymes might be good markers for early diagnosis of breast cancer. Moreover, we showed a prognostic value of the KDM5C histone demethylase.
In conclusion, the above data should provide a better understanding of breast cancer biology and diversity, and this should bring new insights to improve breast cancer patient management.
Doctorat en Sciences biomédicales et pharmaceutiques
info:eu-repo/semantics/nonPublished
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Krůpa, Tomáš. "Univerzální zavaděč pro mikrokontrolér Kinetis K60." Master's thesis, Vysoké učení technické v Brně. Fakulta informačních technologií, 2016. http://www.nusl.cz/ntk/nusl-255480.
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The scope of this work was to design a bootloader for Kinetis K60, an ARM Cortex-M4 microcontroller. The bootloader should simplify the process of loading user applications to the flash memory of the microcontroller on the Minerva development kit. Based on a quick research of existing bootloader solutions, new bootloader was designed together with communication protocol that would suit the needs for transfer of both the file data and configuration information through all the supported communication interfaces - USB, SDHC, Ethernet and RS-232. On the PC side, development of bootloader’s application library and two supporting utilities with graphical and command line interfaces was made. The system can be used out of the box as well as it can be further extended in the future.
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Santibáñez, Daniel Gustavo San Martín. "Mineração de interesses no processo de modernização dirigida a arquitetura." Universidade Federal de São Carlos, 2013. https://repositorio.ufscar.br/handle/ufscar/549.
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Previous issue date: 2013-08-27Universidade Federal de Sao Carlos
Software systems are considered legacy when they were developed many years ago with outdated technologies and their maintenance process consumes a large amount of resources. One cause of these problems is the inadequate modularization of its crosscutting concerns. In this situation, an alternative is to modernize the system with a new language to provide better support for concern modularization. ADM (Architecture-Driven Modernization) is an OMG model-driven proposal to modernize legacy systems and consist of a set of metamodels in which the main metamodel is KDM (Knowledge Discovery Metamodel), which allows to represent all the characteristics of a system. The modernization process begins with reverse engineering to represent the legacy system in a KDM model. Thereafter, refactorings can be applied to the model and then generate the modernized code. However, the current proposals do not support crosscutting concerns modularization. This occurs because the first step is to identify the elements which contribute with the implementation of a particular concern and it is not supplied by ADM. In this sense, this dissertation presents an approach for mining crosscutting concerns in KDM models, thus establishing the first step towards to a Concern-Driven modernization. The approach is a combination of two techniques, a concern library and a modified K-means clustering algorithm, which comprises four steps where the input is a KDM model and the result is the same KDM model with annotated concerns and some log files. In addition, we developed an Eclipse plugin called CCKDM to implement the approach. An evaluation was performed involving three software systems. The results show that for systems using APIs to implement their concerns the developed technique is an effective method for identifying them, achieving good values of precision and recall.
Sistemas de software são considerados legados quando foram desenvolvidos há muitos anos com tecnologias obsoletas e seu processo de manutenção consome uma quantidade de recursos além da desejada. Uma das causas desses problemas é a modularização inadequada de seus interesses transversais. Quando se encontram nessa situação, uma alternativa é modernizar o sistema para novas linguagens que forneçam melhor suporte à modularização desse tipo de interesse. A ADM (Architecture-Driven Modernization) é uma proposta do OMG para a modernização orientada a modelos de sistemas legados, sendo composta por um conjunto de metamodelos, em que o principal é o KDM (Knowledge Discovery Metamodel), que permite representar todas as particularidades de um sistema. O processo de modernização inicia-se com a engenharia reversa, em que o sistema legado é inteiramente representado em KDM. Depois disso, pode-se aplicar refatorações nesse modelo e gerar o código modernizado. Entretanto, a proposta atual da ADM não inclui suporte para modularizar interesses transversais de um sistema. Isso ocorre porque o primeiro passo desse processo é minerar e encontrar os elementos que contribuem para a implementação de um dado interesse, e isso não é fornecido pela ADM. Nesse sentido, nesta dissertação é apresentada uma abordagem para mineração de interesses no metamodelo KDM, estabelecendo o primeiro passo para um processo de modernização dirigido a interesses. A abordagem de mineração proposta atua com uma combinação de duas técnicas; uma biblioteca de interesses e um algoritmo modificado K-means para agrupar strings similares. A abordagem inclui quatro passos onde a entrada é um modelo KDM e o resultado é o mesmo modelo KDM com os interesses anotados e mais alguns arquivos de registro. Além disso, desenvolveuse um plugin chamado CCKDM para o ambiente Eclipse que implementa a abordagem. Uma avaliação foi realizada envolvendo três sistemas de software. Os resultados da avaliação mostraram que para sistemas que utilizam APIs para implementar seus interesses a técnica desenvolvida é efetiva para a identificação deles, atingindo bons valores de precisão e cobertura.
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楊所芳. "The Role of KDM8 in Breast Cancer Cells: Cell Proliferation and Migration." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/15474248973694324183.
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Lin, Tung-Yueh, and 林東岳. "Discovery and Modification of KDM4 Inhibitors in Castration-Resistant Prostate Cancer Treatment." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/zytbkf.
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Lin, Chun-Pu, and 林均璞. "KDM8, an H3K36me2 Histone Demethylase, Regulates Normoxia and Hypoxia Mediated Breast Cancer Cell Proliferation." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/83500026616238105727.
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碩士國立清華大學
分子與細胞生物研究所
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Methylation/demethylation of histone tail, one of the major post-translational modifications (PTMs) in chromatin, plays an important role in chromatin remodeling to regulate gene expression. Dysregulation of these processes links to carcinogenesis. KDM8 (Jmjd5), an H3K36me2 histone demethylase containing jmjC domain, is crucial to regulate embryonic development, osteoclastogenesis and cell proliferation. Along with its general over expression in breast cancer, KDM8 is suggested to play a role in carcinogenesis. Swiftly proliferating cancer cells that encounter intermittent hypoxia trigger the expression of a master regulator, Hypoxia-inducible factor (HIF). We have previously found that KDM8 interacted with HIF1-α and was up-regulated under hypoxia (by Dr. Hung-Jung Wang). Moreover, knockdown KDM8 inhibited breast cancer cell metastasis (by So-Fang Yang). In this study, we aim to address the mechanism in which KDM8 is involved in cell proliferation under hypoxia, as well as tumor metastasis. A significantly reduced level of cell proliferation was found in KDM8 knockdown cells, especially when these cells were cultured under hypoxia. Knockdown cells were arrested in both G1/S and G2/M phases. Several cell cycle transition regulatory proteins including cyclins, cyclin-dependent kinases (CDKs), and cyclin-CDK complex inhibitors were affected accordingly. Moreover, KDM8 knockdown cells significantly lost hypoxia-induced c-Myc and p53 transactivation activity. And several epithelial mesenchymal transition inducers which belong to downstream targets of canonical Wnt signaling exhibited a lower level of expression, suggesting a link to hypoxia-induced Wnt signaling pathway.
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Tilsch, Jan. "Proces s "vedením ilegální protistátní skupiny KDS" v roce 1955 a procesy s ním spojené." Doctoral thesis, 2015. http://www.nusl.cz/ntk/nusl-349344.
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Main Content of this Work is to describe in detail Part of political Trials in Czechoslovakia during the first Part of 1950's, focused against political Opponents coming from Czechoslovak People's Party (ČSL) or Roman Catholic. The Topic - political Trial with "Leaders of illegal anti-state Group Christian-Democratic Party (KDS)" in 1955 and related Trials - is almost unprocessed. The Goal of this Work is to sketch long-lasting "crusade", managed by the communist Power, against "virtual political Entity KDS". This "crusade" should culminate by public political Trial with Leaders of KDS. I'd like to focus on Secret state Police (StB) and its searching of Leaders of KDS, showing the Mechanism of anti-state Groups' Construction too. During the final Part I'd like to show continuance of struggle against other Groups of KDS after the Year 1955 until 1960's and introduce real activities of KDS' Leaders.
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HWANG, SUNHEE. "Efforts to Elucidate the Binding Interaction between Lysine-Specific Demethylase 1 (LSD1/KDM1) and CoREST and Their Roles in Breast Cancer." Diss., 2012. http://hdl.handle.net/10161/5821.
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Histone modifications play important roles in regulating gene expression in various cellular processes by altering the underlying chromatin structure and thus influencing related pathological conditions. Histone methylation is one such modification that was thought to be static and enzymatically irreversible until the recent discovery of histone demethylases. Lysine specific demethylase 1 (LSD1) is a unique histone demethylase that removes methyl groups on lysine residues and mediates expression of many genes important in cancer progression. LSD1 activity and its substrate specificity are mainly regulated by association with a number of co-regulatory proteins. CoREST is one such important binding protein that endows LSD1 with the ability to associate with and demethylate nucleosomal substrates.
Given the significance of CoREST in directing LSD1 activity, herein we report our efforts to regulate LSD1 enzymatic activity by modulating its binding interaction with CoREST in order to provide a new means to inhibit the demethylation activity of LSD1 and thereby suggest a novel therapeutic intervention for breast cancer where LSD1 is implicated. Towards this end, initial steps have been taken to elucidate the molecular basis of the binding interaction between LSD1 and the functional region of CoREST, denoted as CoREST286-482 , by conducting isothermal titration calorimetry (ITC) studies. We found that the proteins tightly interact in a 1:1 stoichiometric ratio with a dissociation binding constant (Kd) of 15.9 ± 2.07 nM, and that their binding interaction is characterized by a favorable enthalpic contribution near room temperature with a smaller entropic penalty at pH 7.4. Furthermore, we defined that the linker region of CoREST286-482 is a key determinant for the tight binding interaction toward LSD1. Accordingly, the peptide corresponding to the linker region of CoREST286-482 (designated as the Linker peptide) was used as a potent competitive modulator of the binding interaction between LSD1 and CoREST286-482 with our expectation that the Linker peptide will compete with CoREST286-482 for binding to LSD1 and thus sequester LSD1 from nucleosomal contexts to inhibit its demethylation activity.
Indeed, the Linker peptide has shown successful inhibitory activity against the binding of LSD1 to CoREST286-482 at nanomolar concentration. We evaluated the potential of the Linker peptide to inhibit LSD1 demethylation activity in cellular models of estrogen receptor a (ERa)-positive breast cancer cell line (MCF7) where LSD1 is known to co-localize with ERa and affect ERa-transcription activities. We were able to observe that the disruption of the binding interaction between LSD1 and CoREST by the Linker peptide affects not only the demethylation activity of LSD1 on both H3K4 and H3K9 but also the ERa-recruitment to promoters of target genes and processes required for proliferation of breast cancer cells. Thus it is believed that LSD1 demethylation activity through its physical and functional interaction with CoREST is essential in the development of ERa-positive breast cancer. Furthermore, we have observed that not LSD1 but CoREST physically interacts with ERa, which suggests a potential role of CoREST as a bridge connecting LSD1 to ERa. At the moment although the precise mechanisms underlying the implication of LSD1 through CoREST interaction in ERa-positive breast cancer still remain elusive, our study has verified that modulating LSD1 enzymatic activity by interrupting a critical protein-protein interaction offers a distinctively new avenue of inhibition of LSD1 activity, which has anti-cancer potential.
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Gronau, Marny [Verfasser]. "Prognosefaktoren für die Entscheidung mono- oder bignather Eingriffe in der orthognathen Chirurgie hinsichtlich der Modell-OP mit dem KDMMS-System / vorgelegt von : Gronau, Marny." 2010. http://d-nb.info/1010015060/34.
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