Fine-scale structural variation of the human genome

Inversions, deletions and insertions are important mediators of disease and disease susceptibility. We systematically compared the human genome reference sequence with a second genome (represented by fosmid paired-end sequences) to detect intermediate-sized structural variants >8 kb in length. We identified 297 sites of structural variation: 139 insertions, 102 deletions and 56 inversion breakpoints. Using combined literature, sequence and experimental analyses, we validated 112 of the structural variants, including several that are of biomedical relevance. These data provide a fine-scale structural variation map of the human genome and the requisite sequence precision for subsequent genetic studies of human disease.     

Feminist Systems Theory: Learning by Praxis

Feminist Systems Theory (FST) is an emerging theory grounded in cultural ecofeminism and critical systems theory. FST’s contribution is in a set of principles that contain implications for community development and social research. FST brings to the fore the importance of valuing and considering the voices of people at the margins of social research and community development projects and is an effort towards a new ontology and language of person and nature to adequately address environmental marginalization. The ‘systems’ theory contribution to FST enriches our repertoires of methods and tools with an emphasis on systems thinking characterised by the use of boundary analysis. FST is ideally situated to enhance systemic intervention practice, an application of action research and participatory research practices. This paper will examine ‘process philosophy’ necessary to understand the nature of boundary analysis and the implications for FST and praxis with relevant examples drawn from case studies of current applications of FST in action research settings; (1) economic analysis and transition pathways; (2) policy analysis of the Close the Gap strategy for Indigenous equality and equity in Australia; (3) a community food distribution system; and, (4) a community health and diabetes prevention program.     

Postnatal loss of Dlk1 imprinting in stem cells and niche astrocytes regulates neurogenesis

The gene for the atypical NOTCH ligand delta-like homologue 1 (Dlk1) encodes membrane-bound and secreted isoforms that function in several developmental processes in vitro and in vivo. Dlk1, a member of a cluster of imprinted genes, is expressed from the paternally inherited chromosome. Here we show that mice that are deficient in Dlk1 have defects in postnatal neurogenesis in the subventricular zone: a developmental continuum that results in depletion of mature neurons in the olfactory bulb. We show that DLK1 is secreted by niche astrocytes, whereas its membrane-bound isoform is present in neural stem cells (NSCs) and is required for the inductive effect of secreted DLK1 on self-renewal. Notably, we find that there is a requirement for Dlk1 to be expressed from both maternally and paternally inherited chromosomes. Selective absence of Dlk1 imprinting in both NSCs and niche astrocytes is associated with postnatal acquisition of DNA methylation at the germ-line-derived imprinting control region. The results emphasize molecular relationships between NSCs and the niche astrocyte cells of the microenvironment, identifying a signalling system encoded by a single gene that functions coordinately in both cell types. The modulation of genomic imprinting in a stem-cell environment adds a new level of epigenetic regulation to the establishment and maintenance of the niche, raising wider questions about the adaptability, function and evolution of imprinting in specific developmental contexts.     

Mediators of vascular remodelling co-opted for sequential steps in lung metastasis

Metastasis entails numerous biological functions that collectively enable cancerous cells from a primary site to disseminate and overtake distant organs. Using genetic and pharmacological approaches, we show that the epidermal growth factor receptor ligand epiregulin, the cyclooxygenase COX2, and the matrix metalloproteinases 1 and 2, when expressed in human breast cancer cells, collectively facilitate the assembly of new tumour blood vessels, the release of tumour cells into the circulation, and the breaching of lung capillaries by circulating tumour cells to seed pulmonary metastasis. These findings reveal how aggressive primary tumorigenic functions can be mechanistically coupled to greater lung metastatic potential, and how such biological activities may be therapeutically targeted with specific drug combinations.