PrP catabolites as determinants of TSE susceptibility

Transmissible spongiform encephalopathies (TSEs) are a group of fatal neurodegenerative diseases that are characterised by long incubation periods, protein aggregation and vacuolation. During TSE pathogenesis the normal, cellular prion protein, (PrPC), which is encoded by the gene PRNP, misfolds and accumulates as abnormal disease associated prion protein, (PrPSc) within the central nervous system. Variants of the Prion protein gene are associated with susceptibility to TSE disease. For example sheep scrapie disease is modulated by several PRNP alleles, with certain alleles carried by susceptible animals being different from those carried by resistant animals. The mechanisms linking PRNP genetics and disease is poorly understood but may involve protein sequence, PrPC expression levels, and possibly differences in protein processing. Post-translational modification of PrPC leads to specific cleavage (alpha cleavage) between amino acids 115/116 of ovine PrP, producing two fragments C1 and N1. Cleavage of PrP may occur as a protective mechanism, as a response to changes in the cellular environment or as a feature of an as yet unknown biological function. In the context of TSEs, alpha cleavage may inadvertently provide a protective role by reducing available PrPC protein for conversion into PrPSc, assuming that the C1 fragment would be an inefficient substrate for conversion, the opposite theory was also proposed. The former hypothesis became the focus of this present study, with the idea that total full-length PrPC, total C1 or the ratio between full-length PrPC and C1 may be linked to differences in scrapie susceptibility. To investigate these aims the C1 fragment was measured as a percentage of total PrPC in different PRNP genotypes with varying degrees of susceptibility to scrapie and in different brain regions. This study found that PrPC alpha cleavage increased during development from the new born lamb to the adult sheep, which may have consequences for the susceptibility differences related to age. There are also variations in the amount of alpha cleavage between brain regions such as cortex and medulla that may influence scrapie strain targeting. Overall the amount of the C1 fragment in the different brain areas varied as much as 10x (range 5% to 60%). There was a significant difference in the ratio of C1 to the other PrPC forms between two PRNP genotype groups carrying the VRQ and ARQ allele but there was no correlation between C1 level and scrapie susceptibility or scrapie incubation period in our scrapie models. Alpha cleavage of PrPC also occurs in various transgenic mouse models expressing different ruminant PrP sequences. In PrPC over-expressing transgenic mouse models a higher ratio of C1 was observed, this may suggest a link between PrPC expression levels and alpha cleavage. Transgenic mice are therefore important models to further investigate the link between PrPC biology and scrapie disease phenotype. In conclusion, this thesis has shown for the first time that certain ovine PRNP alleles can influence alpha cleavage of the PrPC protein; however it appears not to be a significant indicator of TSE disease susceptibility in sheep

An Aboriginal family and community healing program in metropolitan Adelaide: description and evaluation

This paper describes and evaluates the process, impacts and outcomes of an Aboriginal Family and Community Healing (AFCH) Program based in metropolitan Adelaide, South Australia. The evaluation used participatory action oriented methodology, mixed methods and multiple data sources. The AFCH comprised complex and dynamic activities for Aboriginal men, women and youth built around community engagement, and hosted by the regional primary health care Aboriginal outreach service. The AFCH Program was designed to develop effective responses to family violence that took into account the complexities within Aboriginal families and communities. The evaluation identified strengths of the program including: evidence-based design, holistic approach, clinical focus, committed staff, intersectoral linkages, peer support, mentoring, Aboriginal cultural focus, strategic partnerships and creative use of resources. Clients and workers were unanimous in their enthusiastic support for the program; their stories highlight beneficial impacts on Aboriginal clients, families and community. Other services may be able to adapt strategies from this AFCH to address the needs of their Aboriginal communities

PrP catabolites as determinants of TSE susceptibility

Transmissible spongiform encephalopathies (TSEs) are a group of fatal neurodegenerative diseases that are characterised by long incubation periods, protein aggregation and vacuolation. During TSE pathogenesis the normal, cellular prion protein, (PrPC), which is encoded by the gene PRNP, misfolds and accumulates as abnormal disease associated prion protein, (PrPSc) within the central nervous system. Variants of the Prion protein gene are associated with susceptibility to TSE disease. For example sheep scrapie disease is modulated by several PRNP alleles, with certain alleles carried by susceptible animals being different from those carried by resistant animals. The mechanisms linking PRNP genetics and disease is poorly understood but may involve protein sequence, PrPC expression levels, and possibly differences in protein processing. Post-translational modification of PrPC leads to specific cleavage (alpha cleavage) between amino acids 115/116 of ovine PrP, producing two fragments C1 and N1. Cleavage of PrP may occur as a protective mechanism, as a response to changes in the cellular environment or as a feature of an as yet unknown biological function. In the context of TSEs, alpha cleavage may inadvertently provide a protective role by reducing available PrPC protein for conversion into PrPSc, assuming that the C1 fragment would be an inefficient substrate for conversion, the opposite theory was also proposed. The former hypothesis became the focus of this present study, with the idea that total full-length PrPC, total C1 or the ratio between full-length PrPC and C1 may be linked to differences in scrapie susceptibility. To investigate these aims the C1 fragment was measured as a percentage of total PrPC in different PRNP genotypes with varying degrees of susceptibility to scrapie and in different brain regions. This study found that PrPC alpha cleavage increased during development from the new born lamb to the adult sheep, which may have consequences for the susceptibility differences related to age. There are also variations in the amount of alpha cleavage between brain regions such as cortex and medulla that may influence scrapie strain targeting. Overall the amount of the C1 fragment in the different brain areas varied as much as 10x (range 5% to 60%). There was a significant difference in the ratio of C1 to the other PrPC forms between two PRNP genotype groups carrying the VRQ and ARQ allele but there was no correlation between C1 level and scrapie susceptibility or scrapie incubation period in our scrapie models. Alpha cleavage of PrPC also occurs in various transgenic mouse models expressing different ruminant PrP sequences. In PrPC over-expressing transgenic mouse models a higher ratio of C1 was observed, this may suggest a link between PrPC expression levels and alpha cleavage. Transgenic mice are therefore important models to further investigate the link between PrPC biology and scrapie disease phenotype. In conclusion, this thesis has shown for the first time that certain ovine PRNP alleles can influence alpha cleavage of the PrPC protein; however it appears not to be a significant indicator of TSE disease susceptibility in sheep.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The effects of phosphorus pentoxide additions on the thermal, rheological and structural properties of sodium borosilicate glass

This research has characterized the effects of P2O5 additions on the physical, chemical, thermal, rheological properties and the structure of SiO2-B2O3-Na2O glasses relevant to radioactive waste immobilization. Properties analyzed include high-temperature viscosity, glass transition temperature (Tg) and structure. X-ray diffraction (XRD) confirmed a solubility limit of between 3.0 and 4.0 mol% P2O5 for the onset of crystallinity with formation of Na3PO4 and Na4P2O7 in annealed bulk glasses; and between 4.0 and 5.0 mol% P2O5 in unannealed (quenched) glasses. This difference in behaviour is attributed to the bulk glass annealing temperature being greater than Tg of phase-separated, phosphate-rich droplet phases present in the 4.0 mol% P2O5 glass, which promoted crystallization, where back scattered scanning electron microscopy (SEM) images suggested that phase separation had occurred as liquid-liquid phase separation, where there was evidence of a droplet like morphology in glasses containing between 4.0 and 6.0 molar % P2O5. However, the exact mechanism cannot be unequivocally confirmed as nucleation and growth based purely on phase morphology. Differential Thermal Analysis (DTA) and dilatometry showed modest increases in Tg with increasing P2O5 contents below the onset of crystallisation and a more substantial increase coinciding with the onset of crystallisation between 3.0 and 4.0 mol% P2O5. High-temperature viscosity measurements showed that increasing P2O5 contents led to increases in viscosity, with samples containing the highest P2O5 additions displaying non-Newtonian behaviour consistent with the presence of crystals in the melt at 950 °C. Raman difference spectra showed that the increase in P2O5 content resulted in characteristic peak intensities at 729 cm−1, 937 cm−1, 1000 cm−1, 1026 cm−1, 1109 cm−1 and 1445 cm−1 which were associated with phosphate species

Fire! : An Exhibition of 100 Texas Artists

Surls introduces the Fire project and its genesis. Includes statements by most of the 100 exhibiting artists

Analysis of Outcomes in Ischemic vs Nonischemic Cardiomyopathy in Patients With Atrial Fibrillation A Report From the GARFIELD-AF Registry

IMPORTANCE Congestive heart failure (CHF) is commonly associated with nonvalvular atrial fibrillation (AF), and their combination may affect treatment strategies and outcomes