Academisch Proefschrift--Amsterdam. / "Stellingen": 1 leaf laid in. Includes bibliographical references (p. 242-247).

Inaug.-Diss.--Munich. / Vita. Includes bibliographical references.

Inaug.-diss. - Erlangen. / Vita.

Cornelia de Lange Syndrome (CdLS) is a multisystem genetic disorder caused by mutations in the cohesin complex. It is believed that cohesin is able to regulate gene expression with CTCF by holding chromatin in topological complexes, such as active chromatin hubs, and that CdLS is caused by loss of these complexes causing aberrant gene expression. In order to determine if loss of these complexes in CdLS resulted in a general change in the compaction of chromatin, I undertook a series of analyses of the nucleus in CdLS patient lymphoblastoid cell lines (LCLs), compared to wildtype, and later in RNAi knockdown models of CdLS. By fluorescent in situ hybridisation (FISH) I studied the chromatin compaction of different regions of the genome, and found that in some, but not all, CdLS cell lines, gene-rich regions have less compact chromatin compared to wildtype. RNAi knockdown of two proteins that are mutated in CdLS, NIPBL and SMC1, also resulted in decompaction of regions of the genome, however these were different regions than in the patient LCLs, perhaps due to variation between cell lines. This change was not due to the interaction between cohesin and CTCF, as I found that knockdown of CTCF did not result in changes in chromatin compaction. I have also looked at the published data for gene expression in CdLS, and in mouse and Drosophila models of CdLS, and have found no correlation between the genes misexpressed in CdLS in the three species, nor between three cell lines of the same species. These data suggest that the variation in chromatin compaction observed in CdLS may not be due to an interaction between cohesin and CTCF, and that cohesin can act independently of CTCF to regulate gene expression.

No description available.

Thesis (MPhil)--University of Stellenbosch, 2007. / Bibliography. Also available via the Internet.

Zugl.: Kiel, Univ., Diss., 2009

Congenital microcephaly (conMiC) is a manifestation of severely disrupted prenatal brain development, caused by genetic defects, toxins, severe maternal malnutrition, or infection. The Zika virus outbreak and the devastating impact of Zika infection on the fetal brain have focused much attention on the cellular and molecular pathophysiology of conMiC. Mendelian conMiC disorders offer a unique opportunity for understanding gene and protein networks that direct cellular processes essential for prenatal brain development. Using OMIM and literature searches, I analyzed 68 conMiC disorders and their 65 corresponding genes. ConMiC-disorder phenotypes were characterized by analyzing the co-occurrence of ID, retinal abnormalities, seizures, and short stature. Short stature co-occurred with 70% of conMiC disorders, while seizures and retinopathy co-occurred with 68% and 37%, respectively. In 53% of conMiC disorders, seizures and short stature overlapped, while all features overlapped in 22% of conMiC disorders; only 7% of conMiC disorders lacked one of these co-occurring features. This shows conMiC genes are rarely specialized for brain growth, with generalized functions in overall body growth, retinal development, and/or regulation of neural activity. ConMiC-gene transcript accumulation in the brain is typically greatest during the prenatal period, and then declines postnatally, suggesting active transcriptional repression. Nonetheless, in neurons and glia of the adult brain, 44 conMiC genes had confirmed persistent protein accumulation. Experimental evidence indicates transcription in neural progenitor cells (NPCs) for at least 82% of conMiC genes. The spatiotemporal expression patterns of conMiC genes tend to align well with their biological functions and corresponding mutant phenotypes. Nearly 60% of conMiC gene products have functions in the cell cycle and/or DNA repair. Most conMiC disorders are caused by recessive, loss-of-function mutations. There are direct binding and regulatory interactions amongst many conMiC genes, which interact in larger networks and shared pathways. Depletion of single conMiC gene products can affect the transcript and/or protein levels of other conMiC gene products, which could have a “domino effect”, and disrupt entire networks important for brain development. Further evidence for this model is that 22 conMiC genes are consistently dysregulated in Zika-infected developing human brain tissue. Due to the complexity of conMiC genes and their interactions, there are many unique challenges to developing treatments for conMiC, particularly conMiC caused by maternal Zika-virus infection. However, insights to treatment strategies could be gained by using human genetics to find potential modifiers, screening for drugs that can normalize disrupted cell cycle and DNA-repair processes, or can stabilize protein complexes that are disrupted due to a conMiC gene mutation.

No description available.

Thesis (MPhil (Afrikaans and Dutch))—University of Stellenbosch, 2007. / At present there is an extreme shortage in the publication of Afrikaans children’s books. Although revised publications of popular, classic series, such as the Maasdorp-, Trompie- and Saartjie-series can help fill the void in the market, the contribution made by translations of children’s books should not be underestimated: Afrikaans translations of popular children’s books, such as the Harry Potter- and Narnia-series are well-liked and can even encourage young readers to develop an Afrikaans reading culture. Young readers throughout the world get pleasure from the books written by the renowned German author Cornelia Funke. Funke is viewed as an influential author of children’s books and this is largely due to her popular fantasy-adventure Tintenherz; the extremely original plot of this fantasy-adventure, which forms part of a trilogy, persuades young readers to change their unenthusiastic approach towards reading by showing them that reading can be a pleasant, thrilling experience. This study attempts to prove that an Afrikaans translation of Tintenherz can make an important contribution to fill the void in the Afrikaans children’s literature, as well as encourage young readers to read more. Critics fear that translations of popular children’s books might flood the market with books that might be cheaper, but that are second-rate versions of the original texts since the translations fail to achieve the same literary standards as the original texts. This study attempts to prove that knowledge of theoretical translation strategies, such as George Steiner’s hermeneutic motion, Lawrence Venuti’s approaches of foreignisation and domestication, as well as André Levere’s approach of rewrite as a form of translation do in fact make it possible to produce an Afrikaans translation of Tintenherz which not only meets the requirements of the target-culture and satisfies the wants of the target-readers, but also upholds the literary standard of the original German text.