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The autonomous behaviour of sex-linked recessive temperature-sensitive lethal mutants in Drosophila melanogaster could be demonstrated by the presence of mosaic patches of tissue hemizygous for the mutant created by loss of a ring X chromosome in cells at the permissive temperature (21.5°C) and the absence of such patches at the restrictive temperature (29°C), The presence of patches at both temperatures indicated that the mutant was non-autonomous. Such non-autonomous behaviour might be attributed to the existence of a substance capable of diffusing from the wild type tissue to supplement the mutant tissue. The experiments carried out showed that the presence or absence of mosaic patches could not be directly interpreted as demonstration of autonomous or non-autonomous properties of the mutant. Other factors such as the time of activity of the ts mutant and the type of tissue undergoing ring X loss affected mosaic tissue production. Therefore, the mere presence of mosaic tissue at 29°C could not be used as a criterion for the non-autonomous behaviour of the ts mutants. However, these mutants can be graded according to the degree of autonomy of ts lethality after alterations due to XO survival frequencies, lethal periods, and temperature-sensitive periods have been placed onmosaic frequencies at 29°C. Of the thirteen ts mutants studied, six can he classed as autonomous lethals. The others are equally autonomous as lethals but only in specific tissues, while others do not appear to be as autonomous. In fact, one of these may be considered non-autonomous. / Science, Faculty of / Zoology, Department of / Graduate

Two types of sex-linked recessive mutations in Drosophila melanogaster have been investigated in the present study. The first type includes 5 different mutations which exhibit a stress-sensitive (ses) phenotype. Flies of all five mutant stocks become paralyzed when their containers are lightly tapped; wild type flies are unaffected by the same treatment. The five mutations form three complementation groups (cistrons). Flies mosaic for mutant and non-mutant tissue were studied to determine the foci of their action in embryos by fate mapping. These studies suggest that the mutation ses D² has 6 foci in the presumptive nervous system of the blastoderm. Each focus corresponds to a site in the thoracic ganglion which controls the movement of one leg. The focus for ses E¹ mutation is rather diffuse and occupies a larger area in the thoracic nervous system of the blastoderm fate map. Focus mapping studies with the ses B¹ mutation were inconclusive because of the highly variable expressions of the adult behavioural phenotype in mosaic individuals. Developmental studies, involving temperature shifts from 22°C to 29°C (permissive to restrictive temperatures) revealed that the ses E¹ mutation has 2 temperature-sensitive periods (TSPs) for lethality during its development, one in the late 2nd larval instar stage and the other in the late pupal stage. In addition to developmental TSPs of ses B² at the embryonic, 1st larval instar and pre-pupal stage, temperature-shift studies also revealed a ts maternal- effect lethal for ses B². The second type of mutation studied has a temperature-sensitive (ts) phenotype of adult death induced by shifting up to the restrictive temperature. The add Atsl flies have normal behaviour and longevity at 22°C but die within 24 hours after shift-up to 29°C. In contrast, the ses E¹ flies are less active and require 168 hours at 29°C to induce death. Both mutations studied have a 3rd larval instar-pupal TSP with add Atsl and ses E¹ also having an additional TSP at the embryonic and 1st larval instar-2nd larval instar stage respectively. Fate mapping studies suggest that the adult lethal phenotype of add Atsl is caused by a lesoon in tissues derived from the mesodermal cells of the blastoderm, and for ses E¹ the lesion is in the neural cells. / Science, Faculty of / Zoology, Department of / Graduate

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No description available.

Ovarian cancer, primarily diagnosed at advanced stages of the disease, is the most lethal of all gynaecological malignancies, with a 5-year survival of only 45%. Increasing age and number of ovulations are the primary non-hereditary risk factors, with the median age of onset being 63 years. Considering that risk peaks upon onset of menopause and that 50% of all cases of ovarian cancer have non-ovarian origins, it is believed that the physiological aging of the ovary renders it an appealing pre-metastatic niche. Mutations in the tumor suppressor genes BRCA1 and BRCA2 are the primary hereditary risk factors, accounting for 20-25% of all cases. We have preliminary data showing that BRCA1 mutation carriers tend to develop ovarian fibrosis, a phenomenon that naturally accompanies ovarian aging, at premenopausal ages, whereas age-associated fibrosis becomes evident after menopause in non-carriers. Consistently, BRCA1/2 mutation carriers are at elevated risk for premature cessation of ovarian function. With the median age of cancer onset decreasing from 63 to 50 years of age in BRCA1 mutation carriers, these data collectively suggest accelerated ovarian aging in these women and highlights an association between ovarian aging and increased risk for cancer. As such, we hypothesized that loss of Brca1 in murine ovarian fibroblasts (MOFs) may accelerate the onset of ovarian fibrosis through fibroblast hyperactivation, contributing to ovarian aging. Using primary MOFs isolated from Brca1 LoxP/LoxP mice and adenoviral cre mediated recombination, we generated Brca1 deficient MOFs. RNA sequencing was used to characterize the transcriptomic changes associated with the loss of Brca1. Our findings suggest that Brca1 deficiency in MOFs induces cellular senescence and enhances their myofibroblastic function, likely yielding increased stiffness of the ovarian extracellular matrix due to the dysregulated synthesis and degradation of its constitutive components, contributing to accelerated ovarian aging.

Biological and environmental factors contribute collectively to the development of human cancers. The primary focus of this research project was to investigate the impact of germline gene mutations, as a significant biological factor, on 29 major primary human cancers. For this I obtained data from multiple databases, including the Genetic Association Database (GAD), Sanger database (COSMIC), HGMD database, OMIM data and PubMed literature. Using the Extraction Transform and Load (ETL) process, 424 genes were obtained with 8,879 cancer mutation records. By integrating these gene mutation records a Human Cancer Map (HCM) was constructed, from which several sub-maps were derived based on particular mutation classes. Furthermore, a Protein-Protein Interaction Map (PPIM) was constructed based on the encoded proteins of the 424 gene set. Several key questions were addressed using the HCM and its sub-maps including the following: (i) Are individual groups of primary cancers associated with specific subset of genes (within the 424 full set)? (ii) Are groups of primary cancers associated with particular mutation classes? (iii) If both questions prove to be true, are groups of cancers associated with particular mutation class of target genes? This project also explored whether a corresponding Protein-Protein Interaction Map, derived from the Missense/Non-sense Mutation portion of the HCM gene set, would provide further information on gene associations between primary cancers in terms of the consequent identical amino acid changes involved. Results showed that: (1) closely-connected human cancers in the HCM exhibited a strong association with a particular mutation class; (2) Missense /Nonsense and Regulatory mutations played a central role in connecting cancers (i.e. via primary nodes) and so significantly influenced the construction of the HCM; (3) Genes with Missense/Nonsense and Regulatory mutations tended to be involved in cancer-associated pathways; (4) Using the kappa test to measure the extent of agreement between two connected primary cancers in the sub-HCMs, BRCA1, BRCA2, PALB2, MSH2, MSH6, MLH1, CDKN2A, and TP53 showed highest agreement for 5 of 10 mutation classes; (5) From the PIPM, it was evident that BRCA1, MSH6, BARD1, TP53, MSH2 and CHEK2 proteins best connected Breast, Ovarian, Prostate and Bowel primary cancers, and so the latter could represent ¿driver proteins¿ for these cancers. In summary, this project has approached the analysis of gene involvement in human primary cancers from the starting position of the mutation class that harbours the specific gene mutation. Together with their downstream resultant alterations in the associated proteins, this analysis can provide insights into the relatedness of primary human cancers and their potential gene hierarchies. These data may therefore help us to understand more fully the etiology, diagnosis and potentially personalized treatments for cancer.

The early gene region, EIA, of Adenovirus is responsible for two mRNAs that appear to be, along with their protein products, necessary for oncogenic transformation. The two proteins differ only in that the larger 289R protein has an extra internal sequence of 46 amino acids. This single difference must account for the functional differences between the two proteins. One function associated with this unique sequence is transactivation, the ability to transcriptionally activate the other early viral genes. In this thesis the construction and analysis of three in-frame deletion mutants are described. These three deletions, along with a fourth previously made, span the entire unique region. All three mutants had lost their transactivation ability, suggesting that the entire domain is necessary for transactivation. Transformation assays with these mutants also suggest that this function blocks transformation. Thus, the unique domain must encode another as yet unidentified function necessary for full transformation. Further evidence for another function in the unique domain comes from the differently reduced abilities of the mutants to grow on HeLa cells. Each mutant has differentially affected some function that is also necessary for lytic infection. / Thesis / Master of Science (MS)

No description available.

Notre projet consiste à saisir et étudier les changements immanents du design leurs effets et leurs enjeux, leurs limites aussi, au tournant du XXIe siècle. Les technologies du numérique, celles des TIC, ont amorcé un phénoménal mouvement de reconfiguration de nos modes de faire, vivre et penser le monde, ainsi que de nous-mêmes. L’humain et les différents types d’organisations de ses activités connaissent de profondes mutations. Les ères de productions se déplacent sous la poussée d’une pensée de la collaboration et de la participation. Il semble que nous soyons entrés dans une ère du design des existences / Our project consists of capturing and studying immanent changes in design, their effects and their stakes, their limits as well, at the turn of the twenty-first century. Digital technologies, those of ICT, have initiated a phenomenal movement of reconfiguration of our ways of doing, living and thinking the world, as well as ourselves. The human and the different types of organizations of its activities are undergoing profound changes. The eras of productions move under the pressure of a thought of collaboration and participation. It seems that we have entered an era of the design of existences