The ancient gene C12orf29 : an exploration of its role in the chordate body plan

The sheep (Ovis aries) is commonly used as a large animal model in skeletal research. Although the sheep genome has been sequenced there are still only a limited number of annotated mRNA sequences in public databases. A complementary DNA (cDNA) library was constructed to provide a generic resource for further exploration of genes that are actively expressed in bone cells in sheep. It was anticipated that the cDNA library would provide molecular tools for further research into the process of fracture repair and bone homeostasis, and add to the existing body of knowledge. One of the hallmarks of cDNA libraries has been the identification of novel genes and in this library the full open reading frame of the gene C12orf29 was cloned and characterised. This gene codes for a protein of unknown function with a molecular weight of 37 kDa. A literature search showed that no previous studies had been conducted into the biological role of C12orf29, except for some bioinformatics studies that suggested a possible link with cancer. Phylogenetic analyses revealed that C12orf29 had an ancient pedigree with a homologous gene found in some bacterial taxa. This implied that the gene was present in the last common eukaryotic ancestor, thought to have existed more than 2 billion years ago. This notion was further supported by the fact that the gene is found in taxa belonging to the two major eukaryotic branches, bikonts and unikonts. In the bikont supergroup a C12orf29-like gene was found in the single celled protist Naegleria gruberi, whereas in the unikont supergroup, encompassing the metazoa, the gene is universal to all chordate and, therefore, vertebrate species. It appears to have been lost to the majority of cnidaria and protostomes taxa; however, C12orf29-like genes have been found in the cnidarian freshwater hydra and the protostome Pacific oyster. The experimental data indicate that C12orf29 has a structural role in skeletal development and tissue homeostasis, whereas in silico analysis of the human C12orf29 promoter region suggests that its expression is potentially under the control of the NOTCH, WNT and TGF- developmental pathways, as well SOX9 and BAPX1; pathways that are all heavily involved in skeletogenesis. Taken together, this investigation provides strong evidence that C12orf29 has a very important role in the chordate body plan, in early skeletal development, cartilage homeostasis, and also a possible link with spina bifida in humans.

Investigating the association between sun exposure and folate degradation in the human body

This thesis is the first study to investigate the associations between sun exposure and folate degradation in a group of childbearing age women in a high UV environment. It examined whether the degree of sun exposure experienced by women influenced blood folate levels following a period of folic acid supplementation and found a strong significant relationship between increased sun exposure and folate degradation. This relationship has strong implications for public health and the thesis has provided a foundation for further research in this area.

Repair and regeneration of osteochondral defects in the articular joints

People suffering from pain due to osteoarthritic or rheumatoidal changes in the joints are still waiting for a better treatment. Although some studies have achieved success in repairing small cartilage defects, there is no widely accepted method for complete repair of osteochondral defects. Also joint replacements have not yet succeeded in replacing of natural cartilage without complications. Therefore, there is room for a new medical approach, which outperforms currently used methods. The aim of this study is to show potential of using a tissue engineering approach for regeneration of osteochondral defects. The critical review of currently used methods for treatment of osteochondral defects is also provided. In this study, two kinds of hybrid scaffolds developed in Hutmacher's group have been analysed. The first biphasic scaffold consists of fibrin and PCL. The fibrin serves as a cartilage phase while the porous PCL scaffold acts as the subchondral phase. The second system comprises of PCL and PCL-TCP. The scaffolds were fabricated via fused deposition modeling which is a rapid prototyping system. Bone marrow-derived mesenchymal cells were isolated from New Zealand White rabbits, cultured in vitro and seeded into the scaffolds. Bone regenerations of the subchondral phases were quantified via micro CT analysis and the results demonstrated the potential of the porous PCL and PCL-TCP scaffolds in promoting bone healing. Fibrin was found to be lacking in this aspect as it degrades rapidly. On the other hand, the porous PCL scaffold degrades slowly hence it provides an effective mechanical support. This study shows that in the field of cartilage repair or replacement, tissue engineering may have big impact in the future. In vivo bone and cartilage engineering via combining a novel composite, biphasic scaffold technology with a MSC has been shown a high potential in the knee defect regeneration in the animal models. However, the clinical application of tissue engineering requires the future research work due to several problems, such as scaffold design, cellular delivery and implantation strategies.

Using a pharmacokinetic model to interpret biomonitoring data of PBDEs in the Australian population

From human biomonitoring data that are increasingly collected in the United States, Australia, and in other countries from large-scale field studies, we obtain snap-shots of concentration levels of various persistent organic pollutants (POPs) within a cross section of the population at different times. Not only can we observe the trends within this population with time, but we can also gain information going beyond the obvious time trends. By combining the biomonitoring data with pharmacokinetic modeling, we can re-construct the time-variant exposure to individual POPs, determine their intrinsic elimination half-lives in the human body, and predict future levels of POPs in the population. Different approaches have been employed to extract information from human biomonitoring data. Pharmacokinetic (PK) models were combined with longitudinal data1, with single2 or multiple3 average concentrations of a cross-sectional data (CSD), or finally with multiple CSD with or without empirical exposure data4. In the latter study, for the first time, the authors based their modeling outputs on two sets of CSD and empirical exposure data, which made it possible that their model outputs were further constrained due to the extensive body of empirical measurements. Here we use a PK model to analyze recent levels of PBDE concentrations measured in the Australian population. In this study, we are able to base our model results on four sets5-7 of CSD; we focus on two PBDE congeners that have been shown3,5,8-9 to differ in intake rates and half-lives with BDE-47 being associated with high intake rates and a short half-life and BDE-153 with lower intake rates and a longer half-life. By fitting the model to PBDE levels measured in different age groups in different years, we determine the level of intake of BDE-47 and BDE-153, as well as the half-lives of these two chemicals in the Australian population.

Gender, sexuality, and rurality in the mining industry

Sexuality is a subject that has been, at best, marginal in the significant body of literature that has examined gender and mining in contemporary Western nations. This is despite the fact that academics have circled, if not almost bumped into the topic in closely related discussions of hegemonic masculinity and mining work, and of patriarchal familial relations and mining communities. This scholarship has documented what has been and remains women’s primary relationship to mining—that is, as a “mining wife.” How patriarchal relations are manifest in and emerge from this state of affairs has been critiqued with research on the gendered implications of housing arrangements in mining towns, the division of household labor, changing shift-work mining rosters, and the gendered consequences of strikes and mine closures (Williams 1981; Gibson 1992; Gibson-Graham 1996; Rhodes 2005; McDonald, Mayes, and Pini 2012). Despite the centrality of the heterosexual relationship—and indeed heteronormativity—to these discussions, scholars of gender and mining have had little to say on the subject of sexuality. In response to this lacuna, this chapter takes an exploratory lens to the subject of sexuality and the mining industry. We approach the task from the perspective that the mining industry is gendered as masculine. That is, definitions of mining mobilize around masculinized notions of physicality, technical competence with machinery, and strength, as well as emphasize the harshness and dirtiness of the work (Mayes and Pini 2010).

Multimodal imaging of the collagen and elastic fibre networks in the bovine intervertebral disc

INTRODUCTION. The intervertebral disc is the largest avascular structure in the human body, withstanding transient loads of up to nine times body weight during rigorous physical activity. The key structural elements of the disc are a gel-like nucleus pulposus surrounded by concentric lamellar rings containing criss-crossed collagen fibres. The disc also contains an elastic fiber network which has been suggested to play a structural role, but to date the relationship between the collagen and elastic fiber networks is unclear. CONCLUSION. The multimodal transmitted and reflected polarized light microscopy technique developed here allows clear differentiation between the collagen and elastic fiber networks of the intervertebral disc. The ability to image unstained specimens avoids concerns with uneven stain penetration or specificity of staining. In bovine tail discs, the elastic fiber network is intimately associated with the collagen network.

Recent insights into microbial triggers of interleukin-10 production in the host and the impact on infectious disease pathogenesis

Since its initial description as a Th2-cytokine antagonistic to interferon-alpha and granulocyte-macrophage colony-stimulating factor, many studies have shown various anti-inflammatory actions of interleukin-10 (IL-10), and its role in infection as a key regulator of innate immunity. Studies have shown that IL-10 induced in response to microorganisms and their products plays a central role in shaping pathogenesis. IL-10 appears to function as both sword and shield in the response to varied groups of microorganisms in its capacity to mediate protective immunity against some organisms but increase susceptibility to other infections. The nature of IL-10 as a pleiotropic modulator of host responses to microorganisms is explained, in part, by its potent and varied effects on different immune effector cells which influence antimicrobial activity. A new understanding of how microorganisms trigger IL-10 responses is emerging, along with recent discoveries of how IL-10 produced during disease might be harnessed for better protective or therapeutic strategies. In this review, we summarize studies from the past 5 years that have reported the induction of IL-10 by different classes of pathogenic microorganisms, including protozoa, nematodes, fungi, viruses and bacteria and discuss the impact of this induction on the persistence and/or clearance of microorganisms in the host.

Bone response to unloaded titanium implants in the fibula, iliac crest, and scapula: an animal study in the Yorkshire pig

The reconstruction of extended maxillary and mandibular defects with prefabricated free flaps is a two stage procedure, that allows immediate function with implant supported dentures. The appropriate delay between prefabrication and reconstruction depends on the interfacial strength of the bone–implant surface. The purpose of this animal study was to evaluate the removal torque of unloaded titanium implants in the fibula, the scapula and the iliac crest. Ninety implants with a sandblasted and acid-etched (SLA) surface were tested after healing periods of 3, 6, and 12 weeks, respectively. Removal torque values (RTV) were collected using a computerized counterclockwise torque driver. The bicortical anchored 8 mm implants in the fibula revealed values of 63.73 Ncm, 91.50 Ncm, and 101.83 Ncm at 3, 6, and 12 weeks, respectively. The monocortical anchorage in the iliac crest showed values of 71.40 Ncm, 63.14 Ncm, and 61.59 Ncm with 12 mm implants at the corresponding times. The monocortical anchorage in the scapula demonstrated mean RTV of 62.28 Ncm, 97.63 Ncm, and 99.7 Ncm with 12 mm implants at 3, 6, and 12 weeks, respectively. The study showed an increase of removal torque with increasing healing time. The interfacial strength for bicortical anchored 8 mm implants in the fibula was comparable to monocortical anchored 12 mm implants in the iliac crest and the scapula at the corresponding times. The resistance to shear seemed to be determined by the type of anchorage (monocortical vs. bicortical) and the length of the implant with greater amount of bone–implant interface.

Engineering an Ecosystem : Taking Cues from Nature’s Paradigm to Build Tissue in the Lab and the Body

This manuscript took a 'top down' approach to understanding survival of inhabitant cells in the ecosystem bone, working from higher to lower length and time scales through the hierarchical ecosystem of bone. Our working hypothesis is that nature “engineered” the skeleton using a 'bottom up' approach,where mechanical properties of cells emerge from their adaptation to their local me-chanical milieu. Cell aggregation and formation of higher order anisotropic struc- ture results in emergent architectures through cell differentiation and extracellular matrix secretion. These emergent properties, including mechanical properties and architecture, result in mechanical adaptation at length scales and longer time scales which are most relevant for the survival of the vertebrate organism [Knothe Tate and von Recum 2009]. We are currently using insights from this approach to har-ness nature’s regeneration potential and to engineer novel mechanoactive materials [Knothe Tate et al. 2007, Knothe Tate et al. 2009]. In addition to potential applications of these exciting insights, these studies may provide important clues to evolution and development of vertebrate animals. For instance, one might ask why mesenchymal stem cells condense at all? There is a putative advantage to self-assembly and cooperation, but this advantage is somewhat outweighed by the need for infrastructural complexity (e.g., circulatory systems comprised of specific differentiated cell types which in turn form conduits and pumps to overcome limitations of mass transport via diffusion, for example; dif-fusion is untenable for multicellular organisms larger than 250 microns in diameter. A better question might be: Why do cells build skeletal tissue? Once cooperatingcells in tissues begin to deplete local sources of food in their aquatic environment, those that have evolved a means to locomote likely have an evolutionary advantage. Once the environment becomes less aquarian and more terrestrial, self-assembled organisms with the ability to move on land might have conferred evolutionary ad-vantages as well. So did the cytoskeleton evolve several length scales, enabling the emergence of skeletal architecture for vertebrate animals? Did the evolutionary advantage of motility over noncompliant terrestrial substrates (walking on land) favor adaptations including emergence of intracellular architecture (changes in the cytoskeleton and upregulation of structural protein manufacture), inter-cellular con- densation, mineralization of tissues, and emergence of higher order architectures?How far does evolutionary Darwinism extend and how can we exploit this knowl- edge to engineer smart materials and architectures on Earth and new, exploratory environments?[Knothe Tate et al. 2008]. We are limited only by our ability to imagine. Ultimately, we aim to understand nature, mimic nature, guide nature and/or exploit nature’s engineering paradigms without engineer-ing ourselves out of existence.

Exploring the role of the governing body (board) in information technology governance : a study of Australian universities

In this thesis, I advance the understanding of information technology (IT) governance research and corporate governance research by considering the question “How do boards govern IT?” The importance of IT to business has increased over the last decade, but there has been little academic research which has focused on boards and their role in the governance of IT (Van Grembergen, De Haes and Guldentops, 2004). Most of the research on information technology governance (ITG) has focused on advancing the understanding and measurement of the components of the ITG model (Buckby, Best & Stewart, 2008; Wilkin & Chenhall, 2010), a model recommended by the IT Governance Institute (2003) as ‘best practice’ for boards to use in governing IT. IT governance is considered to be the responsibility of the board and is said to form an important subset of an organisation’s corporate governance processes (Borth & Bradley, 2008). Boards need to govern IT as a result of the large capital investment in IT resources and high dependency on IT by organisations. Van Grembergen, De Haes and Guldentops (2004) and De Haes & Van Grembergen (2009) indicate that corporate governance matters are not able to be effectively discharged unless IT is being governed properly, and call for further specific research on the role of the board in ITG. Researchers also indicate that the link between corporate governance and IT governance has been neglected (Borth & Bradley, 2008; Musson & Jordan, 2005; Bhattacharjya & Chang, 2008). This thesis will address this gap in the ITG literature by providing the bridge between the ITG and corporate governance literatures. My thesis uses a critical realist epistemology and a mixed method approach to gather insights into my research question. In the first phase of my research I develop a survey instrument to assess whether boards consider the components of the ITG model in governing IT. The results of this first study indicated that directors do not conceptualise their role in governing IT using the elements of the ITG model. Thus, I moved to focus on whether prominent corporate governance theories might elucidate how boards govern IT. In the second phase of the research, I used a qualitative inductive case based study to assess whether agency, stewardship and resource dependence theories explain how boards govern IT in Australian universities. As the first in-depth study of university IT governance processes, my research contributes to the ITG research field by revealing that Australian university board governance of IT is characterized by a combination of agency theory and stewardship theory behaviours and processes. The study also identified strong links between a university’s IT structure and evidence of agency and stewardship theories. This link provides insight into the structures element of the emerging enterprise governance of IT framework (Van Grembergen, De Haes & Guldentops, 2004; De Haes & Van Grembergen, 2009; Van Grembergen & De Haes, 2009b; Ko & Fink, 2010). My research makes an important contribution to governance research by identifying a key link between corporate and ITG literatures and providing insight into board IT governance processes. The research conducted in my thesis should encourage future researchers to continue to explore the links between corporate and IT governance research.