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    Loss of HP1α alters nuclear integrity to promote cellular invasion : a thesis presented in partial fulfilment of the requirements for the degree of Master of Science in Biochemistry at Massey University, Manawatū, New Zealand
    (Massey University, 2019) Solomon, Raoul
    The onset of invasion is a key step towards the development of metastatic cancer. For a cell to invade through interstitial spaces in the tissue requires a reduction in nuclear rigidity as the cell needs to deform to squeeze through small spaces. Heterochromatin Protein 1α (HP1α) is a protein that defines domains of heterochromatin, the highly compact regions of the genome, and is essential for maintaining the appropriate patterns of gene expression and genome stability. Loss or reduction of HP1α has been correlated with an increase in invasive potential in human tumours. Using an established model of Drosophila melanogaster epithelial cell invasion, the causative role HP1α plays in suppressing cellular invasive is confirmed within an epithelial tissue microenvironment. This model also demonstrates that loss of the Drosophila melanogaster HP1 homologue synergistically promotes cellular invasion in conjunction with an activated malignant signalling pathway. Importantly, human HP1α is shown to rescue this highly invasive Drosophila phenotype and demonstrates the relevance of this model to human disease, and its use for exploring protein interactions in a cellular microenvironment. As loss of nuclear integrity has been linked to a reduction in peripheral heterochromatin, the biophysical mechanisms by which HP1α acts as a suppressor of invasive potential were explored in the poorly invasive MCF7 breast cancer cell line with constitutive HP1α knock-down. These cells with reduced HP1α expression had a significant loss of nuclear membrane integrity and stiffness. The underlying nuclear lamina meshwork and associated peripheral heterochromatin was disrupted. This was associated with an increased solubility of lamina proteins, particularly lamin A, as well as the altered localisation of a number of peripheral nuclear proteins. In summary, this work established the important contribution of HP1α to the mechanical integrity of the nucleoskeleton and the role HP1α plays in suppressing malignant signalling pathways that promote cell invasion.
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    The effect of incubation temperature on early malformation, regionalisation and meristic characters of the vertebral column in farmed Chinook salmon (Oncorhynchus tshawytscha) : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Science at Massey University, Manawatū, Palmerston North, New Zealand
    (Massey University, 2018) De Clercq, Adelbert
    Skeletal deformities are a recurrent problem in farmed Chinook salmon which limit production and have animal welfare impacts. Skeletal deformities of a variety of types are recognised especially when the external phenotype of the animal is affected. These types are well described in juvenile and adult stages of the production cycle. Which skeletal malformations affect early life stages in salmonids is less well known. Temperature is commonly manipulated in fish farming husbandry. High rearing temperatures are related to higher growth rates and in Atlantic salmon, elevated temperature has been inferred as a potential risk factor for skeletal deformities. In this thesis, malformations of the vertebral column in post-hatch to first feed life stages (500-900 degreedays) were studied in farmed Chinook salmon (Oncorhynchus tshawytscha) in New Zealand. Fish were reared at a constant 4°C, 8°C and 12°C, from fertilisation to juvenile stages. The effects of rearing fish at these temperatures on malformations of the vertebral column were studied in specimens whole-mount stained for cartilage and mineralised bone, and in histological sections. The external phenotype of post-hatch stages could be linked to internal skeletal malformations such as notochord malformations, chordacentra fusions and malformations of the associated elements. In all temperature groups, externally normal specimens could have internal malformations, predominantly fused chordacentra. Conversely, externally malformed fish usually displayed internal malformations. Specimens raised at 8°C had fewest malformations, followed by specimens of the 12°C group. Specimens raised at 4°C had the highest number of malformations. This study indicates that 8°C is the best incubation temperature of those tested. In addition, the effects of rearing temperature on morphological variation of skeletal elements such as vertebrae, vestigial ribs and vestigial elements in the caudal fin were studied. Six vertebral column regions were identified. The defining characters of each of these regions remained independent of the rearing temperature. Still, the postcranial, transitional and ural regions showed temperature sensitive meristic variation of the vertebrae, vestigial ribs, arches, epurals and uroneurals. Meristic variation can foreshadow skeletal malformations that emerge late in life and thus be significant for the early diagnosis of vertebral deformities.
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    Limb growth and development in the endangered, captive reared, black stilt (Himantopus novaezelandiae) : a thesis presented in partial fulfilment of the requirements for the degree of Master of Science in Conservation Biology at Massey University, Turitea, Palmerston North, New Zealand
    (Massey University, 2006) Wrenn, Bridget Jane
    Captive management is a crucial part of the conservation of one of New Zealand's endemic and critically endangered wading birds, the black still (Himantopus novaezelandiae). Acquired limb deformities have become apparent in captive reared black stilt, highlighting a lack of knowledge of normal limb growth and maturation. Body weight, and tarsus, carpal and remex length were measured on stilts on ad libitum and restricted fed diets. It was found that body weight, and carpal and remex length was significantly slowed by food restriction. Male stilts did not fully compensate in subsequent growth, whereas female stilts compensated in subsequent growth to greater than that of females previously on ad libitum diets. Food restriction also significantly increased the percentage of time stilts spent foraging and interacting with each other. Bone histology was undertaken on the tarsus and first phalanx of the wing. This data, combined with the morphological measurements enabled the identification of the critical growth periods, in which black stilt are most likely to develop limb abnormalities. These periods include: the first three weeks of age for leg abnormalities and between 13-25 days of age for wing abnormalities. The manganese (Mn) concentration in black stilt bone and feathers was also investigated. Key findings were that stilts with acquired limb deformities were not deficient in Mn, and feather Mn did not correlate with bone Mn concentration, and therefore can not be used as a non-invasive technique to monitor Mn bioavailability in the black stilt. The cause of angel wing and slipped tendon in captive reared black stilt was not resolved by the research. A Mn deficiency was eliminated but it is still uncertain whether rapid growth rates may have contributed to the abnormalities. This research has shown that dietary restriction in the early growth phase can be used to limit growth rates of black stilt, although the effects of this restriction on long term growth show sex-dependent differences. Further research into the incidence of limb abnormalities in the black stilt is encouraged, with the aim of contributing to the recovery of the critically endangered, wild population.
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    Flexural limb deformities in thoroughbred foals in New Zealand : a thesis presented in partial fulfilment of the requirements for the degree Master of AgriScience (Equine) at Massey University, Manawatu, New Zealand
    (Massey University, 2014) Shotton, Amanda Kylie
    The aims of this thesis were to describe the descriptive epidemiology of congenital flexural limb deformities (FLD) in foals on commercial Thoroughbred stud farms, and to describe the management and treatment of these foals. Data were collected on five commercial Thoroughbred stud farms in the Auckland and Waikato regions. Data were collected primarily by stud farm personnel, and assisted by study personnel when on farm. Data were collected on a selective population of 203 foals during the 2013/2014 season. Pre-selection by stud farm personnel towards foals with FLD prevented the calculation of prevalence and resulted in 67% (135/203) of the foals with records having one or more FLD recorded. Laxity was observed to affect 87/135 foals, contracture of at least one joint region 57/135 foals and 6/135 foals were back at the knee; nine foals suffered from multiple forms of deformity. The median score for laxity was 2 (IQR 2-3) on a four point scale. The median score for contracture affecting hoof-ground contact was 2 (IQR 2-3) on a three point scale, while the median score for contracture affecting the fetlock and carpal regions was 2 (IQR 2-2). Multiple scorings over time were provided for 69/135 foals, 64 of these foals showed improvement in the severity of deformities by the final scoring. Inter-observer agreement (between study personnel) was strong when scoring flexural laxity (k=0.95), contracture affecting hoof-ground contact (k=1.00) and contracture in the joint regions (k=0.85). In contrast, inter-observer agreement between study personnel and stud farm personnel was lower when scoring flexural laxity (k=0.69) and when scoring contracture in the fetlock and carpal regions (k=0.14). Treatment data were provided for 40/135 foals. Confinement was the most common form of treatment provided for mild and moderate cases of flexural contracture and flexural laxity; severe cases of flexural contracture required more invasive forms of treatment in combination with confinement. Improvement in the severity of deformities was observed following treatment in 28/42 (67%) cases of contracture observed to effect hoof-ground contact, 33/43 (77%) cases of contracture affecting the fetlock and carpal regions and 36/56 (64%) cases of laxity. This thesis provides insight into the effect of FLD on Thoroughbred foals in New Zealand. The results indicate that foals tend to be mildly or moderately affected by FLD at birth and that treatment by stud farms is pragmatic.
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    Caudal cervical vertebral malformation in the Dobermann pinscher : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy at Massey University
    (Massey University, 1999) Burbidge, Hilary Margaret
    The objective of this research was to further the knowledge and understanding of caudal cervical vertebral malformation, a feature of caudal cervical spondylomyelopathy in the Dobermann pinscher. The first study involved surveying 170 Dobermanns to determine the prevalence of caudal cervical vertebral malformation and neurological signs associated with caudal cervical spondylomyelopathy within this sample population. In addition, the relationship between the presence of cervical vertebral malformation, body conformation and neurological findings was investigated. It was found that 48.8% of adult Dobermanns and 28% of puppies had some feature of caudal cervical vertebral malformation. Dogs with radiological signs of caudal cervical vertebral malformation were 5.56 times more likely to have neurological deficits. In both instances the severity of these changes increased with age. Although the radiological signs of caudal cervical vertebral malformation were present throughout a wide age range (3 to 156 months), the associated neurological signs tended to appear at a later age (six years and over). There was no statistically significant association between body conformation and the radiological signs of caudal cervical vertebral malformation. The fact that caudal cervical vertebral malformation was found in young Dobermann puppies led to a morphological study of the post-natal ossification of the canine caudal cervical vertebrae. The caudal cervical spines of 51 puppies (aged from 0 to 12 weeks) were examined grossly, histologically and radiographically. This revealed that at birth, three centres of ossification were present: one in the vertebral body and one in the base of the pedicle of each neural arch. By one month of age, secondary centres of ossification were present in the cranial and caudal epiphyses of the vertebral body, and bony fusion of the laminae had occurred at the dorsal aspect of the neural arches. It was deduced that after one month of age and during normal development, the shape of the neural canal could be influenced only by changes within the physes between the vertebral body and the neural arch, or by remodelling of bone formed by intramembranous ossification. A prospective study investigating the presence of caudal cervical vertebral malformation in 15 Dobermann puppies (from 0 to 16 weeks of age) found that two of these puppies had radiological signs of the condition by six weeks, and another three by between 12 to 16 weeks of age. The diets of these puppies were either balanced or only transiently deficient or excessive in protein, calcium, phosphorus and/or magnesium. There was no significant association between the growth rate of the puppies, in terms of body weight gain or increase in ulna length, and the presence of caudal cervical vertebral malformation. The cervical spines from 27 neonatal Dobermanns (Group D) were examined grossly, radiographically and using computerized tomography for the presence of any caudal cervical vertebral malformation changes. The findings were compared to those of six, similarly examined cervical spines from other large breed canine neonates (Group O). A significant difference was found between the two breed groups with the Dobermann spines having evidence of relative stenosis of the cranial neural canal opening (p = 0.000l)and some features of vertebral body asymmetry (p = 0.04). In addition, the seventh cervical vertebra was found to have the most marked morphological changes when compared to the fifth and sixth. It was concluded that cervical vertebral malformation is a congenital malformation in the Dobermann breed. In addition to the above studies, the growth characteristics of three breeds of dogs, Dobermanns, Labrador retrievers and Heading Dogs were investigated. It was found that each individual breed grew at a different rate to the other (with the largest breed growing faster than smaller) and that males grew faster than females. It was also realized that both measurement of body weight and increase in bone length was required to characterize canine growth, since there was a poor predictive relationship between these two parameters as the puppies aged. It was concluded from the studies that caudal cervical vertebral malformation is a congenital malformation and that growth rate, dietary imbalances and body conformation were not significant factors in its initial development. Possible implications of these findings and recommendations for future research are discussed.