919 resultados para Sacred-secular divide
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Mitosis is under the stringent quality control of the spindle assembly checkpoint (SAC). However, in cancer cells this control can fail, leading to excessive cellular proliferation and ultimately to the formation of a tumor. Novel cancer cell selective therapies are needed to stop the uncontrolled cell proliferation and tumor growth. The aim of the research presented in this thesis was to identify microRNAs (miRNAs) that could play a role in cancer cell proliferation as well as low molecular weight (LMW) compounds that could interfere with cell division. The findings could be used to develop better cancer diagnostics and therapies in the future. First, a high-throughput screen (HTS) was performed to identify LMW compounds that possess a similar chemical interaction field as rigosertib, an anti-cancer compound undergoing clinical trials. A compound termed Centmitor-1 was discovered that phenocopied the cellular impact of rigosertib by affecting the microtubule dynamics. Next, another HTS aimed at identifying compounds that would target the Hec1 protein, which mediates the interaction between spindle microtubules and chromosomes. Perturbation of this connection should prevent cell division and induce cell death. A compound termed VTT-006 was discovered that abrogated mitosis in several cell line models and exhibited binding to Hec1 in vitro. Lastly, using a cell-based HTS two miRNAs were identified that affected cancer cell proliferation via Aurora B kinase, which is an important mitotic regulator. MiR-378a-5p was found to indirectly suppress the production of the kinase whereas let-7b showed direct binding to the 3’UTR of Aurora B mRNA and repressed its translation. The miRNA-mediated perturbation of Aurora B induced defects in mitosis leading to abnormal chromosome segregation and induction of aneuploidy. The results of this thesis provide new information on miRNA signaling in cancer, which could be utilized for diagnostic purposes. Moreover, the thesis introduces two small compounds that may benefit future drug research.
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The molecular functions of the non-cell cycle-related Cyclin-dependent kinase 5 (Cdk5) have been of primary interest within the neuroscience field, but novel undertakings are constantly emerging for the kinase in tissue homeostasis, as well as in diseases such as diabetes and cancer. Although Cdk5 activation is predominantly regulated by specific non-cyclin activator protein binding, additional mechanisms have proved to orchestrate Cdk5 signaling in cells. For example, the interaction between the intermediate filament protein nestin and Cdk5 has been proposed to determine cellular fate during neuronal apoptosis through nestin-dependent adjustment of the sensitive balance and turnover of Cdk5 activators. While nestin constitutes a crucial regulatory scaffold for appropriate Cdk5 activation in apoptosis, Cdk5 itself phosphorylates nestin with the consequence of filament reorganization in both neuronal progenitors and differentiating muscle cells. Interestingly, the two proteins are often found coexpressed in various tissues and cell types, proposing that nestin-mediated scaffolding of Cdk5 and its activators may be applicable to other tissue systems as well. In the literature, the molecular functions of nestin have remained in the shade, as it is mostly exploited as a marker protein for progenitor cells. In light of these studies, the aim of this thesis was to assess the importance of the nestin scaffold in regulation of Cdk5 actions in cell fate decisions. This thesis can be subdivided into two major projects: one that studied the nature of the Cdk5-nestin interplay in muscle, and one that assessed their role in prostate cancer. During differentiation of a myoblast cell line, the filament formation properties of nestin was found to be crucial in directing Cdk5 activity, with direct consequences on the process of differentiation. Also the genetic knockout of nestin was found to influence Cdk5 activity, although differentiation per se was not affected. Instead, the genetic ablation of nestin had broad consequences on muscle homeostasis and regeneration. While the nestin-mediated regulation of Cdk5 in muscle was found to act in multiple ways, the connection remained more elusive in cancer models. Cdk5 was, however, established as a significant determinant of prostate cancer proliferation; a behavior uncharacteristic for this differentiation-associated kinase. Through complex and simultaneous regulation of two major prostate cancer pathways, Cdk5 was placed upstream of both Akt kinase and the androgen receptor. Its action on proliferation was nonetheless mainly exerted through the Akt signaling pathway in various cancer models. In summary, this thesis contributed to the knowledge of Cdk5 regulation and functions in two atypical settings; proliferation (in a cancer framework) and muscle differentiation, which is a poorly understood model system in the Cdk5 field. This balance between proliferation and differentiation implemented by Cdk5 is ultimately regulated (where present) by the dynamics of the cytoskeletal nestin scaffold.
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No Brasil, a partir da última década do século XIX, com a organização republicana da instrução pública, observa-se o início de um movimento de escolarização das práticas de leitura e escrita e de identificação entre o processo de ensino inicial dessas práticas e a questão dos métodos. A partir de então, a cartilha vai-se consolidando como um imprescindível instrumento de concretização dos métodos propostos e, em decorrência, de configuração de determinado conteúdo de ensino, assim como de certas silenciosas, mas operantes, concepções de alfabetização, leitura, escrita e texto, cuja finalidade e utilidade se encerram nos limites da própria escola e cuja permanência se pode observar até os dias atuais. O objetivo deste artigo é, mediante análise dessas questões, problematizar a relação entre cartilha de alfabetização e cultura escolar e seus desdobramentos na história da educação e da alfabetização em nosso país.
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Addiction, and the experience of being addicted, is notoriously difficult to describe verbally and explain rationally. Would multifaceted and multisensory cinematic images work better in making addiction understandable? This study enquires how cinematic expression can render visible the experience of being addicted which is invisible as such. The basic data consists of circa 50 mainly North American and European fiction films from the early 1900s to the early 2000s that deal with addictive disorders as defined in the psychiatric DSM-V classification (substance dependence- and gambling disorders). The study develops an approach for analyzing and interpreting a large volume of digital film data: digital cinematic iconography is a framework to study the multifaceted cinematic images by processing and viewing them in the “digital image-laboratory” of the computer. Images are cut and classified by editing software and algorithmic sorting. The approach draws on early 1900s German art historian Aby Waburg’s image research and media archaeology, that are connected to film studies inspired by the phenomenology of the body and Gilles Deleuze’s film-philosophy. The first main chapter, “Montage”, analyses montage, gestural and postural images, and colors in addiction films. The second main chapter, “Thingness”, focuses on the close-ups of material objects and faces, and their relation to the theme of spirituality in cinema and art history, The study argues that the cinema engages the spectator to "feel" what addiction is through everyday experience and art historical imagery. There is a particular, historically transmitted cinematic iconography of addiction that is profane, material, thing-centered, abject, and repetitive. The experience of being addicted is visualized through montages of images characterized by dark and earthy colors, horizontal compositions and downward- directed movements. This is very profane and secular imagery that, however, circulates image-historical traces of Christian iconography, such as that of being in the grip of an unknown power.
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This arts-based thesis, written from my perspective as a Manitoba Mennonite woman and English Language Arts educator, is a memoir of books and reading. As a voracious reader, I am dismayed by the general perception of literacy in public schools as being a set of measureable tasks, and I have found that reading, in particular, has become divorced from its traditional link to life-giving and sacred things. In this thesis, I used life writing to share some of my reading history to illustrate, in part, the degree to which books may enrich our lives by helping us understand the past, present, and future - but only if we allow them to do so.
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This qualitative study explores Thomas Green's (1999) treatise, Voices: The Educational Formation of Conscience; for the purpose of reconstruing the transformative usefulness of conscience in moral education. Conscience is "reflexive judgment about things that matter" (Green, 1999, p. 21). Paul Lehmann (1963) suggested that we must "do the conscience over or do the conscience in" (p. 327). Thomas Green "does the conscience over", arguing that a philosophy of moral education, and not a moral philosophy, provides the only framework from which governance of moral behaviour can be understood. Narratives from four one-to-one interviews and a focus group are analysed and interpreted in search of: (a) awareness and understanding of conscience, (b) voices of conscience, (c) normation, (d) reflexive emotions, and (e) the idea of the sacred. Participants in this study (ages 16-21) demonstrated an active awareness of their conscience and a willingness to engage in a reflective process of their moral behaviour. They understood their conscience to be a process of self-judgment about what is right and wrong, and that its authority comes from within themselves. Narrative accounts from childhood indicated that conscience is there "from the beginning" with evidence of selfcorrecting behaviour. A maturing conscience is accompanied by an increased cognitive capacity, more complicated life experiences, and individualization. Moral motivation was grounded in " a desire to connect with things that are most important." A model for conscience formation is proposed, which visualizes a critical path of reflexive emotions. It is argued that schools, striving to shape good citizens, can promote conscience formation through a "curriculum of moral skills"; a curriculum that embraces complexity, diversity, social criticism, and selfhood.
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